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Progress in Polymer Science xxx (2017) xxxxxx

Contents lists available at ScienceDirect

Progress in Polymer Science


journal homepage: www.elsevier.com/locate/ppolysci

Antimicrobial polymeric nanoparticles


Shu J. Lam a,1 , Edgar H.H. Wong b,1 , Cyrille Boyer b, , Greg G. Qiao a,
a
Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, VIC 3010, Australia
b
Centre for Advanced Macromolecular Design (CAMD) and Australian Centre for NanoMedicine (ACN), School of Chemical Engineering, UNSW Australia,
Sydney, NSW 2052, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Currently, infections caused by multidrug-resistant bacteria have reached critical levels. Thus, various
Received 8 April 2017 approaches are being explored for the development of new and effective antimicrobial agents, one
Received in revised form 26 June 2017 of which lies in the form of polymeric nanoparticles. Driven by the signicant advancements in con-
Accepted 18 July 2017
trolled polymerization techniques over the last few decades, antimicrobial polymeric nanoparticles have
Available online xxx
recently been investigated as potential new antibiotics to combat the rise of infectious diseases. This
review aims at presenting an overview of the history and state-of-the-art of antimicrobial polymeric
Keywords:
nanoparticles including their available structure-activity relationship, and highlights the impact of con-
Polymer nanoparticles
Controlled polymerization
trolled polymerization has on the antimicrobial eld as well as some of the key challenges that still need
Antimicrobial to be overcome for potential clinical applications. Herein, potential new developments are suggested as
Bacteria well.
Biolm 2017 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Polymer nanoparticles as active antimicrobial agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Self-assembled polymer nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1.1. Polymer micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Abbreviations: AgNP, silver nanoparticle; AIE, aggregation-induced emission; ATRP, atom transfer radical polymerization; AuNP, gold nanoparticle; CAC, critical
aggregation concentration; CEVE, 2-chloroethyl vinyl ether; CFU, colony forming units; CLSI, Clinical and Laboratory Standards Institute; CMC, critical micelle concen-
tration; C-PVPS, catechol-conjugated poly(N-vinylpyrrolidone) sulfobetaine; CVC, critical vesiculation concentration; Dh, hydrodynamic diameter; DPn, number-averaged
degree of polymerization; FA, folic acid; HC10, concentration of a compound that cause 10% red blood cell lysis; HC50, concentration of a compound that cause 50% red
blood cell lysis; MBC, minimum bactericical concentration; MDR, multidrug-resistant; MIC, minimum inhibitory concentration; MRI, magnetic resonance imaging; MRSA,
methicillin-resistant S. aureus; MTC-(CH2)3Br, 5-methyl-5-(3-bromopropyl) oxycarbonyl-1,3-dioxan-2-one; MTC-BnCl, 5-methyl-5-(4-(chloromethyl)benzyl) oxycarbonyl-
1,3-dioxan-2-one; MTC-Et, 5-methyl-5-ethyloxycarbonyl-1,3-dioxan-2-one; NCA, N-carboxyanhydride; NIR, near-infrared; NMR, nuclear magnetic resonance; P4VMP,
poly(4-vinyl-N-methylpyridinium iodide); P4VP, poly(4-vinylpyridine); PAA, poly(acrylic acid); PAH, polycyclic aromatic hydrocarbon; PAN, polyacrylonitrile; PBA, poly(butyl
acrylate); PBMA, poly(butyl methacrylate); PCL, poly(-caprolactone); PDEA, poly[2-(diethylamino)ethyl methacrylate]; PDMAEMA, poly[2-(dimethylamino)ethyl methacry-
late]; PDMC, poly(methacryloyloxy ethyl trimethylammonium chloride); PEB, poly(ethylene-co-butylene); PEDOT, poly(3,4-ethylenedioxythiophene); PEG, poly(ethylene
glycol); PEGDMA, poly(ethylene glycol dimethacrylate); PEHA, poly(ethylhexyl acrylate); PEI, poly(ethylene imine); PEO, poly(ethylene oxide); PGA, poly(glutamic acid);
PGSA, polyglucosamine; PHMG, poly(hexamethylene guanidine hydrochloride); PHNA, poly[2-hydroxy-3-(naphthalene-1-ylamino)propyl methacrylate]; PIC, polyion com-
plex; PLA, polylactide; PLL, poly(l-lysine); PMA, poly(maleic anhydride); PMAG, poly[(2-methacrylamide) glucopyranose]; PMEO2MA, poly[2-(2-methoxyethoxy)ethyl
methacrylate]; PMMA, poly(methyl methacrylate); PMTC-(CH2)3Cl, poly(5-methyl-5-(3-chloropropyl) oxycarbonyl-1,3-dioxan-2-one); PNETA, poly(N-ethylaniline); PNI-
PAM, poly(N-isopropylacrylamide); PPEG, poly[poly(ethylene glycol) methyl ether methacrylate; PPhe, polyphenylalanine; PPy, polypyrrole; PQA, poly(quaternary
ammonium); PS, polystyrene; PSA, poly(sulfone amine); PTBAM, poly[(2-tert-butylaminoethyl) methacrylate]; PTEPM, poly[3-(triethoxysilyl)propyl methacrylate]; PTMC,
poly(trimethylene carbonate); PZLL, poly(Z-l-lysine); qPDMAEMA, quaternized poly[2-(dimethylamino)ethyl methacrylate]; RBC, red blood cell; RNA, ribonucleic acid;
ROMP, ring-opening metathesis polymerization; ROP, ring-opening polymerization; ROS, reactive oxygen species; SCPN, single-chain polymeric nanoparticle; SLS, static light
scattering; SNAPP, structurally nanogineered antimicrobial peptide polymer; SPION, superparamagnetic iron oxide nanoparticle; TEM, transmission electron microscopy;
TiO2, titanium(IV) oxide; TPE, tetraphenylethylene; UV, ultraviolet; VBC, vinylbenzyl chloride; VEAH, N-(4-vinylbenzyl)-N,N-diethylamine hydrochloride; VRE, vancomycin-
resistant Enterococci; WHO, World Health Organization.
Corresponding authors.
E-mail addresses: cboyer@unsw.edu.au (C. Boyer), gregghq@unimelb.edu.au (G.G. Qiao).
1
These authors contributed equally to the manuscript.

http://dx.doi.org/10.1016/j.progpolymsci.2017.07.007
0079-6700/ 2017 Elsevier B.V. All rights reserved.

Please cite this article in press as: Lam SJ, et al. Antimicrobial polymeric nanoparticles. Prog Polym Sci (2017),
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2.1.2. Polymer vesicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00


2.2. Star polymer nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3. Inorganic-polymer hybrid nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.1. Silica-polymer core-shell nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.2. Metal/metal oxide-polymer core-shell nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.4. Other core-shell polymer nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Summary and future outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction 2. Polymer nanoparticles as active antimicrobial agents

Recently, the World Health Organization (WHO) revealed that By mimicking the general chemical structure of naturally-
the threat of antibiotic resistance has reached critical levels world- occurring AMPs [52], synthetic polymers could be endowed
wide [1]. Specically, WHO has identied 12 emerging superbugs with intrinsic antimicrobial activity by incorporating cationic and
that are resistant to many antibiotics as priority targets to combat, hydrophobic moieties into the polymer chains [27,53]. The overall
grouping them into three categories: critical, high, and medium. For cationic charge of the polymer enables interaction with bacterial
instance, carbapenem-resistant Acinetobacter baumannii and Pseu- cell walls that are typically negatively charged, while the hydropho-
domonas aeruginosa were listed as critical, methicillin-resistant bic counterparts facilitate microbial membrane penetration [27]. It
Staphylococcus aureus (MRSA) can be found in the high category, should be noted, however, that antimicrobial polymers with dif-
whereas ampicillin-resistant Haemophilus inuenza was classied fering chemical structures (e.g., quaternary ammonium-containing
as medium [2]. Coupled with the lack of new product discovery polymers without any hydrophobic components [54,55]) have
due to the near-complete screening of available natural resources, also been reported. The possible enhancement of antimicro-
the world is facing the risk of reverting back to the medical dark bial activity through nanoparticle formation was inspired by
ages (i.e., the pre-antibiotic era). Many world governments thus multivalent interactions found ubiquitously throughout biol-
recognize the urgent need for new solutions to combat this global ogy, where the simultaneous binding of multiple ligands from
healthcare issue. Driven by the signicant advancements in con- one entity to multiple receptors on another could lead to
trolled polymerization techniques [314], that have enabled the stronger effects than corresponding monovalent systems [56].
production of nanomaterials with tailorable biological properties This hypothesis was substantiated by studies reported by Yang
for a wide range of biomedical applications [1523], synthetic poly- and co-workers in 2009 and 2010, where core-shell micellar
mers potentially represent a promising approach to curb the rise of nanoparticles based on the self-assembly of an amphiphilic pep-
antibiotic resistance. In fact, there are various examples in literature tide (prepared by solid phase peptide synthesis) showed superior
that describe the synthesis of linear polymers with antimicrobial efcacy against a range of Gram-positive bacteria and fungal
properties [2435], mostly by mimicking the chemical structure species (Fig. 1) [57,58]. Improved antimicrobial properties in the
of antimicrobial peptides (AMPs), while others include the con- assembled state were attributed to increased and more local-
jugation of synthetic polymers with conventional antibiotics (to ized density of cationic charges and peptide mass, resulting in
improve pharmacokinetics for instance) [3638]. stronger electrostatic interactions with anionic microbial mem-
However, there has been growing interest recently in the devel- branes.
opment of antimicrobial polymeric nanoparticles. This is because Here, synthetic polymer-based nanoparticles (mainly made
the formulation of polymers into nanoparticles (e.g., micelles, vesi- from controlled polymerization techniques) displaying direct
cles, star polymers, and inorganic-polymer hybrids) of various antimicrobial activity will be reviewed. These polymer nanopar-
shapes and sizes has been shown to yield many advantages over ticles are categorized based on their complex macromolecular
linear polymers in other targeted applications such as drug/gene architecture, and the effects of these polymer architectures on the
delivery [3942]. For instance, a main advantage is the multivalency antimicrobial performance and biocompatibility of such nanopar-
of polymeric nanoparticles, where the presentation of a clus- ticles will be discussed.
ter of (multiple) functional groups from a nanoparticle construct
enables higher cell recognition and binding capabilities compared
to linear polymers [43,44]. In addition, polymer nanoparticles like
micelles, vesicles or star polymers allow for the efcient encap- 2.1. Self-assembled polymer nanoparticles
sulation of cargo molecules that can be released at targeted sites
[4548]. Furthermore, the fabrication of inorganic-polymer hybrid Self-assembly has been recognized as one of the most com-
nanoparticles provides new avenues for synergistic therapy (e.g., monly used routes for the construction of nanostructured materials
photodynamic therapy) and/or diagnostic purposes (e.g., biosens- from small building blocks [59]. Inspired by nature, the forma-
ing) [4951]. tion of highly complex molecular and supramolecular structures
In this review, we present an overview of the history and recent in the most thermodynamically stable form, such as micelles and
advances of polymeric nanoparticles that have been applied in the vesicles, is made possible by multiple weak and non-covalent inter-
antimicrobial eld where some of these nanoparticles have been actions between the chemical building blocks [5961]. In the eld
demonstrated to be effective against the pathogens specied above of therapeutics, self-assembly has been increasingly used for the
by WHO. Specically, the review focuses on the development of synthesis of nano-sized biomaterials due to the relative ease, pre-
polymeric nanoparticles that demonstrate inherent antimicrobial cision and versatility of the method, enabling the incorporation of
properties (i.e., the nanoparticle acts as the active antimicrobial functions such as stimuli-responsiveness, recognition and target-
agent) and highlights any structural-activity relationship that will ing [62]. More specically, micelles and vesicles formed through
aid our understanding on the rational design of polymer-based the self-assembly of polymer building blocks have been explored
antimicrobial agents. for possible use as novel antimicrobial agents.

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Fig. 1. The simulated formation of micelles from an amphiphilic peptide obtained from the conjugation of cholesterol, glycine, arginine, and the TAT (YGRKKRRQRRR) peptide
[57]. Copyright 2009. Reproduced with permission from the Nature Group.

2.1.1. Polymer micelles as polymers with low CMCs were less antibacterial than those with
Polymer micelles, core-shell nanoparticles typically formed higher CMCs. The authors postulated that the polymer chains might
through the self-assembly of amphiphilic block copolymers [63], be more active as free molecules in solution and hence the forma-
are regarded as one of the most extensively studied nanostructure tion of supramolecular structures could reduce the polymer chain
type for antimicrobial applications. This is possibly contributed by mobility. Through static light scattering (SLS) and nuclear magnetic
the fact that such nanostructures have been the focus of numerous resonance (NMR) analysis as well as membrane interaction studies,
studies in drug delivery for the past three decades [63]. Inter- the authors concluded that aggregation processes were not a major
estingly, with respect to polymer micelles that are inherently determinant for antibacterial efcacy for the polyoxazoline system
antimicrobial, the role of micellization on antimicrobial activity has investigated [66].
been frequently debated. The following discussion will be divided A similar observation was made by Kiss et al., where a study
into two categories, where studies that dismissed the positive con- was conducted to investigate the structure-activity relationship of
tributory role of micellization on antimicrobial activity will be cationic polyelectrolytes, in the form of branched poly(ethylene
rstly presented [6472], followed by reports that suggested the imines) (PEIs) functionalized with various quaternary ammo-
importance of self-assembly in promoting efcacy [7384]. nium compounds and alkyl groups, with bacteria [67]. Through
Waschinki et al. prepared a series of poly(2-alkyl-1,3- in vitro antibacterial susceptibility tests and model membrane
oxazolines) through living cationic polymerization, where the experiments, the authors observed a trend between antibacte-
types of polymer backbone, starting end-groups (also known as rial behavior and polymer hydrophobicity, where the activity and
satellite groups) and terminal biocidal functional groups were var- membrane binding ability of the modied PEIs decreased with
ied [64]. As polyoxazolines have been known to be low-fouling and increasing hydrophobicity. This observation was attributed to a
bacteria-repelling [85,86], bactericidal properties were imparted stronger tendency for micellization for the PEIs that were more
through the introduction of bactericidal end-groups. The minimum hydrophobic, where the hydrophobic components required for
inhibitory concentrations (MICs) of the functionalized polyoxazo- microbial membrane interactions were shielded within the core,
lines ranged from 0.2 to 4.7 mg/mL (equivalent to 0.080.94 mM) therefore hampering binding between the polymer and membrane
against Staphylococcus aureus. While the polymers were capable lipid layers.
of self-assembly, the authors did not observe any distinct trend In other polymeric systems such as polyvinyl ethers [68], poly-
between the critical micelle concentrations (CMCs) of the polymers methacrylates [69], polycarbonates [70], and polyacrylates [71,72]
and their MICs. Instead, the experimental results suggested that where the synthesized polymers were able to self-assemble into
the chemical structure of the polymers, including the nature of the micelles, the notion of self-assembly as a prerequisite for antimicro-
backbone and the type of satellite groups, seemed to be of greater bial activity was also dismissed. Kuroda and co-workers developed
inuence towards antimicrobial activity. In a follow-up study by a library of amphiphilic block and random vinyl ether copolymers
the same research group, the role played by the satellite groups using base-assisting living cationic polymerization, where all syn-
in determining the antimicrobial performance of poly(2-alkyl-1,3- thesized copolymers displayed bactericidal activity against E. coli
oxazolines) against Escherichia coli and S. aureus was validated, and hemolytic behaviors at lower concentrations than their criti-
where polymer self-assembly into micelles was again demon- cal aggregation concentrations (CACs) [68]. The authors observed
strated to be redundant for antibacterial activity [65]. In fact, the that the copolymer structure and conformation as individual poly-
results suggested that micellization was detrimental to biological mer chains were more crucial than macromolecular assembly in
activity against both Gram-positive and Gram-negative bacteria, determining biological activity. By performing molecular dynamics

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Fig. 2. Single-chain folding of various amphiphilic ternary random copolymers in aqueous media to form antimicrobial SCPNs [88]. Copyright 2017. Reproduced with
permission from the American Chemical Society.

simulations to investigate the interactions of several random and copolymers that combat various Gram-negative bacteria including
amphiphilic methacrylate-based copolymers with model bacterial E. coli, Pseudomonas aeruginosa and Vibrio cholerae, killing 99.99%
membranes, the same research group postulated that while the for- of both planktonic and biolm bacteria within an hour of treatment
mation of micelle-like structures in solution phase could promote [88]. Interestingly, these terpolymers, comprising poly(ethylene
faster binding with bacterial membranes, the polymer aggregates glycol) (PEG), hydrophobic, and primary amine groups, undergo
would dissociate into single polymer chains upon contact with bac- self-folding in aqueous media to form single-chain polymeric
terial membranes, due to more favorable polymer-membrane lipid nanoparticles (SCPNs) [88] (also known as unimolecular micelles)
interactions compared to the weaker intermolecular bonds within via intramolecular hydrophobic interactions (Fig. 2), as evidenced
the micelles [69]. by dynamic light scattering and atomic force microscopy experi-
In a polycarbonate-based system reported by Engler et al., a ments. Although the link between micellization and antimicrobial
library of homopolymers and statistical copolymers with pendant activity was not determined due to the difculty in obtaining the
quaternary ammonium groups separated from the backbone by a CMCs of the SCPNs, the study provided experimental evidence
hydrophobic spacer was developed [70]. While the self-assembling regarding the inuence of polymer hydrophobicity on cell mem-
ability of all polymers was demonstrated, their MICs against a range brane wall disruption and rate of resistance acquisition in bacteria.
of Gram-positive and Gram-negative bacteria were lower than their In addition, the study also revealed the importance of incorporating
CMCs, suggesting that bacterial growth inhibition was effected by low-fouling components such as PEG into the design of antimicro-
the polymers as individual chains. Additionally, the authors con- bial polymers to prevent complexation with proteins in biological
cluded that the balancing of charge and hydrophobicity was more medium and therefore maintain the antimicrobial efcacy of a
important in optimizing antibacterial activity. material.
With the ultimate goal of fabricating dual-functionalized To the best of our knowledge, the contributory role of
polymers with antibacterial and antioxidative properties to com- polymer micelle formation on antimicrobial activity was
bat bacterial biolms, self-assembled micelles that consisted of rst suggested by Lenoir et al. through self-assembled
cationic and amphiphilic random polyacrylates bearing tertiary micelles formed by poly(ethylene-co-butylene)-b-poly[2-
amine (N,N-diethylethylenediamine) and hydrophobic catecholic (dimethylamino)ethylmethacrylate] (PEB-b-PDMAEMA) block
(hydroxytyrosol) side chains were prepared [71,72]. Besides being copolymers that were quaternized with octyl bromide [73]. The
a well-known antioxidant, the activity of hydroxytyrosol against polymers synthesized were found to have a bimodal size distribu-
certain Gram-positive species has been reported [87]. The combi- tion with two populations bearing hydrodynamic diameters (Dh )
nation of both tertiary amine and hydroxytyrosol moieties at an of 25 and 85 nm present, where the larger of the two populations
optimal ratio resulted in antibacterials that were effective against was speculated to be micellar aggregates. Efcient activity against
Staphylococcus epidermis and possessed low hemolytic activities E. coli that resulted in a 4-log (99.99%) reduction in cell counts
[71]. However, a comparison of their MICs and CMCs revealed that within 30 min at a polymer concentration of 100 g/mL was
the copolymers acted against bacteria as single chains and not inter- demonstrated. The antibacterial properties of the block copoly-
molecular aggregates [72]. It was further elucidated by molecular mers were attributed to micellization, although the relationship
dynamics simulations that the antibacterial copolymers displayed between polymer CMCs and effective antibacterial concentrations
single chain folding behavior, postulated to promote exposure of was not shown.
the cationic groups and facilitate electrostatic interactions with the In 2011, a notable study was published by Yang and co-workers,
anionic bacterial cell membranes. where the rst biodegradable antimicrobial polymer micelles were
Recently, Wong, Boyer and co-workers reported the devel- reported (Fig. 3) [74]. The micelles were self-assembled from
opment of new antimicrobial amphiphilic ternary random amphiphilic triblock polycarbonates synthesized via metal-free

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Fig. 3. General strategy for the controlled synthesis of cationic amphiphilic polycarbonates via metal-free organocatalyzed ROP [74]. Copyright 2011. Reproduced with
permission from the Nature Group.

organocatalyzed ring-opening polymerization (ROP) that resulted rmed through imaging experiments, from which the random
in a central poly(5-methyl-5-(3-chloropropyl) oxycarbonyl-1,3- copolymers were validated to be more efcient at membrane dis-
dioxan-2-one) (PMTC-(CH2 )3 Cl) block sandwiched between two ruption than block copolymers. Growth inhibitory effects (MICs
poly(trimethylene carbonate) (PTMC) blocks. The PMTC-(CH2 )3 Cl within 63250 g/mL) were displayed by some of the polycar-
block was subsequently quaternized with trimethylamine to ren- bonates against both Gram-positive (S. aureus) and Gram-negative
der it cationic for electrostatic interactions with bacterial cell species (E. coli and Pseudomonas aeruginosa), and self-assembly
membranes. Depending on the length of the PMTC and PTMC was again demonstrated as necessary for activity. Interestingly, by
blocks, micelle-like nanoparticles ranging from 43 to 402 nm varying the molecular weights of the copolymers, it was shown
in diameter were fabricated. The nanoparticles exhibited MICs that a lower overall molecular weight facilitated better activity
between 4.3 and 10.8 M against a range of Gram-positive bacte- against S. aureus, while higher molecular weight polymers were
ria, including Bacillus subtilis, Enterococcus faecalis, S. aureus, MRSA, more effective against the Gram-negative species. This distinction
and Cryptococcus neoformans, a fungal species. It is noteworthy was attributed to the morphological differences of Gram-positive
that the MICs of the best-performing nanoparticles were all above and Gram-negative bacterial cell membranes, where the former
their CMCs, indicating an obvious link between micellization and possesses a thick outermost peptidoglycan layer known to entrap
antimicrobial efcacy. The nanoparticles were conrmed to be higher molecular weight polymers [91]. In terms of nanoparti-
bactericidal as their minimum bactericidal concentrations (MBCs) cle biocompatibility, the polymers displayed minimal hemolytic
corresponded to the MICs. By imaging the bacterial cell morphology effects over a wide range of concentrations, where the selectivity
post-treatment using transmission electron microscopy (TEM), the (determined using the ratio of polymer concentration that caused
nanoparticles were shown to effect their antimicrobial action by 50% red blood cell (RBC) lysis, HC50 , to MIC, i.e. HC50 /MIC) of the
cell wall and membrane disruption as well as cell lysis. In addition polymers with the highest antibacterial activities was greater than
to the low hemolytic behaviors of the polycarbonate micelles, the 16 towards both Gram-negative and Gram-positive species.
authors demonstrated that the nanoparticles did not induce signif- As their previous study indicated the importance of polymer-
icant toxicity to mice. Despite the signicant achievements of this membrane integration in enhancing antimicrobial activity [75],
study, the inability of the nanoparticles to combat Gram-negative Yang, Hedrick and co-workers investigated the effect of incor-
bacteria was recognized as a drawback. Gram-negative bacteria porating cholesterol in polycarbonate oligomers [76]. Besides
have been recently viewed as a more critical healthcare issue than its well-known membrane assimilation characteristic, cholesterol
Gram-positive bacteria, primarily due to a shortage in effective also possesses the propensity for rotative face-on-face stack-
and biocompatible drugs targeting resistant Gram-negative bac- ing [92] that would promote self-assembly when conjugated to
teria [89,90]. a polymer or oligomer. Using different cholesteryl initiators, a
In order to endow polycarbonate-based micelles with the capa- 4-(chloromethyl)benzyl-functionalized carbonate monomer, MTC-
bility to kill both Gram-positive and Gram-negative bacteria, Yang BnCl, was polymerized to varying number-averaged degree of
and co-workers devised a series of micelles based on random polymerization (DPn ) and further subjected to quaternization
copolymers of MTC-(CH2 )3 Cl and 5-methyl-5-ethyloxycarbonyl- by either trimethylamine or trimethyl phosphine. The resulting
1,3-dioxan-2-one (MTC-Et) monomers (Fig. 4) [75]. Similar to their polymers were found to self-assemble in water into 1011 nm
previous study [74], quaternization using trimethylamine was per- coin-shaped micelles (Fig. 5). Compared to analogous polycarbon-
formed on the resulting copolymers. The authors hypothesized that ates without any cholesteryl groups, the cholesterol-functionalized
a random copolymer design would result in micelles with more polymers displayed enhanced activities against S. aureus, E. coli
accessible hydrophobic moieties compared to a block copolymer and P. aeruginosa while the hemolytic effects remained simi-
structure (such as that used in their previous study [74]) where lar to before. Oligomers with DPn above 10 generally had lower
the hydrophobic parts are shielded in the core, therefore increas- MICs resulting in higher selectivities (HC50 /MIC). Depending on
ing the likelihood of membrane insertion and disruption induced the hydrophobic-hydrophilic balance, MICs ranging from 3.9 to
by the hydrophobic components. This hypothesis was later con- 250 g/mL were attained by the optimized oligomers against S. epi-

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Fig. 4. Synthetic scheme of random copolymers of MTC-(CH2 )3 Cl and MTC-Et [75]. Copyright 2012. Reproduced with permission from Elsevier Ltd.

Fig. 5. Illustration of the self-assembly of cholesteryl cationic polycarbonate oligomers in aqueous media [76]. Copyright 2014. Reproduced with permission from John Wiley
& Sons Inc.

dermis, S. aureus, E. coli, P. aeruginosa, and Candida albicans (i.e., a radical polymerization (ATRP). The hydrophobic PCL block was
fungal species). Notably, a model oligomer with a selectivity of 13 incorporated to drive self-assembly and impart biodegradability,
against E. coli did not induce any observable resistance in E. coli even whereas PEO was thought to provide better biocompatibility
after 19 passages, and was further shown to be effective against and colloidal stability. In contrast to most studies that relied on
drug-resistant E. coli. However, it should be noted that several quaternization for antimicrobial activity, the micelles reported
oligomers in this study were found to be antimicrobial as individual in this study are inherently antibacterial and membrane-active
chains (rather than as self-assembled structures), as they registered because the PTBAM block contained secondary amine that is
MICs that were less than their CMCs. cationic under physiological conditions. The use of PTBAM could
Following the earlier reports on polycarbonate-based potentially circumvent the signicant hemolytic effects of qua-
micelles by Yang and co-workers [74,75], increasing interest ternary ammonium-based antimicrobials [93]. The most potent
has been generated in the development of antimicrobial, self- polymer had the highest PTBAM content, with MICs of 0.19 mM
assembled micelles using other polymer systems. For example, and 0.06 mM against E. coli and S. aureus, respectively. Further, the
antibacterial and biodegradable poly(ethylene oxide)-b-poly(- MICs of the best-performing polymer were found to be at least 10
caprolactone)-b-poly[(2-tert-butylaminoethyl) methacrylate] times greater than its CMC (5.5 M), that agreed with previous
(PEO-b-PCL-b-PTBAM) micelles were reported by Yuan et al. in studies by Yang and co-workers that demonstrated self-assembly
2012 (Fig. 6) [77]. A two-step synthetic process was adopted to as a prerequisite for antimicrobial efcacy.
prepare the triblock copolymers, where the PEO-b-PCL diblock Biodegradable core-shell nanoparticles that were self-
copolymer was rst synthesized by ROP and then chain-extended assembled from PEG-functionalized amphiphilic polypeptides
through the polymerization of TBAM monomer via atom transfer were reported by Costanza et al. [78]. ROP of -amino acid N-

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Fig. 6. Illustration of the self-assembly of PEO-b-PCL-b-PTBAM copolymer into micelles in aqueous media, postulated to interact with bacterial membranes through
electrostatic interactions [77]. Copyright 2012. Reproduced with permission from the Royal Society of Chemistry.

Fig. 7. Synthetic strategy for the PEG-poly(amino acid) copolymers [78]. Copyright 2014. Reproduced with permission from the Royal Society of Chemistry.

carboxyanhydrides (NCA-ROP) initiated by PEG-NH2 was used to hand, the amphiphilic nanoparticles with 5060% hydrophobic
synthesize poly(Z-l-lysine) (PZLL) as the second block and a sta- content exhibited broad-spectrum efcacy against multidrug-
tistical copolymer of PZLL and polyphenylalanine (PZLL-stat-PPhe) resistant (MDR) S. epidermis, B. subtilis, Klebsiella pneumonia,
as the third block (Fig. 7). Following the removal of carboxyben- and MDR P. aeruginosa, with MICs that ranged from 5 to 92 M
zyl groups, 50200 nm micelles with a hydrophobic core and a depending on polymer and bacteria types. The high hemolytic
PEG-containing hydrophilic shell were formed via self-assembly in activities (i.e., HC50 56 M) of these nanoparticles, however,
water. In general, the nanoparticles were more active against the rendered them non-selective towards bacteria. The results from
Gram-positive strains, where activity was attributed to membrane this study highlighted the importance of balancing polymer
disruption as demonstrated through uorescence and scanning hydrophilicity and hydrophobicity to modulate antimicrobial
electron microscopy (SEM). Nanoparticle biocompatibility was efcacy and biocompatibility.
evaluated in terms of HC50 values. The most biocompatible Du and co-workers recently reported the preparation of antibac-
nanoparticles were those that were purely hydrophilic (no PPhe) terial micelles from a polylactide (PLA)-b-polypeptide diblock
with HC50 values that were greater than 50 M; however they copolymer made via tandem ROP and NCA-ROP reactions [94]. The
were only effective against the Gram-positive species. On the other polypeptide segment composed of statistically distributed pheny-

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Fig. 8. (A) Dissipative particle dynamics (DPD) simulations of the cross-sectional view of PPEG/PQA mixed micelles quaternized with 1-bromobutane (PPEG/PQA4c), 1-
bromooctane (PPEG/PQA8c) and 1-bromododecane (PPEG/PQA12c). (B) Schematic illustrations of the mixed micelles [79]. Copyright 2015. Reproduced with permission from
the Royal Society of Chemistry.

lalanine and lysine units along the backbone, and formed the polymer-bacteria activity as compared to PQAs alone, the authors
hydrophilic shell of the micelles in water. Although TEM analysis successfully showed that this shielding effect was able to reduce
of challenged E. coli and S. aureus samples revealed the micelles the toxicity of PQAs towards mammalian cells. As such, the treat-
effected their antimicrobial action through membrane disruption, ment of mice broblast L929 cells by PPEG/PQA mixed micelles at
the MIC values of the micelles were in the range of 300600 g/mL. 100 g/mL for 72 h resulted in only a marginal loss in cell viability
The CMC of the micelle was ca. 13 g/mL. In addition, cytotox- (<10%). This was in stark contrast to cases where PQA homopoly-
icity studies of the polypeptide-based micelles against liver L02 mers were administered, in which more than 60% loss in cell
cells showed the micelles were cytotoxic even at a polymer con- viability was observed.
centration of 100 g/mL, where only ca. 20% of cell viability was Chitosan and its derivatives are often used to confer antimi-
observed. Taken together, this rendered the micelles non-selective crobial efcacy and biocompatibility to synthetic polymers [26].
towards bacteria. This study further highlights the necessity for However, the poor solubility of chitosan in conditions other than a
tuning the bactericidal properties and mammalian cell biocompat- low pH environment limits its applicability in biomedical applica-
ibility in antimicrobial polymers. tions [96,97]. In a study conducted by Lin et al., chitosan was grafted
An interesting approach to modulate antimicrobial activ- with poly(methacryloyloxy ethyl trimethylammonium chloride)
ity and biocompatibility was employed by Wan et al., where (PDMC) with DPn ranging from 50 to 400 via single electron trans-
mixed micelles were fabricated from the cross-assembly of fer living radical polymerization (SET-LRP) in an ionic liquid system
poly(quaternary ammoniums) (PQAs) in the form of quaternized [80]. The PDMC-functionalized chitosan displayed self-assembly
PDMAEMA (qPDMAEMA) and poly[poly(ethylene glycol) methyl behavior into monodispersed spherical micelles (120200 nm in
ether methacrylate] (PPEG) (Fig. 8) [79]. Despite being a well- diameter) in acetone. The PDMC-grafted chitosan was able to
known antibacterial agent, PQAs, similar to many polycations, have inhibit the growth of E. coli by reducing its rate and extent of growth
limited therapeutic utility due to their high toxicity towards mam- more effectively compared to unmodied chitosan, although quan-
malian cells [95]. Hence, the addition of PPEG that is non-ionic titative growth inhibition was not attainable within the timeframe
was expected to improve the biocompatibility of the polymer con- of the experiments (24 h). The authors postulated that an increase
struct, ideally without compromising the potency of the PQAs in positive charge density was achieved through the addition of
against bacterial cells. As expected, the PQA homopolymers exhib- quaternary ammonium groups found on PDMC, possibly resulting
ited efcacy against S. aureus (MIC 1.2540 g/mL) and E. coli in improved adsorption of the material on bacterial cell surfaces.
(MIC 10160 g/mL). Following the addition of PPEG to form However, the role of self-assembly, if any, in inuencing the bio-
PPEG/PQA mixed micelles, the resulting MICs were affected to logical activity of chitosan was not clearly elucidated in this study.
different extents depending on the alkyl chain lengths of the Harnessing the potential of macromolecular assemblies to
PQAs. A greater reduction in activity against E. coli (up to 8 fold) incorporate multiple functionalities, Li et al. successfully fabricated
occurred when the PQAs in the mixed micelles had shorter alkyl novel polyion complex (PIC) micelles capable of both (uorometric)
chains. The authors demonstrated that the PPEG chains shielded the detection and inhibition of bacteria, formed through the inter-
cationic charges of the PQAs, thereby reducing polymer-membrane actions between negatively-charged tetraphenylethylene (TPE)
interactions. Despite this, mixed micelles composed of PPEG and sulfonate derivatives and neutral-cationic PEO-b-qPDMAEMA
PQAs quaternized by 1-bromooctane displayed MICs of 39.1 and copolymers (Fig. 9) [81]. The cationic moieties were expected
19.5 g/mL against E. coli and S. aureus, respectively. While the to be shielded within the micellar cores by the anionic sul-
shielding of cationic PQAs by the PPEG chains led to reduced fonic acid functionalities in an aqueous environment. When

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Fig. 9. Synthesis of polyion complex (PIC) micelles from TPE sulfonate derivatives (BSTPE or TSTPE) and PEO-b-qPDMAEMA block copolymers [81]. Copyright 2014. Reproduced
with permission from Elsevier Ltd.

placed in a bacteria-containing medium, the authors postulated


that more favorable ionic interactions between bacterial sur-
faces and qPDMAEMA would lead to micellar disassembly. In fact,
the nanostructure disassembly upon bacteria contact resulted in
the bacteria sensing capability of these micelles, characterized
by a decrease in TPE uorescence intensity due to the loss of
aggregation-induced emission (AIE) following the release of free
TPE upon micelle disintegration. In addition to their ability to detect
E. coli, the PIC micelles were found to be bactericidal through mem-
brane disruption, with the most potent variant registering an MIC
of 19.7 g/mL against E. coli. However, a similar level of efcacy was Fig. 10. The formation of spherical and rod-like assemblies from terephthalamide-
polylactidepolycarbonate triblock copolymers, and their antimicrobial properties
not shown against S. aureus. When tested for its hemolytic activ- [83]. Copyright 2012. Reproduced with permission from the American Chemical
ity, the micelle with the best antimicrobial activity demonstrated Society.
negligible (<2%) hemolysis at a high concentration of 400 g/mL.
Another example of multifunctional micelles was demonstrated
wherein the self-assembled nanoparticle displayed antimicrobial
by Luo and co-workers in the form of poly(caprolactone)-
activity as well as drug loading capability [98]. The polymers were
poly(quaternary ammonium) (PCL-PQA)-based micelles that pos-
made via a combination of click chemistry and organocatalyzed
sessed antibacterial and drug loading properties [82]. This study
ROP. When tested against S. aureus and E. coli, the micelles have
was aimed at exploring the possibility of exploiting the synergis-
MBC values ranging from 31 to 490 M (based on the concentration
tic effects of inherently antimicrobial polymers and conventional
of phosphonium groups) depending on the alkyl chain length of the
antimicrobial agents to produce hybrid materials with enhanced
phosphonium group. In addition, the micelles demonstrated low
antimicrobial properties. Linear, 3- and 6-arm star copolymers of
hemolytic activity (<10% at 530 M), suggesting good mammalian
PCL and PDMAEMA quaternized with methyl chloroacetate were
cell biocompatibility and selectivity. The authors also showed that a
shown to self-assemble into spherical micelles with PDMAEMA
small molecule hydrophobic antibiotic, tetracycline, can be encap-
forming the corona and PCL located within the core. All micelles
sulated (ca. 42% encapsulation efciency) and released using the
formed, either from linear or star copolymers, were able to encap-
micelles. However, antibacterial assays with E. coli revealed no
sulate an antimicrobial drug, triclosan, in the core and demonstrate
observable synergistic effects of the phosphonium micelles and
two-phase drug release proles characterized by an initial burst
tetracycline.
release followed by a slower and more sustained release pro-
While most studies focused on the fabrication of spherical
cess. At a polymer concentration of 0.1 mg/mL, all blank micelles
micelles, the potential of rod-shaped micelles as effective antimi-
(containing no drug) exhibited bactericidal activities to varying
crobials was demonstrated by Fukushima et al. [83,84] In 2012,
extents, with the micelles formed from the 6-arm star copoly-
an interesting study was published to elucidate the shape effects
mer displaying the highest potency (i.e., a 4-fold reduction in
of a self-assembled polycarbonate-based system by comparing the
E. coli colony-forming units, CFU). After the loading of triclosan
biological activities of spherical and rod-like micelles with simi-
into the core, enhanced activity against E. coli was observed, with
lar size and charge density (Fig. 10) [83]. The nanostructures were
near-quantitative (99%) killing reported for the 3- and 6-arm star
constructed from triblock copolymers synthesized via organocat-
copolymer-based micelles. Using a standard broth microdilution
alyzed ROP and initiated by a terephthalamide-bisurea bifunctional
assay to monitor bacterial growth inhibition, only the 6-arm star
initiator that forms a rigid, assembly-directing core. The inner
copolymer micelles that were loaded with triclosan were able to
block consisted of PLA whereas the hydrophilic outer block was
cause quantitative growth inhibition, while the inhibitory activi-
composed of quaternized poly[2-(3-bromopropyl)oxycarbonyl-
ties of the other micelle types were insufcient to prevent bacterial
2-methyl trimethylenecarbonate] that conferred the resulting
re-growth within the incubation period. In general, the authors
nanostructures with antimicrobial activity. Direct self-assembly
concluded that star-shaped copolymer micelles were more effec-
in aqueous media was shown, where spherical or rod-shaped
tive than micelles formed from the linear copolymers, that was
nanostructures were obtained depending on the chemical struc-
likely due to a higher charge density provided by the star copoly-
ture of the core. The addition of a methylene spacer in the core
mers.
resulted in rod-shaped supramolecular structures (ca. 10 nm in
In another example, Gillies and co-workers fabricated antimi-
diameter and aspect ratios 10), instead of the typical spherical
crobial micelles from PEO-b-PCL diblock copolymers with
assemblies (ca. 20.4 nm in diameter) that were obtained when the
alkylated-phosphonium cations at the terminus of the PEO block,
spacer was absent. It was noted that the role of lactide stere-

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ochemistry on nanostructure size and shape was minimal. The hydrophobic core and a hydrophilic shell, the complex morphology
assemblies, regardless of shape and lactide stereochemistry, were of polymer vesicles allows for more enhanced compartmentaliza-
non-hemolytic even at high concentrations of 15 mg/mL. Both tion and increased versatility in functionalization [106], proven to
spherical and rod-shaped nanostructures exhibited broad spec- be useful in applications such as drug delivery [107109]. For exam-
trum efcacy against bacteria such as S. aureus, MRSA, VRE, E. ple, polymer vesicles are capable of encapsulating both hydrophilic
coli, and fungal species C. neoformans. The MICs ranged from 20 to and hydrophobic compounds within their cavities and membranes,
150 g/mL and 20100 g/mL for the spherical and rod-like assem- respectively [100]. In the area of antimicrobial research, several
blies, respectively, with poly(L-lactide) inner blocks. Interestingly, investigations have been performed on polymer vesicles to explore
while the spherical nanoparticles were inactive against C. albi- their potential as antimicrobials, although vesicles are not as exten-
cans (MIC > 500 g/mL), the poly(L-lactide)-based rods were able to sively studied as polymer micelles. More importantly, researchers
cause quantitative fungal growth inhibition at 75 g/mL. Through have attempted to utilize the compartmentalization offered by
TEM and confocal microscopy imaging, the nanostructures were polymersomes, coupled with the judicious selection of polymer
shown to kill bacteria and fungus through membrane disruption. building blocks, to develop multifunctional antimicrobial nanos-
As fungal species such as C. albicans are more difcult to kill due to tructures.
their multi-layered, thicker and less negatively charged cell walls, The solvent-switch method is conventionally used to prepare
the results reported in this study are signicant and represents polymer vesicles, where the copolymers are rst solubilized in
advancement in the development of antifungal drugs. However, an organic solvent that is then gradually replaced with water
it should be noted that although the MICs recorded against most to induce vesicle formation [110]. This strategy was adopted by
species were greater than the polymer CMCs, antimicrobial action Du and co-workers to prepare well-dened and water-dispersible
against certain microbial species (such as C. neoformans) occurred poly(methyl methacrylate)-b-PTBAM (PMMA-b-PTBAM) vesicles
at polymer concentrations below the CMCs. [111]. The merging of PMMA, one of the most widely used poly-
Encouraged by the antifungal efcacy of rod-shaped polymer meric materials, and the antimicrobial PTBAM in a single construct
assemblies in the earlier study [83], Fukushima et al. devel- was intended to impart antibacterial properties to the biologically
oped a novel class of cationic, amphipathic and low-molecular inert PMMA, that may further expand the applicability of PMMA
weight compounds, capable of forming antifungal high-aspect in the biomedical eld. The vesicles were approximately 250 nm
ratio supramolecular assemblies with a low propensity for resis- in diameter with a membrane thickness of 16 nm. Efcacy against
tance development [84]. Despite the fact that the assemblies were both E. coli and S. aureus was demonstrated with MICs of 0.505 and
not constructed from polymers, the self-assembled nanostructures 0.252 mM, respectively, where a higher activity was shown against
manifested polymer-like properties such as a glass transition tem- the Gram-positive species.
perature (Tg ) and the formation of ber-like morphologies in water. Recognizing the limitations of the solvent-switch method
The antifungal agents were based on terepthalmide-bisurea com- due to the use of organic solvents, Du and co-workers devised
pounds bearing different spacer groups between the urea and an organic solvent-free approach for the fabrication of water-
cationic charge, and the formation of nanorods was induced and soluble and antibacterial polymer vesicles [112,113]. Amphiphilic
stabilized by hydrophobic interactions and amideamide hydrogen block copolymers of poly[2-(2-methoxyethoxy)ethyl methacry-
bonding. Depending on the type of spacer incorporated, nanobers late] (PMEO2 MA) and PTBAM were synthesized via ATRP and
of varying rigidity and sizes were fabricated. In this study, the MICs self-assembled into ca. 240 nm vesicles in low-pH aqueous buffer
of all compounds against C. albicans and C. neoformans were found by heating to 37 C (Fig. 11) [112]. Using the spread plate method
to be greater than their CMCs, indicating that the antifungal agents where the bacterial solution was incubated for 2 h with vesicle solu-
were active as supramolecular assemblies. The authors further pos- tion that was spread on a glass sheet, near-quantitative (close to
tulated that the formation of these high-aspect ratio assemblies 3-log or 99.9%) reductions in E. coli and S. aureus cell counts were
allowed for more efcient fungal cell wall and membrane insertion, observed at a polymer concentration of 0.25 mg/mL. In contrast,
subsequently validated through electron microscopy in the form of the bulk copolymer (in the non-assembled state) was only able to
observable membrane damage and cell lysis following treatment. reduce the bacterial cell counts by half at the same concentration.
Rigid nanobers assembled from terepthalmide bisurea with ben- It was hypothesized that vesicle formation led to an increased local
zyl amine spacer groups demonstrated the highest efcacy against concentration of positive charges, resulting in stronger polymer-
C. albicans and C. neoformans, with an MIC of 31.2 g/mL against bacteria afnity compared to unassembled polymer chains. In
both species. Further, the nanorods were shown to be effective a subsequent study conducted by the same group, 3040 nm
against C. neoformans resistant to uconazole, a common antifungal polymer vesicles based on triblock copolymers, PEO-b-poly[(2-
drug. Notably, a representative nanorod variant displayed in vitro diethylamino)ethyl methacrylate] (PDEA)-b- PTBAM, prepared via
and in vivo efcacy against C. albicans biolm, suggesting the poten- pH switching from acidic to neutral was reported [113]. Self-
tial of these nanostructures in combating fungal infections such as assembly by adjusting the pH of the medium was possible due to
those associated with medical implants and fungal keratitis. This the pH-responsive nature of PDEA, where the polymer becomes
was supported by the general lack of signicant hemolytic effects hydrophobic in neutral or basic environments. The best-performing
and mammalian cell toxicity within the therapeutic concentration polymersome in terms of antibacterial ability was determined to be
range, as well as in vivo biocompatibility demonstrated through a the variant with the highest PTBAM content (i.e., PEO43 -b-PDEA20 -
mice cornea model. b- PTBAM 30 ), suggesting that a higher positive charge density on
the polymer would promote more efcient interactions with bacte-
2.1.2. Polymer vesicles rial cell membranes. Interestingly, the PEO43 -b-PDEA20 -b- PTBAM
Polymer vesicles, also known as polymersomes, are spherical 30 -based polymersome was more effective against E. coli (MIC
polymeric capsules with an inner hollow compartment conned 0.15 mM) than S. aureus (MIC 0.6 mM), contrasting the trend shown
by a bilayered membrane that is composed of amphiphilic block in their previously reported PTBAM-based polymer vesicle system
copolymers [99104]. Acting as simple mimics of biological cells, [111].
polymer vesicles provide three compartmentalized regions avail- One of the earliest studies on polymer vesicles with com-
able for functionalization, namely the inner hydrophilic cavity, bined antibacterial and drug delivery capabilities was reported
the polymer shell, and the periphery in contact with the environ- by Zhu et al. in 2013 [114]. An interesting class of antibacterial
ment [105]. Compared to typical micelles that possess an inner vesicles in the form of high-genus, perforated vesicles was devel-

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Fig. 11. The formation of antibacterial vesicles from block copolymers of PMEO2 MA and PTBAM, and their postulated antibacterial mechanism [112]. Copyright 2013.
Reproduced with permission from the Royal Society of Chemistry.

oped from PMEO2 MA-b-PTBAM copolymers synthesized via ATRP. The authors were unable to compare the efcacy of the nanocap-
A two-stage assembly process aided by the phase transition of sules with the non-assembled form as the critical concentration for
the thermo-responsive PMEO2 MA block was employed, where an nanocapsule formation was less than their MIC. Hence, compar-
initial solvent-switching step yielded branched cylinders that tran- isons could only be made with the individual polypeptide chains
sited to a high-genus vesicular morphology following heating to before grafting to chitosan as well as nanocapsules where the
37 C. The resulting vesicles had an average overall diameter of ca. chitosan was not esteried. The formation of these vesicle-like
400 nm with ca. 20 nm pores on the surface. With MICs of 0.7 and assemblies resulted in a 2-fold improvement in efcacy against
0.35 mM against E. coli and S. aureus, respectively, and quantitative E. coli and S. aureus (MIC 16 g/mL) compared to linear polypep-
bacterial cell killing at 0.25 mg/mL, the high-genus vesicles exhib- tides PLL-stat-PPhe, that are the effective antibacterial component
ited improved efcacy compared to the bulk copolymer and simple of the nanocapsules. Besides the charge localization effects brought
vesicles based on the same polymer system. This was attributed to about by self-assembly, antibacterial activity was also promoted by
the more complex hierarchical structure of the high-genus vesicles the esterication of carboxylic acid groups on the chitosan back-
synthesized in this study. When tested against mammalian cells, bone, as this reduced the overall negative charge of the construct.
the vesicles demonstrated low toxicity (dened as >80% cell viabil- Interestingly, compared to linear PLL-stat-PPhe, the nanocapsules
ity) against human HCCLM3 liver cancer cells and L02 liver cells showed higher hemo-compatibility (HC50 700 g/mL; HC50 /MIC
up to 0.5 mg/mL, as well as excellent blood compatibility (HC50 44) and cyto-compatibility with human HCCLM3 liver cancer cells
4.7 mg/mL). However, it should be noted that a direct comparison (i.e., 70% cell viability after 72 h incubation at 100 g/mL). Addition-
of the antibacterial and mammalian cell studies to yield selectiv- ally, the encapsulation and subsequent enzyme-triggered release
ity indices was not possible as the effective concentrations were of both anticancer and antiepileptic drugs were demonstrated for
reported in different units. Further, the high-genus vesicles were these vesicle-like nanostructures.
able to encapsulate doxorubicin (a hydrophobic anticancer drug) In a follow-up study by Wang et al., a fully biodegradable,
and manifest an acid-accelerated drug release prole that could peptide-based vesicle platform was developed with added cancer-
be useful for targeted drug delivery to tumor sites. As such, the targeting ligands, a lower critical vesiculation concentration (CVC),
authors postulated that these complex nanoparticles have poten- and demonstrated stability in animal serum [116]. Statistical
tial to be used in applications where simultaneous antibacterial and polypeptide copolymers, PZLL-stat-PPhe, and the hydrophobic PCL
anticancer therapies are required. were synthesized by NCA-ROP and organocatalyzed ROP, respec-
In line with the ultimate goal of developing drug-carrying tively. The polypeptides and PCL were then conjugated, followed by
antibacterial nanostructures, Zhou et al. reported the synthesis of the deprotection of PZLL and post-functionalization with cancer-
polypeptide- and chitosan-based nanocapsules, where statistical targeting folic acid moieties. Using the solvent-switch method,
copolymers of poly(l-lysine) (PLL) and PPhe from NCA-ROP were vesicles with a Dh of 301 nm and a CVC of ca. 13 ug/mL were
statistically grafted onto an acid-functionalized chitosan back- obtained where PLL-stat-PPhe and PCL constituted the corona
bone (Fig. 12) [115]. Subsequently, half of the chitosan carboxyl and membrane, respectively. Compared to the free PLL-stat-PPhe
groups were esteried, whereas the remaining acid groups were copolymer chains that registered an MIC of 32 g/mL against E. coli
left unmodied for drug conjugation. The self-assembled nanos- and S. aureus, the vesicles were more active with an MIC of 16 g/mL
tructures were hypothesized to possess a hydrophilic corona and a against both bacterial species. This enhancement in activity was
complex membrane composed of both hydrophobic and entrapped attributed to vesiculation and possible synergistic interactions
hydrophilic moieties due to hydrogen bonding and steric effects. between PCL and the polypeptides. However, the reader should be

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Fig. 12. Schematic illustration of the self-assembly of polypeptide-grafted chitosan-based nanocapsules, and its ability for drug release upon enzymatic (protease) degradation
[115]. Copyright 2013. Reproduced with permission from the American Chemical Society.

made aware that the denition of MIC adopted in this study was nanostructures with a branched architecture consisting of several
based on a more than 50% inhibition in bacterial growth relative linear chains linked to a central core, thereby forming 3D glob-
to the untreated control, that is different from the more widely ular structures [118]. Such nanoparticles have gained scientic
used convention where MIC is taken as the concentration where interest due to their unique structural properties. It is possible to
quantitative growth inhibition (characterized by the absence of synthesize high molecular weight star-shaped polymer nanoparti-
visible growth) occurs [74]. In terms of the toxicity of these vesi- cles while still retaining a solubility and viscosity similar to that of
cles towards normal liver cells L02, only marginal (<20%) decrease low molecular weight linear or branched polymers [119]. Other
in cell metabolic activity was observed after 72 h when treated attractive features of star polymers include their encapsulation
with a wide range of vesicle concentrations (62250 g/mL), sug- capabilities [118,120122], and a vast range of internal, peripheral
gesting that these nanostructures have relatively low toxicity. A and compartmentalized functionalities [118]. The reader is referred
preliminary antitumor activity study was also conducted, where to a comprehensive review published by Qiao and co-workers on
the vesicles were loaded with doxorubicin and shown to be capable the synthesis, characterization, properties and applications of star
of killing liver cancer cells through the released doxorubicin. polymers [44].
In addition to the potential applications of antibacterial poly- Recently, the applicability of star polymers in the eld of
mer vesicles in the eld of nanomedicine, Geng et al. demonstrated nanomedicine has been suggested and reviewed by Li and
their possible use in water remediation, where effective bacterial co-workers [46], with applications in targeted drug delivery
growth inhibition and the eradication of carcinogenic organic pol- [123127], gene therapy [128131], bioimaging [126,132,133], and
lutants, such as polycyclic aromatic hydrocarbons (PAHs), are often tissue engineering [134] being explored by numerous research
required in parallel [117]. Vesicles were constructed from a statisti- groups. However, in comparison to the other biomedical applica-
cal copolymer, poly[2-hydroxy-3-(naphthalene-1-ylamino)propyl tions, the design and development of star polymer nanoparticles
methacrylate] (PHNA)-stat-PTBAM, synthesized using reverse with inherent antimicrobial properties has not been studied exten-
addition-fragmentation chain-transfer (RAFT) polymerization. The sively. The research efforts thus far will be highlighted in this
PTBAM component imparted antibacterial properties to the vesi- section.
cles, while PHNA is capable of sequestering PAHs through - Early studies in this area were aimed at covalently linking bac-
stacking. The vesicles were able to reduce bacterial growth by half tericidal compounds such as antibiotics and AMPs to a polymeric
at ca. 26.2 and 15.5 M against E. coli and S. aureus, respectively. scaffold, resulting in antibacterial nanostructures with a star-like
In a simulated polluted water environment containing pyrene (as a architecture. Arimoto et al. synthesized a multivalent polymer of
PAH mimic) and E. coli, complete eradication of bacteria and pyrene the antibiotic vancomycin via ruthenium-catalyzed ring-opening
was observed after vesicle treatment. metathesis polymerization (ROMP) by conjugating vancomycin
to a metathesis-active norbornene unit [135]. This was done in
2.2. Star polymer nanoparticles an attempt to enhance the potency of vancomycin in response
to the rise of vancomycin-resistant Enterococci (VRE). While the
Despite the versatility of self-assembly and the potential shown branched polymer was found to have broad molecular weight dis-
by self-assembled polymer nanoparticles in the antimicrobial eld, tributions, an 860-fold enhancement in potency against VREs was
the reversible and dynamic nature of self-assembly renders the observed compared to unmodied vancomycin. Taking inspiration
fabricated nanostructures prone to disassembly, providing the from antimicrobial dendrimeric peptides, comprising a multiva-
possibility that they are not sufciently robust for practical appli- lent core with an array of branching peptides tethered to it [136],
cations [59]. In contrast to self-assembled polymer nanoparticles, Kallenbach and co-workers fabricated multivalent AMPs using non-
star polymer nanoparticles are covalently-bonded unimolecular antimicrobial poly(maleic anhydride) (PMA) chains as a scaffold

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Fig. 13. Schematic illustration of the structure of TPEcore P(qDMAEMA-co-BMA-co-Gd)arm star polymers [141]. Copyright 2014. Reproduced with permission from John Wiley
& Sons Inc.

to link antimicrobial tetrapeptides (either RRWW-NH2 or RWRW- By taking advantage of hierarchical functionalities spanning
NH2 ) into a branched-like nanostructure [137]. The tethered AMPs from the periphery along the arms and to the core afforded by the
demonstrated a 10-fold improvement in MIC50 (i.e., one-half of star architecture, recent studies on star polymer nanoparticles in
the MIC) against E. coli and B. subtilis, hypothesized to be due the antimicrobial eld tend to focus on the development of multi-
to the increase in local density and synergy of the linked pep- functional polymer platform technologies by imparting diagnostic
tides. However, the tethering of these AMPs to the PMA scaffold [141], antiviral [142], or targeting [143,144] functionalities on top
did not improve the selectivity of the peptides, as the aforemen- of the inherent antibacterial properties of the star nanoparticles.
tioned improvement in growth inhibitory activity after tethering A bacterial detection and inhibition system based on four-arm star
was accompanied by an increase in hemolytic activity. While fur- polymers with a tetraphenylethylene (TPE) core and PDMAEMA-co-
ther investigations and optimizations are warranted for these early poly(butyl methacrylate)-co-Gd, P(DMAEMA-co-BMA-co-Gd) arms
studies, they formed the groundwork for subsequent work by was developed by Li et al. through a combination of ATRP
demonstrating that antimicrobial efcacy could be enhanced with a and post-modication reactions (Fig. 13) [141]. Bacterial inhibi-
multivalent display of microbicidal components achieved through tion capabilities were provided by the cationic and amphiphilic
a star-like architecture. star arms, while the T1 -type magnetic resonance imaging (MRI)
Extending from this concept, Liu et al. synthesized star- contrast agent, DOTA-Gd, enabled bacterial detection via uo-
shaped molecular brushes composed of qPDMAEMA via ATRP rescence and MRI. In terms of antimicrobial performance, the
using cyclotriphosphazene initiators [138]. The effect of side star polymer with the most abundant hydrophobic (BMA) moi-
chain hydrophobicity was evaluated by using quaternizing agents eties, TPE-star-P(DMAEMA0.79 -co-BMA0.15 -co-Gd0.06 )4 , was found
with different alkyl lengths. Increased activity against E. coli was to be the most effective against E. coli, P. aeruginosa and S. aureus
observed with longer hydrophobic alkyl side chains. Comb-shaped with higher efcacy observed against the Gram-negative species
qPDMAEMA brushes were also synthesized but were found to be over the Gram-positive species tested (i.e., MICs of 5.5 g/mL
inferior in antibacterial efcacy compared to the star polymers. and 0.12 g/mL against E. coli and P. aeruginosa compared to an
It was postulated that while a more condensed positive charge MIC of 30 g/mL against S. aureus). As visualized through SEM,
density could lead to better antibacterial activity, an overly dense treatment of E. coli with the star polymer resulted in outer and
grafted brush structure such as in the case of the comb-shaped poly- inner membrane deformation. However, it is noteworthy that the
mers could make the active polymeric components less accessible most antimicrobial star polymer was found to possess the highest
by bacterial cells. The best-performing star polymer had a moderate hemolytic activity with a HC10 value (i.e., the polymer concentra-
MIC of 250 g/mL against E. coli; however, a comparison of the bio- tion required to cause 10% hemolysis) of 0.01 g/mL, therefore
efcacy with linear qPDMAEMA and mammalian cell compatibility rendering the polymer non-selective towards bacterial cells. In
studies were not conducted. order to mitigate the lack of biocompatibility, quaternization of
Using a similar core-rst approach, star-shaped polymers with PDMAEMA on the star arms was performed and resulted in signif-
polystyrene-b-poly(4-vinyl-N-methylpyridinium iodide) (PS-b- icantly lowered haemolytic activity by more than 70,000-fold for
P4VMP) arms were prepared by anionic polymerization as reported the star polymer with the highest antimicrobial efcacy, although a
by Tiller and co-workers [139]. Poly(4-vinyl-N-alkylpyridinium)- slight reduction in inhibitory activity (MIC 11 g/mL against E. coli)
based polymers, that contain quaternary ammonium groups, have was observed.
attracted great interest as antimicrobial materials because of their With the aim of developing nanoparticles that are both antibac-
superior antibacterial efcacy against both Gram-positive and terial and antiviral, Xiao and co-workers fabricated 5 and 8-arm star
Gram-negative bacteria [140]. While the primary goal of the study polymers by randomly polymerizing poly(hexamethylene guani-
was to develop semi-permanent antimicrobial coatings, the star dine hydrochloride) (PHMG) macromonomers and acrylamide via
polymers were found to be active against Staphylococcus aureus ATRP initated by -cyclodextrin [142]. Polymeric guanidines such
in solution, with MICs ranging from 78 to 156 g/mL. Contrary to as PHMG are well-known membrane-disrupting antimicrobials
the earlier studies on potency enhancement through multivalent that are effective against a range of Gram-positive and Gram-
nanostructures, the MICs of the star polymers were found to be negative bacteria, fungi, and yeasts [145]. The 8-arm star variant
similar to that of linear P4VMP, suggesting that the star architec- with an acrylamide:PHMG molar ratio of 20:3 exhibited the high-
ture and the additional PS block had no effect on the antimicrobial est efcacy against E. coli (MIC 0.78 g/mL). When compared to
properties of the nal construct. the PHMG homopolymer that has a lower activity against E. coli
(MIC 7.8 g/mL), the authors postulated that the star architecture

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Fig. 14. Chemical structure of cationic and mannose (man)-functionalized star-shaped polycarbonates [143]. Copyright 2016. Reproduced with permission from John Wiley
& Sons Inc.

was responsible for enhancing the antimicrobial performance of cellular Mycobacterium bovis BCG (a Gram-positive bacterium) in
PHMG. However, while PHMG was identied as the antibacterial human monocytic THP-1 cells via the targeting of mannose recep-
component, the role of acrylamide in the star polymer system tors present on the THP-1 cell surface. However, the cytotoxicity
was not elucidated. The authors further demonstrated that the of the star polymer towards THP-1 cells at concentrations above
best-performing star polymer exhibited antiviral activities against 0.2 M (that fall within the MIC range of the polymers against
non-enveloped adenovirus, while remaining non-toxic towards certain bacteria) could hinder its clinical use.
human embryonic kidney cells (HEK 293) at or below 50 g/mL. In order to modulate the antimicrobial activity and mam-
While earlier studies have shown that proper design of star poly- malian cell compatibility of star polymers, Wong et al. constructed
mer nanoparticles could facilitate excellent antimicrobial activity, a series of 1426 nm, glucosamine-functionalized star polymers
the toxic, off-target side-effects of some of these nanoparticles, such with 1219 arms using an arm-rst approach (Fig. 15) [144]. PLL
as towards healthy mammalian cells or probiotic bacteria, are a and polyglucosamine (PGSA)-based arms were synthesized and
major concern. In their efforts to achieve targeted antimicrobial then converged to a central cross-linked core using a combina-
therapy, several research groups have focused on the attachment tion of NCA-ROP, click chemistry and RAFT polymerization. PLL was
of targeting ligands such as sugar-based moieties on antibacterial designed to be the antimicrobial component, while the glycopoly-
star polymers [143,144]. Using a multifunctional -cyclodextrin- mer was introduced to reduce mammalian cell toxicity and improve
based macroinitiator, Yang and co-workers reported the synthesis the inltration of the star polymers through the peptidoglycan layer
of star-shaped polycarbonates by metal-free organocatalytic of bacterial cells. Despite moderate star conversions (6065%) and
ROP of MTC-BnCl and mannose-functionalized cyclic carbonate the absence of hydrophobic groups, the miktoarm star polymers
monomers (Fig. 14) [143]. The star arms were synthesized as either exhibited preferential activity against Gram-positive bacteria over
block or random copolymers, were further subjected to the removal the Gram-negative species, and were effective against a range of
of mannose protecting groups, and quaternization of the chloro Gram-positive bacteria including MRSA and VRE. Notably, the PLL-
groups with various N,N-dimethylalkylamines. It was envisioned PGSA star with 25% GSA content (S-GSA 25) was found to be the
that the mannose functional groups would facilitate the target- most potent, with MICs ranging from 16 to 64 g/mL against S.
ing of mannose receptors expressed on the surface of macrophages aureus, MRSA, E. faecalis, and VRE. All star polymers synthesized
(i.e., a type of immune cells), leading to the internalization of the were non-hemolytic even at a high concentration of 10 mg/mL,
polymers and subsequent killing of the intracellular pathogenic likely to be attributed to the lack of hydrophobic groups. While
bacteria. The mannose-functionalized star polymers were shown most polycations such as PLL are known for their high toxicity
to be membrane-lytic and capable of eradicating both Gram- towards eukaryotic cells [146], the incorporation of PGSA mitigated
positive (S. aureus) and Gram-negative (E. coli and P. aeruginosa) the toxicity of the PLL-PGSA stars against human aortic smooth
bacterial species as unimolecular nanostructures, although pref- muscle cells, resulting in high cell viability (>80%) for all GSA-
erential activity was shown towards the Gram-positive species containing stars at 100 g/mL. The authors further demonstrated
(MIC 0.092.78 M). While mannose functionalization reduced the that the excellent biocompatibility of the stars was afforded by the
activity of the star polymers against the Gram-negative species, star architecture, as a blend of linear PLL and PGSA homopolymers
potency against S. aureus was still retained. A linear analogue could not provide the same biocompatibility as observed for the
was also synthesized but its antibacterial efcacy was found to heteroarm PLL-PGSA stars. It was hypothesized that when locked
be inferior to the corresponding star polymer. By systematically in a star-shaped nanoparticle form, PLL arms were shielded by the
varying the compositions of the star polycarbonates, it was demon- PGSA-based chains, thereby reducing the likelihood of non-specic
strated that increasing the arm length (by increasing the DPn of interactions between PLL and mammalian cell surfaces. With negli-
the MTC-BnCl carbonate monomer units) and quaternizing with gible hemolytic activity, S-GSA 25 was shown to possess favorable
more hydrophobic agents led to improved activity. However, an therapeutic indices and hence outperformed conventional AMPs
increase in polymer hydrophobicity also led to increased hemolytic such as indolicidin and polymyxin B.
activities, while the introduction of more mannose groups reduced In light of the increasing number of infections caused by
the RBCs lytic properties of the polymers. The star nanoparticles MDR Gram-negative bacteria, Lam et al. developed a new class
with the highest bacteria over RBC selectivity were found to be of amphiphilic peptide-based star polymers that exhibited sub-
those that were mannose-functionalized, possessed a high DPn of M antimicrobial activity toward Gram-negative bacteria with
MTC-BnCl units, and quaternized with the least hydrophobic group. minimal cytotoxicity [147]. These 16- and 32-arm star polymer
This highlighted the importance of balancing hydrophilicity and nanoparticles, termed structurally nanoengineered antimicrobial
hydrophobicity as well as the degree of mannose functionalization peptide polymers (SNAPPs), were synthesized by NCA-ROP of
on the star nanostructure for optimal antimicrobial activity and Z-l-lysine and valine NCA monomers using polyamidoamine den-
selectivity. Additionally, the authors also demonstrated the ability drimers as initiators via a core-rst approach, followed by the
of a model star polycarbonate in reducing the number of intra- removal of carboxybenzyl protecting groups (Fig. 16). The NCA

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Fig. 15. Illustration of the chemical structure of glucosamine-functionalized star polymers [144]. Copyright 2016. Reproduced with permission from the American Chemical
Society.

Fig. 16. Synthesis of SNAPPs via the NCA-ROP of Z-l-lysine and valine NCA monomers from polyamidoamine dendrimers, followed by removal of protecting groups [147].
Copyright 2016. Reproduced with permission from the Nature Group.

Fig. 17. The antimicrobial mechanism of (a) typical AMPs that disrupt the cytoplasmic membrane and (b) SNAPPs that effect their bactericidal action via a multimodal
pathway [147]. Copyright 2016. Reproduced with permission from the Nature Group.

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monomers were randomly polymerized from the dendrimer cores the use of a biologically inert silica core coated with a layer of bac-
to form the star polymer arms where the lysine-to-valine molar tericidal polymer [150153]. More recent studies, however, have
ratio was set at 2:1 and the DPn per arm was 30. Unlike conventional highlighted the potential of harnessing the synergistic functions of
AMPs, SNAPPs demonstrated equipotency in vitro against various bactericidal metal-based nanoparticles and polymers with direct
ESKAPE pathogens such as wild type E. coli, P. aeruginosa, K. pneu- antimicrobial properties [154,155].
moniae and Acinetobacter baumannii, as well as colistin-MDR strains The following discussion will be divided into two parts, namely
of P. aeruginosa and A. baumannii. It is worthwhile noting that antimicrobial silica-polymer core-shell nanoparticles and polymer-
colistin has been regarded as the last line of defence against Gram- coated metal-based nanoparticles.
negative bacteria infections but over the years some strains have
acquired resistance toward colistin. When tested in a mouse peri- 2.3.1. Silica-polymer core-shell nanoparticles
tonitis model, SNAPPs resulted in >4-log reduction in colistin-MDR Using vapor deposition polymerization, the fabrication of silica
A. baumannii bacterial cell counts (i.e., >99.99% killing efciency). nanoparticles coated with either PTBAM-co-poly(ethylene gly-
In addition, no resistant mutants were detectable after serial- col dimethacrylate) (PEGDMA) or PDMAEMA-co-PEGDMA was
passaging with sub-lethal concentrations of SNAPP for 24 days (600 reported by Jang and co-workers [150,151]. PTBAM and PDMAEMA
generations), even though colistin-MDR strains are highly capa- are known microbicidal polymers, whereas EGDMA was used as
ble of genetic mutation and rapid resistance acquisition, indicating a cross-linker to improve structural stability and reduce protein
that resistance to SNAPPs is not easily acquired. The authors pos- fouling on the nanoparticles. It is unclear as to whether the incor-
tulated that the excellent antimicrobial activity of SNAPPs was due poration of EGDMA to the nanoparticle construct would result in
to a multimodal mechanism. Compared to AMPs (and potentially the lowering of antimicrobial activity compared to similar nanopar-
other antimicrobial polymers), this multimodal mechanism may ticles with a purely PTBAM or PDMAEMA coating. Using differently
be unique to SNAPPs (Fig. 17). Using a range of microscopy imaging sized silica nanoparticles as the core, core-shell nanostructures
techniques (e.g., cryo-TEM and super resolution uorescence imag- with average diameters that ranged from 17 to 69 nm and a
ing) and (bio)assays, it was concluded that SNAPPs induce bacterial consistent average polymer shell thickness of 34 nm were syn-
cell death through a cascade of events that include binding with the thesized. As a result of their large surface areas, the nanoparticles
lipopolysaccharide and outer membrane of Gram negative bacteria with the smallest size (regardless of the type of polymer coat-
via electrostatic and/or hydrogen bonding interactions leading to ing) were able to eradicate E. coli and S. aureus quantitatively and
outer membrane destabilization, followed by migration of SNAPPs at the highest rate with the lowest MIC (<2 mg/mL) compared to
to the cytoplasmic (inner) membrane causing membrane perturba- the larger nanoparticles and bulk copolymer controls. Contrary
tion and unregulated ion movements. These events induce either to most studies where additional quaternization of PDMAEMA
apoptotic-like death followed by cell lysis at low SNAPP concentra- was required to provide antibacterial efcacy [79,81,138], the
tions, or direct cell lysis at high SNAPP concentrations. On the basis silica-PDMAEMA-co-PEGDMA core-shell nanoparticles were active
of this study, it is possible that a multimodal mechanism may be without quaternization [151]. The authors hypothesized that the
necessary to effectively combat MDR strains. densication of protonated amine groups on the nanoparticle sur-
The presence of salts and proteins in biological uids could mask face afforded by the large surface area was sufcient to promote
key functional groups in antimicrobial polymers thereby affecting antibacterial performance. In order to investigate factors affecting
their biological activity in vivo. This is a key point to consider for the antibacterial activities of amine-functional polymer-coated sil-
any potential clinical applications although limited studies have ica nanoparticles, the authors prepared a series of uniform-sized
been conducted thus far. Following on from their previous study, silica nanoparticles coated with different amine-functionalized
Lam et al. investigated the bionano interaction of SNAPPs by deter- polymer shells [152]. While the PDMAEMA-, qPDMAEMA-, PTBAM-
mining the antimicrobial activity against different Gram-negative and polydiallylamine-coated silica nanoparticles produced sig-
bacteria in complex biological media (i.e., simulated body uid and nicant killing against E. coli and S. aureus at 1 mg/mL, the
animal serum) [148]. It was found that the presence of divalent silica-polypyrrole (PPy) nanoparticles were non-active at the same
cations reduced the antimicrobial activity of SNAPPs toward E. coli, concentration. As all other polymers contain nitrogen atoms that
P. aeruginosa and K. pneumoniae because of the decrease in the are protonated under antimicrobial test conditions, except for PPy
ability of SNAPPs to cause membrane disruptions. However, the due to extensive lone-pair electron delocalization over the diene
potency of SNAPPs could be re-established with the coadministra- [156], the study suggested that the presence of amino groups on a
tion of a chelating agent such as ethylenediaminetetraacetic acid. polymer construct does not guarantee antibacterial activity. On the
Interestingly, the activity against A. baumannii was not affected other hand, antibacterial activity is more dependent on the state of
even under high salt concentrations. On the other hand, the bind- the amine groups such that N-protonation can be induced.
ing of serum proteins generally reduced the antimicrobial activity In a separate study by the same research group, the ability to
of the star polymer nanoparticles. The study thus highlights the coat silica nanoparticles with the antibacterial polyrhodanine
need for understanding the bionano interaction of antimicrobial known for its ability to kill bacteria by inhibiting bacterial ribonu-
polymers under physiological conditions as this would aid in the cleic acid (RNA) synthesis via chemical oxidation polymerization
development of systems that can retain clinical effectiveness. was demonstrated [153]. When tested against E. coli and S. aureus,
nanoparticles with diameters of 15 nm were found to be the most
2.3. Inorganic-polymer hybrid nanoparticles potent, registering MICs of 0.75 and 1 mg/mL, respectively. A simi-
lar trend as that reported in their previous studies was observed
Inorganic-polymer core-shell nanoparticles are typically com- [150,151], where the bacterial growth inhibitory activity of the
posed of a metal- or silica-based core with a polymer shell [149]. nanoparticles decreased with nanoparticle size. Using a combina-
To expand the applicability of inorganic nanoparticles such as metal tion of SEM and TEM, the authors postulated that the nanoparticles
or metal oxide nanoparticles to suit a wider range of applications, interacted with bacterial cell membranes, resulting in the loss of
they are often coated with polymer to improve the oxidation stabil- membrane integrity and, possibly, DNA damage.
ity of the core, reduce particle aggregation in solution, and improve
mammalian cell compatibility for bio-applications [149]. In the 2.3.2. Metal/metal oxide-polymer core-shell nanoparticles
development of inorganic-polymer hybrid core-shell nanostruc- Silver-containing systems, especially silver nanoparticles
tures for antimicrobial applications, earlier studies have focused on (AgNPs), have gradually gained recognition as a promising class

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of microbicidal agents to combat antimicrobial resistance [157]. Recently, recyclable antibacterials with targeted efcacy against
Harnessing the broad-spectrum antimicrobial properties of AgNPs, pathogenic E. coli in the form of 1822 nm AuNPs with immobilized
Wang et al. synthesized a series of polymer-Ag nanocomposites poly[(2-methacrylamide) glucopyranose] (PMAG) and qPDMAEMA
using cationic branched poly(sulfone amines) (PSAs) as templates were reported by Yuan et al. [162]. The polymers were syn-
[158]. The PSAs were obtained through the reaction of divinyl- thesized by RAFT polymerization and subjected to aminolysis to
sulfone and 1-(2-aminoethyl)piperazine, a trifunctional amine afford terminal thiol groups for grafting onto AuNPs (Fig. 19).
monomer, via Michael addition in a DMF-water mixed solvent qPDMAEMA formed the antibacterial component as it contains qua-
system. Different branched architectures of PSA were afforded ternary ammonium groups, whereas PMAG is a glycopolymer that
by tuning the volumetric ratio between DMF and water, where could bind with the mannose-binding lectin, FimH, found on the
a higher water content yielded more hyperbranched units. The tips of E. coli mbriae. The target specicity of the nanoparticles
PSA-AgNP nanocomposites were formed as Ag+ ions complexed was demonstrated by evaluating their efcacy against S. aureus,
to the PSAs and underwent in situ reduction. Based on a standard where a much lower bactericidal effect was observed due to the
disk diffusion assay against Aspergillus niger (i.e., a fungal species) absence of sugar-binding mbriae on the Gram-positive bacterial
at a xed nanoparticle concentration of 50 mg/mL, the PSA-AgNP cells. As expected, AuNPs containing more qPDMAEMA exhib-
nanocomposites were found to be more effective than pure PSAs. ited greater activity against E. coli. Notably, using AuNPs with a
An increasing trend in the diameter of the fungal growth inhibition qPDMAEMA:PMAG ratio of either 3:1 or 5:1 at a low concentra-
zone was observed with increasing degree of branching. In general, tion of 12 nM, more than 98% inhibition in bacterial growth was
larger diameters of the growth-free zone surrounding the disk observed after 3 h. PMAG was also deemed necessary for efcacy
signify a greater antimicrobial activity of the material contained as it improves the binding of nanoparticles to E. coli. In fact, the
in the disk. As smaller-sized AgNPs were obtained using more substantially lower MIC of the qPDMAEMA-PMAG-coated AuNPs
hyperbranched PSAs as templates, the authors postulated that this (i.e., 3 nM after an 18 h incubation) compared to qPDMAEMA alone
would yield better surface interactions and penetration ability of suggested the synergistic functions of both qPDMAEMA and PMAG,
the hybrid nanostructures, hence resulting in more efcient anti- where selective binding to FimH on the E. coli cell surface due to
fungal performance. Specically, the nanocomposite formed using PMAG possibly resulted in an increased localization of qPDMAEMA
PSA with the highest degree of branching (i.e., 0.41) resulted in on the bacterial cell wall. As FimH has a stronger afnity for
more than 80% fungal growth inhibition at a low Ag concentration mannose over other sugars, the composite nanoparticles could be
of 3 g/mL. While low toxicity against a model eukaryotic cell recycled following detachment from bacterial cells through the
line (COS-7 cells) was demonstrated by the branched PSAs, the addition of mannose. Retention of efcacy after three consecu-
combined toxicity effects of PSAs and AgNPs in the nanocomposite tive uses was demonstrated. Further, the incorporation of PMAG
form was not evaluated. This constitutes an interesting area to to the hybrid nanoparticles was shown to mitigate the toxicity of
be investigated further as the high toxicity of AgNPs has been qPDMAEMA towards eukaryotic cells, as evidenced by the lack of
suggested in various publications [159]. toxic effects towards L929 broblast cells after a 3-day exposure
Utilizing a similar approach where polymer templates were to the nanoparticles (qPDMAEMA:PMAG of 3:1) at concentrations
used to form polymer-stabilized metal nanoparticles, Jia and co- equivalent to 24 MIC.
workers prepared core-shell nanoparticles with an AgNP core and Titanium(IV) oxide (TiO2 ) is a unique antimicrobial compound
qPDMAEMA polymer shells (Fig. 18) [154]. Linear PDMAEMA was due to its ability to disrupt bacterial cell walls and cause cell death
rst synthesized using RAFT polymerization and then quaternized by producing reactive oxygen species (ROS) in the presence of light
with various alkyl bromides. This was followed by the complex- [163,164]. By combining the photocatalytic bactericidal effect of
ation of Ag+ ions with dithioester end groups present on the TiO2 and the inherent antibacterial properties of amine-containing
alkylated polymer and the subsequent reduction of the dithioester biocidal polymers, Kong et al. developed TiO2 -PTBAM-co-PEGDMA
to thiols, forming AgNP-qPDMAEMA core-shell nanoparticles. Tak- core-shell nanostructures with synergistic antibacterial properties
ing into account the antibacterial activities and cytocompatibility in the absence and presence of light [155]. The formation of the
of the core-shell nanoparticles, nanoparticles with pendant butyl polymer shell proceeded via surface-initiated photopolymerization
groups were found to be the most optimal. The growth of P. using TiO2 nanoparticles as an initiator. This resulted in rod-shaped
aeruginosa and S. aureus was inhibited when nanoparticle concen- nanostructures with an approximate length of 50 nm and a 2 nm
trations greater than 0.4 and 0.2 g/mL were used, respectively. thick polymer shell. When tested against S. aureus, pristine TiO2
Synergistic interactions between AgNPs and qPDMAEMA result- nanoparticles were only effective under ultraviolet (UV) irradia-
ing in enhanced antibacterial effects were validated as the zones tion, while bulk PTBAM-co-PEGDMA showed modest efcacy (i.e.,
of inhibition for AgNP-qPDMAEMA nanoparticles were larger than 67% inhibition) with or without UV light. On the contrary, the
those of either AgNP or qPDMAEMA alone. A preliminary mecha- TiO2 -polymer nanostructures resulted in 95.7% and 99.8% killing
nistic study suggested that the nanoparticles were able to disrupt efciency against S. aureus in the dark and after UV irradiation for
bacterial membranes, penetrate into the cells and inhibit intracel- 2 min, respectively. When the duration of UV irradiation was pro-
lular enzymatic activity. When evaluated against NIH3T3 broblast longed to 30 min, quantitative eradication of E. coli and S. aureus was
cells that act as a model mammalian cell line, cell viability remained observed for the core-shell nanostructures, while substantial viable
above 80% even at a concentration that exceeded the MIC by 20- cell populations were still detectable on the surfaces of the pristine
fold. Using a P. aeruginosa- and S. aureus-induced wound infection TiO2 nanoparticles. The enhanced ability of the hybrid composite
model, nanoparticle treatment was shown to promote wound heal- nanoparticles to deactivate bacteria under both light and dark con-
ing after 24 days in both healthy and immunocompromised (i.e. ditions was attributed to synergy between the TiO2 nanoparticles
diabetic) rats. Notably, no resistant P. aeruginosa or S. aureus species and the biocidal PTBAM, as well as the high surface area-to-volume
were detected against the hybrid nanoparticles. ratio of the nanoparticles compared to the bulk copolymer.
The innate antimicrobial efcacy of gold nanoparticles (AuNPs) Recently, magnetic nanoparticles have proven useful in the
remains a widely debated issue [160]. While AuNPs have been biological eld especially in applications such as cellular ther-
recently thought to be at most weakly bactericidal at high concen- apy, magnetic resonance imaging, tissue repair, targeted drug
trations [160], the ease and versatility of the nanoparticle platform delivery, cell separation, and hyperthermia therapy [165,166]. In
for functionalization (such as with polymers) endow AuNPs with particular, a special class of magnetic nanoparticles termed super-
the potential to act as antimicrobial therapeutic agents [161]. paramagnetic iron oxide nanoparticles (SPIONs) has generated

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Fig. 18. Synthetic pathway towards qPDMAEMA-decorated AgNPs [154]. Copyright 2014. Reproduced with permission from the American Chemical Society.

Fig. 19. Schematic illustration of the synthesis of AuNPs grafted with PMAG and qPDMAEMA [162]. Copyright 2016. Reproduced with permission from the American Chemical
Society.

special interest because of their high biocompatibility compared antimicrobial applications [170]. The nanoparticles with average
to other metal or metal oxide nanoparticles, and the ability to diameters of approximately 10 nm were synthesized in a one-step,
switch off their magnetic property after the removal of the exter- organic solvent-free process, where released Fe3+ ions acted as oxi-
nal magnetic eld [149]. Additionally, moderate activities against dants for the polymerization of rhodanine monomers on the surface
Gram-positive bacteria have been reported for SPIONs [167169], of the ferromagnetic core. Besides stabilizing the -Fe2 O3 nanopar-
that could potentially have synergic antibacterial effects with other ticles, the polyrhodanine shell was thought to provide antibacterial
bactericidal compounds to form multi-modal antimicrobial agents. ability to the nanoparticles. In a preliminary antibacterial assess-
Despite the many unique properties of magnetic nanoparticles, ment, the hybrid nanoparticles were incubated with bacteria for
the potential of magnetic nanoparticles as novel antimicrobials 1 h at a concentration of 15 mg/mL, and were found to result in
has not been extensively researched. The limited studies reported 90.2% and 99.9% reductions in the viable cell counts of E. coli and
in this area typically focused on harnessing the magnetic prop- S. aureus, respectively. However, it is unclear as to whether the
erty of the nanoparticles to afford recyclable antibacterial agents observed antibacterial activities were a result of synergistic killing
[170172]. As magnetic nanoparticles in general still suffer from by both -Fe2 O3 and polyrhodanine, or purely due to the polymer.
drawbacks related to surface oxidation, magnetically induced The recyclability of the nanoparticles by exposure to a magnetic
particleparticle aggregation and the lack of useful functional eld was also demonstrated, albeit with a slight reduction in ef-
groups [173], researchers have looked into the surface modication cacy where killing efciency against S. aureus was reduced to 80%
of such nanoparticles with organic (polymer) coatings as a plausi- after ve cycles.
ble solution to improve their applicability in the biomedical eld Similarly, recyclable antibacterial nanoparticles in the form of
[174]. polymer-coated ferromagnetic nanoparticles were developed by
A study reported by Kong et al. in 2010 on antibacterial -Fe2 O3 - Dong et al. [171] Instead of the -Fe2 O3 nanoparticles used in
polyrhodanine core-shell nanoparticles formed one of the earliest the previous study [170], a different core, Fe3 O4 , was coated with
studies on the use of polymer-coated magnetic nanoparticles for an antibacterial PQA. PDMAEMA brushes were polymerized from

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Fig. 20. Synthesis of qPDMAEMA-coated Fe3 O4 nanoparticles via surface-initiated ATRP [171]. Copyright 2011. Reproduced with permission from the American Chemical
Society.

the Fe3 O4 core using surface-initiated ATRP (SI-ATRP) to produce the polymer-coated nanoparticles allowed the efcient release
50150 nm particles, were then quaternized with ethyl bromide to of thermal heat that was sufcient to induce irreversible bac-
afford a qPDMAEMA coating (Fig. 20). While the bactericidal abil- terial destruction. This was in stark contrast to the mediocre
ity of the pristine Fe3 O4 nanoparticles at 1 mg/mL was discounted, antibacterial efciency (i.e., 5560% killing) of unmodied Fe3 O4
the qPDMAEMA-modied nanoparticles at the same concentration nanoparticles under the same conditions. Further, surface modi-
were able to eradicate E. coli completely after a 50-min incubation cation had negligible effects on the superparamagnetic nature of
period. Further, the efcacy was retained quantitatively after eight Fe3 O4 nanoparticles, and the Fe3 O4 @C-PVPS:PEDOT nanoparticles
cycles of repeated usage where the nanoparticles were recovered were shown to be recyclable with unaffected antibacterial activity
with an external magnet after each use. The high potency exhibited for 3 cycles.
by the nanoparticles against E. coli was attributed to large nanopar- Extending from the concept of hyperthermia-induced bacte-
ticle surface area, high density of biocidal quaternary ammonium rial cell death, Pu et al. investigated the possibility of combining
groups, and the covalent attachment of polymer brushes on the magnetic-induced hyperthermia and treatment with membrane-
surface. disrupting polymers to achieve substantially enhanced antibacte-
Sharma and co-workers reported the development of water- rial effects [176]. To achieve this goal, phosphoester-functionalized
soluble SPIONs with a MnFe2 O4 core and a multi-component shell cationic polycarbonates synthesized via organocatalytic ROP of 5-
consisting of carboxymethyl cellulose for water solubility, folic acid methyl-5-(3-bromopropyl) oxycarbonyl-1,3-dioxan-2-one (MTC-
(FA) as a cancer cell-targeting moiety, and pH- and temperature- (CH2 )3 Br) monomers were quaternized and grafted onto the
responsive poly(N-isopropylacrylamide)-co-poly(glutamic acid) surface of superparamagnetic 10 nm MnFe2 O4 nanoparticles
(PNIPAm-co-PGA) [175]. While the ca. 37 nm core-shell nanoparti- through ligand exchange. The resulting nanoparticles had a Dh
cles, termed poly-SPIONs, were originally designed for the targeted of 17 nm with ca. 213 grafted polymer chains per nanoparticle.
delivery of anticancer hydrophobic drugs, they were also found to The free polymer chains (quaternized PMTC-(CH2 )3 Br) were found
be antibacterial with a low MIC of 20 g/mL against E. coli. The to be bactericidal against E. coli and S. aureus only at a high
authors speculated that the small size of the poly-SPIONs facili- concentration of 100 mg/mL, while the polymer-coated MnFe2 O4
tated internalization to bacterial cells and subsequent interaction nanoparticles displayed a killing efciency of 9798% at 120 g/mL,
with intracellular contents such as DNA, causing membrane dam- approximately 3 orders of magnitude lower than the effective con-
age and cell death. However, as the antibacterial mechanism of centration of the free polymer. Similar to earlier studies reported
these nanoparticles remains elusive, further investigations, specif- by other research groups [151,171], the authors attributed the
ically to identify the antibacterial component in the nanoconstruct enhanced efcacy of the nanoparticles to the anchoring of the poly-
and the driving force for bacterial-nanoparticle interactions, will mer brushes on the nanoparticle surface that led to an increase
yield useful insights. in local charge density. The postulation was substantiated by the
An interesting study was published by Jeong et al. where lower antibacterial effectiveness demonstrated by nanoparticles
recyclable nanoparticles capable of killing bacteria through near- with lower polymer grafting densities. Subsequently, the magnetic
infrared (NIR)-induced photothermolysis were developed [172]. hyperthermia effect of the nanoparticles was investigated by intro-
Magnetic Fe3 O4 nanoparticles were coated with a catechol- ducing an alternating current magnetic eld during incubation.
conjugated poly(N-vinylpyrrolidone) sulfobetaine (C-PVPS) inner Interestingly, the effect of hyperthermia was species-dependent.
layer and a poly(3,4-ethylenedioxythiophene) (PEDOT) outer shell When tested against S. aureus, near-quantitative (97%) and quanti-
through layer-by-layer self-assembly (Fig. 21). The incorporation of tative (100%) killing was achieved at 8 and 60 g/mL, respectively.
PVPS, a polyelectrolyte, was postulated to improve water solubility Although the bactericidal ability of the nanoparticles against S.
and native conduction efciency. The role of PEDOT as a con- aureus in the presence of a magnetic eld was generally improved,
ducting polymer capable of absorbing NIR light (i.e., wavelengths the hyperthermia effect was less pronounced compared to that
of 750950 nm) was substantiated as the Fe3 O4 @C-PVPS:PEDOT observed against E. coli, as complete eradication of S. aureus was
nanoparticles displayed a higher photothermal conversion ef- only achieved at 120 g/mL. Using MnFe2 O4 nanoparticles with a
ciency than the pristine Fe3 O4 nanoparticles. This translated to a PEG shell as a control, the authors demonstrated that the antibacte-
higher killing efcacy shown by the functionalized nanoparticles, rial properties of the quaternized PMTC-(CH2 )3 Br-coated MnFe2 O4
where quantitative killing of E. coli and S. aureus was achieved at a nanoparticles were a result of the synergistic effects of magnetic
concentration of 1 mg/mL after 5 min of NIR irradiation. The authors hyperthermia induced by the metal oxide core and membrane dam-
postulated that the stronger photothermal activation achieved by age caused by the cationic polymer shell.

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Fig. 21. Schematic illustration of the synthesis of Fe3 O4 nanoparticles coated with an inner PVPS layer and an outer PEDOT shell through layer-by-layer assembly [172].
Copyright 2015. Reproduced with permission from the American Chemical Society.

2.4. Other core-shell polymer nanoparticles differences in morphology and surface area across the sheet-like,
spherical and cylindrical nanoobjects, insignicant differences in
In 2006, Kenawy et al. reported the development of a class terms of their activity against E. coli suggested that these factors
of insoluble polymeric biocides in the form of crosslinked core- were not dominant in the system investigated. The authors further
shell nanoparticles for potential use in water treatment [177]. The postulated that other factors such as nanostructure size and the
nanoparticles were obtained from the copolymerization of vinyl- chain length of the grafted qPDMAEMA could be more crucial.
benzyl chloride (VBC) with either 2-chloroethyl vinyl ether (CEVE) An interesting approach was utilized by Zhang et al. to pre-
or MMA monomers in the presence of a cross-linker, divinylben- pare antibacterial, guanidine-based core-shell nanoparticles using
zene. This was followed by quaternization with trimethylamine, a synthetic polymer template [179]. Using templated polymer-
triphenylphosphine or tributylphosphine to confer antimicrobial ization, acrylic acid and N,N-methylene bisacrylamide monomers
properties to the nanostructures. A cut plug method was used were copolymerized in the presence of PHMG in aqueous solu-
to evaluate the antimicrobial effects of the nanoparticles due to tion. Electrostatic interactions between poly(acrylic acid) (PAA)
their water insolubility, where the copolymers were placed in and PHMG led to the formation of insoluble interpolymer com-
wells composed of agar seeded with different microbial species. plexes were then stabilized by PHMG oligomers at the periphery
Nanoparticles synthesized from VBC-CEVE copolymers and func- to remain water-dispersible, forming nanoparticles with an aver-
tionalized with triphenyl phosphonium salts were found to be the age Dh of 190 nm. More than 2-log (>99%) reductions in E. coli and S.
most effective against the range of bacteria and fungi species tested, aureus cell counts were reported following treatment with 5 mg/mL
producing inhibitory zones with diameters that ranged between 9 of the PAA-PHMG nanoparticles, whereby activity was attributed to
and 36 mm at a copolymer concentration of 5 mg. The antimicro- the PHMG shell. However, the effect of nanoparticle formation on
bial ability of the nanoparticles was found to be species-specic. the antibacterial performance of PHMG remains inconclusive as a
At a lower concentration of 2.5 mg/mL, the aforementioned VBC- comparison between the activities of the PAA-PHMG nanoparticles
CEVE nanoparticles were able to produce 70 and 90% killing against and PHMG homopolymers was not presented in the study.
C. albicans and S. aureus; however, mediocre activity (70%) was Conductive polymers are a type of electroactive material that
demonstrated against B. subtilis and a fungal species, Aspergillus have generated increasing interest in the biomedical eld due
avus even when the copolymer concentration was increased to to their potential applications in tissue engineering, drug deliv-
10 mg/mL. ery, biosensing, and bioactuation, among others [180,181]. To
In order to investigate the inuence of shape on antibacterial explore the potential of this unique class of polymers as novel
core-shell nanoparticles, Chen and co-workers pioneered the fabri- antibacterial biomaterials, spherical nanoparticles (>200 nm) of
cation of spherical, sheet-like and cylindrical nanostructures with poly(N-ethylaniline) (PNETA), a type of conductive polymer, were
polysiloxane cores decorated with densely grafted antimicrobial prepared by Chabukswar et al. via photocatalytic oxidative poly-
qPDMAEMA brushes [178]. Block copolymers of PDMAEMA and merization using tartaric acid as a dopant [182]. Interactions
poly[3-(triethoxysilyl)propyl methacrylate] (PTEPM) were synthe- between the dopant and PNETA resulted in the organization of
sized via RAFT polymerization and subjected to bulk microphase PNETA chains in a highly ordered manner to yield denite nanos-
separation. This was followed by chemical cross-linking of the tructures. The PNETA nanoparticles were found to be the most
core, dispersal in acidic water to yield nanoobjects with differ- effective against K. pneumoniae, with the most potent variants pro-
ent morphologies depending on the PTEPM-to-PDMAEMA ratio, ducing inhibitory zones between 28 and 29 mm and an MIC of
and subsequent quaternization with n-octyl bromide. While the 50 g/mL. Moderate efcacies (i.e., inhibitory zones < 20 mm diam-
sheet-like structures (54.1% PTEPM) were several m in size, the eter) were exhibited against the other bacterial species tested,
nanocylinders (27.4% PTEPM) and nanospheres (14.5% PTEPM) pos- including E. coli, Salmonella typhi, B. subtilis, and S. aureus. The
sessed diameters of ca. 32 and 35 nm, respectively. Following a antibacterial properties of the nanoparticles were attributed to
preliminary antibacterial assessment, the treatment of E. coli with PNETA-bacteria electrostatic interactions, and possibly supple-
any of the nanostructures, regardless of morphology, resulted in mented by the presence of the acidic dopants as well as the
quantitative (>99.997%) cell death. Notably, the nanocylinders and hydrophilic and hydrophobic groups in PNETA.
nanospheres registered an MBC of 0.66 mg/mL, that is 10-fold lower Emulsion polymerization has been recognized as one of the most
than that of the qPDMAEMA homopolymer. This was in agreement common methods to synthesize polymer colloids such as core-shell
with earlier studies that theorized that an increased concentration polymer nanoparticles [183,184]. Despite being a relatively com-
and density of positive charges on the surface of a nanoparticle plex process governed by a multitude of factors, the fabrication
facilitated enhanced antimicrobial effects [57]. Despite the obvious of polymer nanoparticles via emulsion polymerization constitutes

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an active research area as the process is versatile and facilitates (PBA-co-PEHA)core PHMGshell nanoparticles exhibited MICs rang-
facile control over particle size as well as the ability to prepare ing from 6.25 to 50 g/mL against E. coli, where MIC was found
monodispersed and uniform particles [149]. to be inversely proportional to the PHMG content. Notably, the
In the eld of antimicrobial research, the synthesis of poly(4- best-performing nanoparticle with the highest (30.2 wt%) PHMG
vinylpyridine) (P4VP)-based particles with bactericidal properties content registered an MIC of 6.25 g/mL lower than that of the
using an oil-in-water microemulsion polymerization system was PHMG homopolymer (MIC 8 g/mL). It was hypothesized by the
attempted by Ozay et al. in 2010 [185]. However, some of the par- authors that nanoparticle-bacteria interactions were promoted by
ticle variants synthesized were within the micron size range and the small size and core-shell structure of the latex nanoparticles,
in general, the polymers exhibited high MICs (10 mg/mL on aver- resulting in the ability to inhibit bacterial growth at a relatively low
age) against a range of Gram-positive and Gram-negative bacteria dose.
even after quaternization or impregnation with metal nanopar- Recognizing the drawbacks of conventional emulsion polymer-
ticles. By combining the hydrophobicity of polyacrylonitrile ization, especially those related to the use of large amounts of
(PAN) and the known antibacterial properties of poly(4-vinyl-N- surfactant, Hazra et al. devised a facile route for the green synthe-
alkylpyridinium), the same research group synthesized a series of sis of 2050 nm spherical PMMAcore biosurfactantshell nanoparticles
PAN-co-P4VP-based core-shell particles by microemulsion poly- by a modied microemulsion process [190]. The biosurfactants
merization [186]. The nanoparticles were post-modied by either used rhamnolipids, surfactin, and trehalose lipids were bio-
converting the cyano groups on the PAN core to hydrophobic ami- compatible, biodegradable, non-toxic, and possessed low CMCs.
doxime groups, or quaternization of the P4VP shell to afford single When tested against B. subtilis and P. aeruginosa, the nanoparti-
or double positively charged materials. In general, the nanopar- cles were generally more potent against B. subtilis with MICs of
ticles with diameters ranging from 270 to 520 nm demonstrated 0.10.32 mg/mL. Compared to pure biosurfactants and bulk PMMA,
moderate efcacy against Gram-positive bacteria that included S. the higher antibacterial efcacies exhibited by the nanoparticles
aureus and B. subtilis, but were non-active against Gram-negative were attributed to larger surface areas that provided more active
bacteria. Taking into account their MICs and MBCs, the most effec- sites for contact with bacterial cells. The PMMAcore surfactinshell
tive variant registered MICs of 500 g/mL against S. aureus and nanoparticles displayed the highest activity, possibly due to the
250 g/mL against B. subtilis, with equivalent MBCs of 1000 and positively charged amine groups found only in surfactin but not in
250 g/mL, respectively. rhamnolipids and trehalose lipids. A mechanistic study performed
Another research group reported the development of nanoparti- on PMMAcore surfactinshell using B. subtilis revealed that a com-
cles possessing a PMMA core and shells composed of chitosan, PEI bination of oxidative stress induction and cellular disintegration
or a combination of chitosan and PEI through an emulsier-free and fragmentation was likely to be involved in the antibacterial
emulsion polymerization approach aided by an amine/tert-butyl mechanism of the nanoparticles. In terms of their hemocompati-
peroxide initiating system [187]. The Dh values of the nanoparticles bility, PMMAcore surfactinshell was found to be the least hemolytic
were within the 140162 nm size range. As a result of the amino compared to bulk PMMA and the nanoparticles with rhamnolipid
groups present on chitosan and PEI, the nanoparticles were pos- or trehalose lipid shells, although all three nanoparticle variants
itively charged in an acidic environment. For the PEI-containing were relatively hemocompatible with less than 2% hemolysis at
nanoparticles, the buffering ability provided by PEI ensured sta- a high concentration of 1 mg/mL. The nanoparticles also demon-
bility and a constant positive charge of the nanoparticles over a strated low toxicity to stimulated peripheral blood mononuclear
wider pH range. When tested against bacteria, preferential activ- cells, where at least 80% of the cells remained viable after a
ity against S. aureus over E. coli was displayed by all nanoparticle 5-day incubation with the nanoparticles at a concentration of
variants, with the highest activity shown by the nanoparticles con- 0.7 mg/mL.
taining a PEI only shell. The high antibacterial efcacy of PEI-coated Another approach utilizing polymerizable surfactants (or
nanoparticles was not unexpected since PEI is a well-known mem- surfmers) for the synthesis of antibacterial core-shell nanoparti-
brane permeabilizer [188]. While the incorporation of chitosan cles to mitigate the surfactant-associated drawbacks of emulsion
resulted in reductions in activity to varying extents depending on polymerization was reported by Li and co-workers [191]. Surfmers
the amount of chitosan added, the authors postulated that the are amphiphilic compounds that possess the ability to act as sur-
presence of chitosan would impart biocompatibility to the oth- factants and monomers [192], thereby enabling the incorporation
erwise toxic PEI nanoparticles; this was however subjected to of the surfactant to the synthesized nanostructure and enhancing
further investigations. The chitosan-PEI nanoparticles with 50 wt% nanoparticle stability while simplifying the nanoparticle purica-
PEI were demonstrated to be membrane-disrupting through SEM tion process [193,194]. A quaternary ammonium cationic surfmer
analysis, and showed comparable activity to the PEI-only nanopar- of N-(4-vinylbenzyl)-N,N-diethylamine hydrochloride (VEAH) was
ticles with MICs ranging from 1.7 to 3.2 mg/mL against S. aureus, introduced as a surfactant and a monomer for copolymeriza-
and 2.84 mg/mL against E. coli. tion with styrene to form PS-co-PVEAH core-shell nanoparticles
Another area of interest in the development of core-shell with average diameters between 96 and 204 nm. As expected, the
nanoparticles with inherent antibacterial properties is the use nanoparticles with the highest PVEAH content (PS:PVEAH = 1:1)
of such nanoparticles as surface modifying agents to introduce were found to be the most effective with MBCs of 15 and 20 mg/mL
antimicrobial functionalities to inert materials such as cellulose against E. coli and S. aureus, respectively. It should be noted
ber, textile, paper, and plastic [189]. To this end, Pan et al. that the bacterial cell concentration used to determine the MBC
developed a class of core-shell latexes based on the hydrophobic value, 1 107 colony forming units (CFU)/mL, was higher than
poly(butyl acrylate)-co-poly(ethylhexyl acrylate) (PBA-co-PEHA) that recommended by the Clinical and Laboratory Standards Insti-
and antimicrobial macromonomers in the form of glycidyl tute (CLSI) [195] and typically used in other studies (i.e., a nal
methacrylate-modied PHMG [189]. In the presence of a cationic concentration of 5 105 CFU/mL for E. coli per well). By fabri-
emulsier and the cross-linker EGDMA, emulsion polymerization cating nanoparticles of varying sizes with an identical amount of
was conducted in two stages to produce 104155 nm nanoparticles, quaternary ammonium moieties, the authors demonstrated that
where the PBA-co-PEHA cross-linked core was rst synthesized fol- nanoparticles with smaller sizes displayed stronger antibacterial
lowed by the formation of the hydrophilic PHMG shell. The PHMG activities, suggesting that a high nanoparticle surface area is favor-
shell was found to be essential for antibacterial efcacy, with- able for antibacterial efciency similar to that previously reported
out which the nanoparticles became ineffective against E. coli. The [190].

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3. Summary and future outlook ies are also necessary to verify the biological activity as in vitro
conditions do not necessarily reect the true outcomes of a
In the last few years, we have witnessed an increasing number of nanomaterial.
publications that describe new and innovative strategies to combat (iv) Immunomodulatory response studies: A less explored area of
the rise of multidrug-resistant bacteria using polymer nanoparti- study is the investigation of the immunomodulatory responses
cles made via controlled polymerization techniques. This review of antimicrobial polymers. Some synthetic antimicrobial poly-
highlighted the history and recent advances of antimicrobial poly- mers have demonstrated additional capability to invoke
meric nanoparticles as new alternatives to conventional antibiotics, immune responses in vivo to combat bacterial infection. The
where the nanoparticles possess inherent bactericidal properties. role of immune responses to the administration of these
To date, almost every antimicrobial polymer system, regardless of antimicrobial nanoparticles in vivo and how they can be con-
whether it is a linear polymer or a nanoparticle, has been built to trolled via the structural design of polymers could lead to new
mimic the cationic and amphiphilic nature of naturally occurring knowledge in the antimicrobial eld.
antimicrobial peptides (AMPs), and therefore, all synthetic antimi-
crobial polymers possessed cationic groups with varying degrees of It is worth emphasizing that these challenges are not a reection
hydrophobicity incorporated into the whole polymer architecture. of the failure of most current systems, but rather a testament to the
Given that AMPs induce their potent antimicrobial activity mainly remarkable advances that they have brought to improve our knowl-
through membrane disruption, that minimizes the chance of resis- edge in this eld. These challenges also signify room for expansion
tance development in bacteria, it comes as no surprise that AMPs in the dynamic eld of antimicrobial polymeric nanoparticles, and
were looked upon as design inspirations. The fact that AMPs are we envisage further future developments in this area of research
in essence, biopolymers, also gave a sense of familiarity and hence that will hopefully lead to new solutions in combating antibiotic
it is only natural for polymer chemists to pursue AMP-mimicking resistance.
designs. However, AMPs tend to be cytotoxic because of the lack
of target specicity, and by imitating the structural composition
of AMPs, most antimicrobial polymers also exhibited toxicity to Acknowledgements
mammalian cells to varying extents.
Thus, the balance between antimicrobial activity and biocom- GGQ and CB acknowledge nancial support provided by
patibility has been the underlying theme in most of the literature the Australian Research Council (ARC) via the Discovery
that was surveyed here. In general, balance (i.e., good antimicrobial Project (DP160101312, DP170104321) and Future Fellowship
activity plus moderate to good biocompatibility) can be achieved (FT120100096) schemes, respectively. SJL acknowledges the
through manipulation of the overall charge density of antimi- Australian Government for providing an International Postgrad-
crobial polymer nanoparticles, where highly cationic character uate Research Scholarship (IPRS) and an Australian Postgraduate
resulted in good antimicrobial activity but poor biocompatibility, Award (APAInt). EHHW acknowledges the receipt of 2016 UNSW
whereas improved biocompatibility with minimal impact on the Vice-Chancellors Research Fellowship from UNSW Australia.
antimicrobial activity can be attained when neutral hydrophilic
molecules are incorporated into nanoparticles to reduce charge References
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Please cite this article in press as: Lam SJ, et al. Antimicrobial polymeric nanoparticles. Prog Polym Sci (2017),
http://dx.doi.org/10.1016/j.progpolymsci.2017.07.007