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80]

Review Article

Filamentous bacteriophage: A prospective

platform for targeting drugs in
phage‑mediated cancer therapy
ABSTRACT Pankaj Garg
A new modality of targeting therapeutic drugs based on the use of bacteriophage (virus), as an emerging tool for specific targeting
Department of
and for vaccine development, has been an area of interest for genetic and cancer research. The approach is based on genetic Chemistry, GLA
manipulation and modification in the chemical structure of a filamentous bacteriophage that facilitates its application not only for University, Mathura,
in vivo imaging but also for therapeutic purpose, as a gene delivery vehicle, as drug carriers, and also as an immunomodulatory Uttar Pradesh, India
agent. Filamentous bacteriophage on account of its high surface holding ability with adaptable genetic engineering properties can
For correspondence:
effectively be used in loading of chemical and genetic drugs specifically on to the targeted lesion location. Moreover, the specific
Dr. Pankaj Garg,
peptides/proteins exhibited on the phage surface can be applied directly as self‑navigating drug delivery nanovehicles. The present Department of
review article has been framed with an objective to summarize the importance of bacteriophage in phage cancer therapy and to Chemistry, GLA
understand the possible future prospective of this approach in developing new tools for biotechnological and genetic research, University, 17‑km
especially in phage ‑mediated cancer therapy. Importantly, the peptides or proteins emerging from the surface of a nano carrier will Stone, NH‑2,
Mathura‑Delhi Road,
make the expense of such peptides economically more effective as compared to other immunological tools, and this seems to be
Mathura ‑ 281 406,
a potential approach for developing a new nanodrug carrier platform. Uttar Pradesh, India.
E‑mail: pankaj.garg@
gla.ac.in
KEY WORDS: Antibody/peptide–drug conjugate, drug delivery vehicle, phage display technology, phage nanoparticle

INTRODUCTION or cytotoxic drugs chemically conjugated on to the

There is a need for intensive research on
bacteriophage and its role in cancer treatment, both
in diagnosis and therapy as reported by researchers
worldwide.[1-4] A filamentous bacteriophage is
considered to be a dependable performer in
antibody engineering and is gaining importance
in nanobiotechnology and cancer research. The
possible specificity of bacteriophage for certain
cell and tissue components makes it a crucial
candidate to fight against cancer.[5-7] The specificity
of the target is related to the proteins or peptides
exhibits on the phage coat, which can further be
conjugated with other therapeutic nanoparticles,
endowing them with much specific targeting and
drug‑loading capacity. The genetic and chemical
modification of these phages opens a modular target
drug‑carrying platform of nanometric dimensions,
where the targeting moieties (biomolecules) and
the conjugated drugs can be delivered at will.[8]
The complete consignment may be assumed as a
wrapped gene linked with bacteriophage genome
for gene delivery applications or as imaging agents
phage coat for therapeutic purposes.
Moreover, the peptides or proteins can also be
directly self‑assemble themselves into the phage
imitative nanoparticles that can further be used
as a self‑guided nanomissile for drug delivery
operations [Figure 1a and b]. The present review
signifies the potential of bacteriophages as an
effective agent for targeted delivery by utilizing
them as antibacterial and more importantly
antitumor cancer cell nanomedicines.[9,10]
THE STRUCTURE AND BIOLOGICAL MECHANISM OF
FILAMENTOUS PHAGE
Filamentous bacteriophages are viruses capable of
infecting a variety of Gram‑negative bacteria. The
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Cite this article as: Garg P. Filamentous bacteriophage: A prospective platform for targeting drugs in phage-mediated cancer
therapy. J Can Res Ther 2019;15:S1-10.

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Garg: Filamentous bacteriophage: A novel nano-drug carrier platform
a
b Current modalities for the treatment of cancer include
Figure 1: (a) Chemically/genetically modified bacteriophage
incorporated with nanocarriers such as liposomes and other
nanoparticles, utilizing them as self‑driven nanovehicles for
gene/drug delivery applications. (b) Bacteriophage fused coat
protein/peptide incorporated with liposomes and other polymeric
nanoparticles self‑assembling them to form a phage mimetic
nanocapsules for successful delivery of gene/drug
most characterized class of bacteriophages is the Ff class
which includes M13, f1, and fd strains. A filamentous
phage particle posses a single‑stranded, closed DNA
genome which includes 11 genes and is encased in a long
capsid protein cylinder with a diameter of 7 nm and a
length of 800–2000 nm. The bacteriophage coat contains
five different proteins [Figure 2]. Approximately 2700
reprints of the major coat protein – pVIII [marked as g8
in Figure 2] – cover the complete surface of the phage
particle, and the remaining four minor coat proteins
pVII, pIX, pIII and pVI [marked as g7, g9, g3, and g6 in
Figure 2] cover five copies per particle.[11,12] All the proteins
bestowed to the structural stability of a phage particle,
but pIII protein is additionally responsible for host cell
recognition and infection. pIII is the largest and most
complicated among all the phage proteins and is composed
of three distinct domains. The N1 terminal domain is
responsible for initiating the translocation of viral DNA
into Escherichia coli, the second N2 domain relates with
host cell identification, while the third C‑terminal domain
is responsible for the integration of pIII on to the phage
coat.[13,14]
Infection in host initiate by the linkage of the phage
through the N‑terminal of the pIII ends to the male
E. coli cell. The coat proteins are then disbanded on the
cytoplasmic membrane, and the viral single‑ stranded
circular DNA is translocated into the cytoplasm, where it
is replicated by bacterial enzymes and converted into a
double‑stranded replicate form molecule. This molecule, in
fact, acts as a template for synthesis of all the phage‑related
proteins.[15,16]
S2
Figure 2: The biological structure of bacteriophage virus with single
strand genome, encapsulated by a protein coat. The positions of phage
coat proteins p‑VIII and minor coat proteins pVII, pIX, pIII, pVI are
marked with their intergenic regions as g8, g7, g9, g3, g6, respectively
BACTERIOPHAGE INTERACTION WITH CANCER CELL! HOW
IDEAL IT MAY BE?
surgery, chemotherapy, radiotherapy, hormonal therapy,
and other advanced treatment methods including
immunotherapy (tumor treatment using monoclonal
antibodies [MoAbs], peptides antisense nucleotides, etc.),
dendritic cell‑based interventions, and immunogenic cell
death inducers are some of the emerging nanobiotechnology
techniques for cancer treatment. In the present scenario for
a personalized medicinal approach, bacteriophage being a
nanoparticle can ideally be suited as a unique component for
various molecular therapies suggested and can be explored
as a promising nanobiotechnological tool for the treatment
of cancer.[17‑19]
The therapeutic potential of bacteriophage lies itself
in its structure. The minute and homogeneous size of
bacteriophage (nanosize) makes it the most promising
nanoparticle for drug delivery as well as for other purposes
including phage display and cancer targeting. Moreover,
bacteriophages are the most heavily populated species in the
biosphere that leads to its licensing for human use due to its
nonpathogenic nature and inert properties. Large amounts
of their detection naturally in the saliva, serum, and stool
sample confirm their findings and justify their observations
as biocompatible.[20,21]
Studies by different scientific groups relating to the interaction
of bacteriophage with cancer cells have been reported in
support. Benhar [22] successfully studied the potential of
bacteriophage as a targeted drug delivery vehicle by utilizing
them as antitumor nanomedicine. The phages were genetically
modified successfully to develop selective target specificity on
the phage minor protein coat. A large payload of a drug was then
chemically conjugated to these targeted phages by means of a
cleavable bond.[23,24] The result obtained shows growth inhibition
with positive toxicity and immunogenicity, thus underscoring
the potential of targeted drug‑carrying nanomedicine platform
for further development.[25,26] Related studies by other scientific
groups in support reported the in vivo and in vitro demonstration
of bacteriophage binding to the cancer cells. Studies relating to
the binding mechanism of bacteriophage T4 to melanoma cells
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Garg: Filamentous bacteriophage: A novel nano-drug carrier platform
and their possible interaction between the phage capsid protein
and also the β1 and β3 integrin receptors on the target cancer
cells confirmed the potential of bacteriophage as an ideal drug
delivery platform.[27‑29]
Bacteriophage interaction in antitumor therapies
The bacteriophage capability of affecting the mammalian
defense immune system has been explored in developing a
link between microbial strategies versus cancer targeting.
The pioneer study in this regard was conducted by Bloch,[30]
suggesting that bacteriophage possessed certain anticancer
activities and was reported to have the preferential
accumulation in tumor tissues for the suppression of tumor
growth. A confirmatory study in this regard was forwarded by
Kantoch and Mordarski, demonstrating that phages expressing
Fab fragments of antibody, selectively assembled in the tumor
cells, induce both humoral and cellular immune responses,
resulting in the regression of solid tumor in mice.[31]
In similar related studies conducted subsequently by
Dabrowska et al.,[32‑34] it was confirmed that T4 bacteriophage
interacting with β3‑integrins receptors at the surface of cancer
cells, capable of modulating the function of human T‑cell, and
delayed tumor growth was observed.
Bacteriophage interaction with reactive oxygen species in
the suppression of cancer cells
The reactive oxygen species (ROS) is reported to be the cause for
the initiation and progression of cancer. High level of oxidative
stress in the microenvironment of cancer cells results in the
promotion of cell proliferation and tumor progression. ROS
suppression may, therefore, be helpful in regulating many
undesirable effects relating to the progression of cancer cells. The
studies supporting the interaction between bacteriophage and
mammalian cell provide sufficient evidence for the inhibition
of ROS formation by bacteriophage.[35,36] It was reported that
bacteriophage has the ability to reduce the production of ROS
by phagocyte in the presence of bacteria.[37,38] The mechanism
of this process is quite complex and involves both the
phage–phagocyte interaction and phage–lipopolysaccharide
interaction. The role of bacteriophage in the suppression of
ROS production seems to be important in contributing to the
beneficial effects of phage‑mediated therapy, especially in
patients suffering from a sepsis disease, where a high level of
ROS production plays a crucial role.[39,40]
Bacteriophage immune response
Bacteriophage is responsible for inducing strong antiphage
humoral responses in the body, recognized as foreign
exogenous antigens. Circulation of phages in the blood is
inactivated by macrophages of the reticuloendothelial cells,
thus synergizing with antiphage antibodies.[41]
Continuous use of a phage as a therapy vehicle causes
stimulation of memory cells with subsequent generation of
antibodies. It is reported that utilization of phage either for
Journal of Cancer Research and Therapeutics - Volume 15 - Supplement Issue 1 - 2019
the production of new therapeutic drugs, as gene delivery
vehicle, as tumor targeting agents, or for other clinical
purpose, demands consideration on phage immunogenicity
and its retention time while developing its efficacious
biological route. Similarly, there are questions arising on the
capabilities of bacteriophage while entering into the blood
circulatory system of higher organisms, behaving like highly
immunogenic foreign antigenic particles and can interact
with the integral immune system, inducing both humoral and
cellular responses [Table 1].[42,43]
PHAGE DISPLAY CONCEPT
The phage display technology of bacteriophage has been
reported to play an important part both in the diagnostic
and therapeutic applications for treating cancer, by helping
in finding the appropriate receptors on the target cells. The
tumor targeting peptides exhibiting on the surface of the
bacteriophage particle is an effective approach for targeting
drugs on to cancer cells with promising results.[44,45]
The therapeutic potential of bacteriophages lies in their
structure itself. Its homogeneous and nanosize diameter makes
it the most promising and ideal candidate suited for drug
delivery vehicle as well as for other therapeutic purposes. The
development of phage display technology has proven out to
be a revolutionary step in the world of MoAbproduction and
have open the way for new innovations.[46,47] The strength
of the technology is based on a simple fact that a peptide
emerging on the surface of a filamentous bacteriophage is
physically connected to that particular DNA which encodes
it. The concept that a polypeptide fused on the surface of a
phage coat protein enabled the development of phage display
technology.[48,49]
Phage display technology is a useful technology that
provides a format for obtaining libraries containing a large
number (millions or billions) of different peptides and proteins,
including antibodies.[50,51] Smith working on filamentous
bacteriophage reported that the location, domain structure,
and flexibility of the pIII bacteriophage minor coat protein
might allow insertion of foreign polypeptides as fusion
proteins to pIII. The display of the protein on the phage surface
would make it accessible to antibodies, thus allowing the
screening of a large library of pIII fusions against a specific
antibody.[52,53] Thus, using a recombinant DNA technology,
large peptide libraries could thus be built, with every phage
displaying a unique random peptide. A direct physical linkage
is created between the displayed protein and its encoding gene.
The phage display technology has been suggested to use for
screening of peptide libraries, identifying peptide receptor
ligands, identifying epitopes for MoAbs, selecting enzyme
substrates, and in screening of cloned antibody repertoires.
The most successful use of phage display technology reported
has been in the isolation of MoAbs and its fragments using
large phage antibody libraries.[54,55]
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Garg: Filamentous bacteriophage: A novel nano-drug carrier platform

Table 1: Effects of bacteriophage interaction against tumor targeting

Phage interaction Immunomodulatory effect References
Bacteriophage Bacteriophage unique anticancer properties reported to have a [22,23,26‑29]
interaction in antitumor preferential accumulation in the tumor tissues for the suppression
therapies of tumor growth. Phages are capable of expressing proteins and
Fab fragments of antibody which selectively assembled in the tumor
cells inducing certain immune responses. This has been further
confirmed by the bacterial interaction with β‑3 integrin receptors at
the surface of cancer cells capable of delaying the tumor growth
Phage‑phagocyte Bacteriophage ability to suppress the production of ROS by [36,38‑40]
interaction (interaction phagocytes, responsible for the undesirable effects for the
with ROS) progression of cancer cells. The mechanism involves both
phage‑phagocyte interactions and phage‑lipopolysaccharide
interaction and was reported to contribute for the beneficial effect on
the suppression of ROS in patients suffering from sepsis disease
Anti‑phage immunity Bacteriophage being recognized as a foreign exogenous antigen [41‑43]
response is responsible for the generation of antibodies in the body. The
repeated use of bacteriophage as a therapeutic vehicle induces
a strong antiphage humoral response in the body, synergizing
with the antiphage antibodies, resulting in their rapid clearance by
macrophages of the reticuloendothelial cells
Bacteriophage ‑ phage The direct linkage between phage phenotype and its encapsulated [46,47,51,54,57,59,61,62]
display interaction genotype leading to the presentation of molecular libraries on
the phage surface, which is utilized in studying protein‑ligand
interaction, receptor binding sites and in improving or modifying the
affinity of protein for their binding partners
ROS=Reactive oxygen species

initial population of phage particles through several rounds

Figure 3: The recognition of target‑specific peptides through
bioscreening or panning process. Screening of combinatorial peptide
libraries has been carried out to identify ligands for peptide receptors.
The phage particles are selected against an appropriate antigen, and
the specific phages are eluted and amplified repeatedly allowing the
selection of phage clones, identified as an appropriate diagnostic and
therapeutic agent
Construction of antibody libraries and their selection
The advent of the phage display technology provides an
excellent means for the construction and selection of antibody
libraries. Antibody genes can be inserted into a phagemid, a
plasmid containing a phage‑derived origin of replication.[56]
The phagemid is then introduced into competent E. coli cells,
which will express the antibody in the form of a fusion
protein to the bacteriophage coat, thus providing a direct
physical linkage between phenotype (antibody specificity)
and genotype (sequence of the variable regions).[57] Selection
of specific antibodies can be achieved by a panning procedure
where phage particles expressing the antibody fragment are
selected against an appropriate antigen and the phage particles
carrying nonspecific antibodies are culled, thereby enriching
only for those expressing specific antibodies.[58,59] Culling the
of selection gives rise to a subpopulation with increased
fitness.[60] In vitro, selection can be performed either on a solid
phase or on an antigen in solution.[61,62] Alternatively, antibody
displaying phage particles can be directly selected against
markers on cell surfaces. Such cell panning selects antibodies
that are more likely to recognize epitopes accessible in vivo
and is important for the selection of therapeutic antibodies.
In vivo panning, where phage repertoires are directly injected
into animals, allows the selection of peptides that home to
target organs [Figure 3].
APPLICATIONS OF BACTERIOPHAGE AS AN IN VITRO AND
IN VIVO IMAGING AND TARGETING AGENT (USING PHAGE
DISPLAY LIBRARY‑BASED SCREENING METHODS)
The use of surface display bacteriophage technology
for displaying proteins or polypeptides on the surface,
in combination with the in vitro and in vivo selection
techniques, has paved the way to scientists in generating and
manipulating ligands, viz., enzymes, antibodies, and peptides.
The technology is based on the ability to express proteins
and peptides on the phage coat of bacteriophage. Libraries
of phage‑displayed polypeptides and proteins in this way are
physically liked to their encoding nucleic acids allowing the
selection of binding partners to the target site.
The phage display can further be translated for various
bacteriophage applications such as in studying protein–ligand
interaction, in identifying receptor binding sites, and also in

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Garg: Filamentous bacteriophage: A novel nano-drug carrier platform
modifying the affinity of proteins for their binding partners.
The corresponding section deals with the advancement in the
therapeutic applications of bacteriophage and phage display
concept through the work by different scientist groups globally,
demonstrating the potential of bacteriophage as a futuristic
drug/gene delivery platform and also as an ideal screening tool.
Imaging using bacteriophages (phages)
The phage library‑related screening methods can be
implemented into the field of in vivo screening of various
targets. The designing of peptides and proteins can bind
various targeting and imaging agents and has opened the
way to in vivo screening and in monitoring of specific targets
using the whole phage body as a targeting as well as an
imaging agent.[63]
A bi‑functional peptide ligand system involving the use
of bacteriophage has been developed for targeting of
receptors.[64] The peptide or protein ligands selectively home
onto tissue‑specific cell receptors can effectively be used as
targeted therapeutic or imaging agents to the selective cells
both in vitro and in vivo. The authors in their reported study
explained that despite extensive advances, such constructs
have been limited to use only for in vitro applications.[65]
Taking a step forward into an in vivo application, the concept
has been expanded by constructing and validating a more
precise bifunctional ligand phage display system with a
dual binding affinity. Finally, they developed a targeting
application in vivo and observed a preferential homing of the
targeted phages to the tumor site, with four times higher
accumulation of targeted phage in tumors in comparison to
control, nontargeted phages. The main achievement of this
study supports the proof of in vivo application of targeted
phages as imaging agents.[66]
A study supporting the use of bacteriophage as a potential
targeting and imaging agent has been reported by developing a
comparative in vivo screening tool of higher value over in vitro
identified clones.[67] Direct labeling of phage clones with far‑red
fluorochromes was reported, imaging them by a multichannel
fluorescence imaging system in mouse tumor models. As a
model targeting moiety, secreted protein acidic rich in cysteine,
and as a target, vascular cell adhesion molecule‑1 were used.
It has been demonstrated that how novel targeted peptide
sequences presented on phages can rapidly be selected against
a particular target and how a fluorescently labeled phage
retained target specificity on labeling.[68,69] Finally, it was
concluded that the fluorescently labeled phage can itself act
as a rechargeable imaging agent. The ease of preparation of the
phage‑imaging agent compared favorably with peptide‑modified
magneto‑fluorescent nanoparticles and was evaluated using the
same model system.[70]
The use of bacteriophage for in vivo imaging of bacterial
infection has been reported involving the use of radiolabeled
technetium (99mTc).[71]
Journal of Cancer Research and Therapeutics - Volume 15 - Supplement Issue 1 - 2019
R a d i o l a b e l i n g o f M 1 3 p h a g e w i t h 9 9 m Tc v i a
mercaptoacetyltriglycine (MAG3) was carried out both with a
target bacterial strain and with a nontarget control bacterial
strain 25922 (E. coli) and strain 29213 of Staphylococcus aureus.
The results obtained from the study revealed that in
the early hours of dose delivery, the organs related to
reticuloendothelial system (RES), i.e. liver, lungs, and spleen,
show higher percentage of phage accumulation, with about
30% accumulation in liver, 8%–10% in lungs, and 2% in spleen
after 30 min. The radioactivity in almost all organs gradually
decreases over time, and after 6 h of delivery, only 1% content
of the injected dose was reported to be present in the kidneys,
spleen, and lungs. It was finally concluded from the study that
the M13 phage when labeled with Tc‑99m using MAG3 shows
no such sign of in vitro instability both in saline and serum and
was reported that the radiolabeled phage shows equal binding
affinity both with live and heat‑killed bacteria and that once
bound, the phage is surprisingly stable to dissociation.
The application of targeted phages as a new tool for magnetic
resonance imaging (MRI) imaging has been demonstrated.[72]
The term “magnetophage” has been coined to describe the
particles they developed. They had isolated peptide displaying
phages that specifically bind phosphatidylserine (PS), a marker
of apoptosis. Magnetophages were prepared by reacting the
phages with ultra‑small particles of iron oxide (USPIO), in a
way that the USPIO reacted with amine groups on the phage
coat. The magnetophages injected to BALB/c mice were
mostly sequestered by the liver. To overcome the nonspecific
liver uptake, “stealthy magnetophages” were prepared using
polyethylene glycol (PEG)‑modified USPIO that were linked
to the PS‑specific phages. These stealthy magnetophages
no longer accumulate in the liver and other organs of
RES.[73,74] The fact that phages are taken up by RES cells is well
documented and considered as an obstacle for their potential
as therapeutics. It was shown that the biodistribution of
phages in mice can be modulated by conjugating sugar groups
to the phage coat.[75] Preparation of stealthy magnetophages
with PEG by Laumonier et al. presented a useful insight to the
unfavorable biodistribution of phages.[76]
Bacteriophage (as internalizing phages) for in vivo gene
delivery
The application of phage display technology has turned out
to be an exploring approach in identifying and selecting
internalizing antibodies from phage library and which in fact
laid the foundation of their application as a gene delivery
vehicle. Antibodies that can bind itself on the surface of
cell receptor are useful molecules for delivering drug or
DNA into the cytosol of mammalian cell. The resulting work
in this regard was reported by Poul and Marks at UCSE,[77]
involving the use of an anti‑ErbB2 (anti‑human epidermal
growth factor [EGF] receptor‑2) antibody for determining the
possibility of a direct selection of an internalizing antibodies
and also in identifying the most efficient display format from
the phage libraries. They used ErbB2 antibody C6.5, in a ScFv
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Garg: Filamentous bacteriophage: A novel nano-drug carrier platform
format, displayed monovalently on phage as a model and
demonstrated that anti ErbB2‑phage antibodies can undergo
receptor‑mediated endocytosis. The same group went on and
isolated internalizing phages by selecting antibody phage
library on cultured tumor cells.[78]
The possible use of bacteriophage as an internalizing gene
delivery vehicle has been explored by researchers at selective
genetics.[79] An example for this was set by them where an
M13 bacteriophage when linked with targeted EGF receptor
is capable of delivering a green fluorescent protein gene to
EGF receptor cells.
Similar approach could then also be applied to select
genetically modified phages that can be selectively designed
and emerge out as gene therapy vectors. Selective genetics
patented the technology of methods using genetic package
display for selecting internalizing ligands for gene delivery
(US patent‑US‑6451527B1).Two years later, the same group
reviewed the technology for efficient selection of internalizing
phages and compared them to viral and synthetic vectors used
for gene therapy. A similar related study at selective genetics
reported the additional advantage of using a phagemid
system over phage vector and was demonstrated successfully
in terms of high vector stability and efficient cell binding
and internalizing capacity. The use of multivalent phagemid
system was suggested to work more efficiently for a targeted
ligand, selectively designed for targeted mammalian cell
transduction.[80]
Gene therapy is a technique in which gene is delivered to the
target cell to restore, over‑express, or inhibit desired gene
product that can further be used to treat various types of
cancers. It is reported that the potential of bacteriophage can
successfully be harnessed in delivery of gene to eukaryotic
cells, through toxic genes transaction to cancer cells. Such
type of delivery of gene will have a great prospective in the
near future. Similarly, identification of tumor‑homing peptides
can be helpful for targeting cancer cells and antigen detection
and in drug and gene delivery.[19]
Bacteriophage as a targeted drug delivery agent
The bacteriophages are reported to be used as a successful
delivery agent for a large number of cyto toxic drugs to
the target cells. The drugs can be linked to a genetically
modified bacteriophage by means of a chemical conjugation.
The phages are modified genetically to exhibit a targeting
species on their phage coat, demonstrating the potential
of using a multiengineered phage as a universal nanodrug
carrier. The main achievement of this approach is the
transformation of drug selectivity itself to target selectivity.
Apart from this, a large number of therapeutic drugs including
antibiotics, anticancer drugs (doxorubicin), radionuclides,
and cytokines, which on account of having higher toxicity
and less sufficient quantity earlier have been excluded from
the list of therapeutics, can now successfully be evaluated for
S6
their therapeutic efficacy using phage‑assisted drug delivery
approach, by making a chemical modification in their groups
including amino (‑NH2), carboxylic (‑COOH), and phenolic
group, which can act as a linker for drug fabrication for its
successful delivery.[13]
The chemical conjugation of biotin (Vitamin H) with phage
nanoparticle to form a biotinylated phage was demonstrated.[81]
The extent of labeling was detected by a confocal fluorescence
microscopy using an avidin‑biotin System. The avidin‑biotin
system has been advocated for the successful delivery of
large number of radioimmune drugs. On account of having
high affinity between avidin and biotin (highest among the
biological system), the approach has been successfully explored
by us (Hazra et al.) both for direct and for indirect targeting
of radionuclides to the tumor cells following the prereported
pretargeting strategies.[82,83]
The approach of using bacteriophage as a drug delivery
platform was successfully evaluated by Benhar for retardation
of tumor cell growth. Antibodies such as anti‑ERGR and
anti‑ErbB2 used as targeting agents were chemically
attached to a drug hygromycin by means of a covalently
linked amide bond. Successful release of a nanoconjugate
drug with significant inhibition in tumor cell growth with
over 1000 times more than the corresponding free drug release
was reported, revealing an important feature of filamentous
phage as a drug delivery platform and also recommends the
application of drug‑carrying phage nanoparticle as an ideal
antibody–drug nanoconjugate.[84]
Polymeric‑encapsulated drugs can be another alternative for
conjugation with phage nanoparticles. Nanoassemblies of
a polymer conjugated with phage particle were developed
with a name FA‑M13‑Poly caprolactone-b-2-vinyl pyridine
coated with folate conjugated M13 bacteriophage (PCL-PLVP)
composed of two functional units. The results from the
study showed that polymeric‑loaded drug with phage
nanoparticle has significantly higher tumor/nontumor
ratio uptake compared to free doxorubicin drug.[85] Similar
therapeutic agents such as photosensitizer and radionuclides
through fabrication with phage nanoparticles via
1‑ethyl‑3‑(3‑dimethylaminocarbodiimide) chemistry can be
used for selective binding of SKBR3 cancer cells.[86] The phage
nanoparticle proved to be useful for targeting cancer cells,
antigen detection, and drug delivery through the identification
of tumor and organ homing peptides. Such approach facilitates
the selective targeting of cancerous cells, through the use of
bacteriophage, and can further be optimized for selective
targeted treatment and as drug delivery vehicle.[87]
Antibody, peptide engineering has proven its importance in
developing tumor‑targeted therapies and diagnostics. However,
the efficacy of this treatment is limited due to nonspecific
uptake of drugs by the RES uptake. Peptides are much smaller
molecule reported to be best suited for specific targeting of
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Garg: Filamentous bacteriophage: A novel nano-drug carrier platform

cancer cells. Combinatorial bacteriophage‑displayed peptide
libraries do offer a good source of potential ligands in
developing various cancer‑related molecular targets. Several
peptides are derived from phage‑displayed screening methods
and can be translated into effective therapeutic agent.
Therefore, the current clinical trials validate the potential
of peptide targeting and also the importance of phage
display technique to identify cancer screening and as a drug
delivery tool, which has been further explored by scientist
through their relevant scientific studies reported.[22,88,89] The
tabular summarization of all the mentioned applications
of bacteria has been collectively summarized in a separate
self‑explanatory [Table 2].
CONCLUSION
earlier has been considered as an obstacle, either to their high
toxicity effect or uptake by RES cells or immunogenicity, can
now be an active participant in the phage‑mediated cancer
therapy. To conclude, we can say that although phages are
being considered as an ideal for therapeutic applications in
phage therapy with their unique structural features, high
drug‑carrying capacity, and diversification in displaying
targeting moieties, with a potential of becoming an additional
advantage to the fast‑evolving modalities of nanomedicine;
however, still, a more intensive and thorough research is needed
so that many remaining questions relating to the possibility
of altering the pharmacokinetic and pharmacodynamic
properties of phages by chemical modification and also about
the safety of using phages in vivo limiting the immune system
reactivity can evidently be explored out.

The current review article has been framed with an aim of
demonstrating the potential of filamentous bacteriophage
as a targeted therapeutic agent, especially for cancer cells
delivery agent. The fact that phages can be used to identify
internalizing antibodies and peptides can successfully be
translated into using the phage as a gene delivery vehicle.
Similarly, the chemical modification on the phage coat, to load
it with different imaging agents and chemotherapeutic drugs,
exploited its role in the development of a new targeted drug
delivery system. A wealth of new targeting moieties such as
imaging agents, radioisotopes, quantum dots, MRI contrast
agents, and cytotoxic drugs of therapeutic importance which
Future prospective
The direct or indirect application of bacteriophage plays
an important role in suppressing cancerous tumor growth.
Since phages can be used to display polypeptides, which
can regulate different peptides, mRNAs, and micro‑RNA that
are interfering in the cancer cell mechanism, modulating
the useful constituent of extracellular matrix is responsible
for regulating the anticancerous activities in the cellular
mechanism. The another futuristic application of phage can
be for the detection of biomarkers, which can be used to
detect bacterial infection in living host and also for detecting
cancerous tissues and organs in humans. Thus, it is hoped that

Table 2: Tabular summarization of bacteriophage application as imaging, gene, and drug delivery agent
Role of bacteriophage Applications References
Bacteriophage as A precise protein/peptide bifunctional ligand system with dual affinity was developed which [67,68,71,72,74,76]
an imaging or in vivo shows a preferential homing of the target phage to the tumor site with four time’s higher
screening tool accumulation as compared to nontargeted phage
Direct labeling of bacteriophage with far‑red fluorochromes was reported as an in vivo screening
tool. A fluorescently labeled bacteriophage itself acts as a rechargeable imaging agent
Radiolabeling of filamentous bacteriophage with Tc‑99 m as an ideal imaging tool and also
subsequent reduction in the accumulation of radioactive dose to the nontargeted site (RES
uptake) was reported therefore increasing the efficacy of targeting tumor cells
The application of targeted bacteriophage as a new tool for MRI imaging was the developed
using healthy magnetophages. The phage was reported to be react with USPIO with significant
reduction in the accumulation of dose to the nonspecific organs

Bacteriophage as The application of bacteriophage as a gene delivery vehicle involving the use of anti‑ErbBr [77‑80]
in vivo gene delivery antibody has been reported for determining the possibility of direct selection of internalization
agent antibodies that can undergo receptor‑mediated endocytosis
The possible use of genetically modified bacteriophages linking it with target receptor for gene
delivery applications by screening of phage libraries capable of delivering DNA to the receptor cells
The use of multivalent phagemid system which seems to be of high stability with efficient cell
binding properties and internalizing capacity can work efficiently for a target ligand system

Bacteriophage as The potential of using a multiengineered filamentous bacteriophage as a universal nanodrug [19,82‑87]
targeted drug delivery carrier in chemical conjugation of drugs by making a chemical modification in the functional
agent groups that can act as a linker for drug fabrication on the phage coat for its successful delivery
The use of biotinylated phage in an avidin‑biotin system for the successful delivery of large
number of radioimmunotherapeutic drugs both for direct and indirect targeting of radionuclides
to the tumor cells
Polymeric encapsulation of drugs with phage nanoparticles
The result showed that these polymeric phage nanoassemblies are having higher tumor/
nontumor uptake compared to free unconjugated drug
Bacteriophage displayed peptide libraries reported to have a fair source of potential ligands for
developing cancer‑related molecular targets for increasing the efficacy of tumor targeting ratio
RES=Reticuloendothelial system, USPIO=Ultra small particles of iron oxide, MRI=Magnetic resonance imaging

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Garg: Filamentous bacteriophage: A novel nano-drug carrier platform
bacteriophage can be used as an efficient cancer research tool,
which can provide us with new futuristic, innovative options
for the treatment of cancer.[90]
Acknowledgment
Ww would like to acknowledge the support of our esteemed
teacher and guide Prof. D. K. Hazra, Emeritus Scientist and
Professor, S. N. Medical College, Agra, for his technical help
and support in designing and reviewing this manuscript.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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