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Expand classical drug administration ways by

emerging routes using dendrimer drug delivery
systems: A concise overview
Impact Factor: 15.04 DOI: 10.1016/j.addr.2013.01.001 Source: PubMed





Sad El Kazzouli

Mosto Bousmina

Euro-Mediterranean University of Fez

Euro-Mediterranean Universit of Fez





Available from: Mosto Bousmina

Retrieved on: 07 March 2016

ADR-12434; No of Pages 15
Advanced Drug Delivery Reviews xxx (2013) xxxxxx

Contents lists available at SciVerse ScienceDirect

Advanced Drug Delivery Reviews

journal homepage:

Expand classical drug administration ways by emerging routes using

dendrimer drug delivery systems: A concise overview
Serge Mignani a,, Sad El Kazzouli b, Mosto Bousmina c, Jean-Pierre Majoral d,

Universit Paris Descartes, PRES Sorbonne Paris Cit, CNRS UMR 860, Laboratoire de Chimie et de Biochimie pharmacologiques et toxicologique, 45, rue des Saints Pres, 75006 Paris, France
INANOTECH, (Institute of Nanomaterials and Nanotechnology), MAScIR (Moroccan Advanced Science, Innovation and Research Foundation), ENSET, Av. Arme Royale, Rabat, Morocco
Hassan II Academy of Sciences and Technology, Avenue MVI, km4, 10222 Rabat, Morocco
Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France

a r t i c l e

i n f o

Article history:
Accepted 30 January 2013
Available online xxxx
Routes of administration
Transdermal diffusion
Ocular drug delivery
Intravenous route
Oral route
Nasal administration
Inhalation administration

a b s t r a c t
Drugs are introduced into the body by numerous routes such as enteral (oral, sublingual and rectum administration), parenteral (intravascular, intramuscular, subcutaneous and inhalation administration), or topical (skin and
mucosal membranes). Each route has specic purposes, advantages and disadvantages. Today, the oral route remains the preferred one for different reasons such as ease and compliance by patients. Several nanoformulated
drugs have been already approved by the FDA, such as Abelcet, Doxil, Abraxane or Vivagel(Starpharma)
which is an anionic G4-poly(L-lysine)-type dendrimer showing potent topical vaginal microbicide activity. Numerous biochemical studies, as well as biological and pharmacological applications of both dendrimer based products
(dendrimers as therapeutic compounds per se, like Vivagel) and dendrimers as drug carriers (covalent conjugation
or noncovalent encapsulation of drugs) were described. It is widely known that due to their outstanding physical
and chemical properties, dendrimers afforded improvement of corresponding carried-drugs as dendrimerdrug
complexes or conjugates (versus plain drug) such as biodistribution and pharmacokinetic behaviors. The purpose
of this manuscript is to review the recent progresses of dendrimers as nanoscale drug delivery systems for the delivery of drugs using enteral, parenteral and topical routes. In particular, we focus our attention on the emerging and
promising routes such as oral, transdermal, ocular and transmucosal routes using dendrimers as delivery systems.
2013 Elsevier B.V. All rights reserved.


Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Main physicochemical aspects of dendrimers in medicine: a concise overview
Main linear polymerdrug conjugates and dendrimer
therapeutic properties
. . . . . . . . . . . . . . . . . . . . . . . . . .
Main dendrimer applications using different routes
of administration
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
Dendrimers in ocular drug molecule delivery
. . . . . . . . . . . .
Dendrimer mediated transdermal drug delivery . . . . . . . . . . .
Dendrimers for oral drug release system . . . . . . . . . . . . . . .
Dendrimers for other controlled drug release systems
. . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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1. Introduction

This review is part of the Advanced Drug Delivery Reviews theme issue on "25th
Anniversary issue - Advanced Drug Delivery: Perspectives and Prospects.
Corresponding authors.
E-mail addresses: (S. Mignani), (J.-P. Majoral).

Drugs are introduced into the body by numerous routes such as

enteral (oral, sublingual and rectum administration), parenteral (intravascular, intramuscular, subcutaneous and inhalation administration), or topical (skin and mucosal membranes). Each route has
specic purposes, advantages and disadvantages [13]. Fundamentally,

0169-409X/$ see front matter 2013 Elsevier B.V. All rights reserved.

Please cite this article as: S. Mignani, et al., Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems:
A concise overview, Adv. Drug Deliv. Rev. (2013),

S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx

the accessibility of drug molecules to their respective target site and

drug treatment is strongly dependent on the route of administration
used. Thus, the route of administration has a profound effect upon
both the speed and the efciency with which the drug acts. The rate
at which a drug reaches it site of action depends on its absorption and
distribution proles. Importantly, everyone responds to drugs differently, and many parameters affect drug response. No single route of administration of drug is ideal for all drugs in all circumstances. In recent
years, development of oral controlled release drug delivery systems
has strongly increased [4].
Nanomedicine, which is the medical application of nanotechnology
and related researches, can be simply dened as the monitoring, repair,
construction and control of human biological systems at the molecular
level, using engineered nanodevices and nanostructures [58]. As a
driving change in R&D research, during the last twenty years, the
pharmaceutical industry began to adopt nanotools to implement high
throughput screening of drug repositories, to nd Hits and leads, to
identify drug targets and biomarkers for both preclinical and clinical studies, to develop of diagnostic and imaging agents, and nally to carry out
new nanotechnologies such as nanoformulations and nanocarriers as
drug delivery approaches. Futuristic scenario for personalized medicine
includes the development of nanoparticles that simultaneously monitor
and treat disease called the theranostic approach [9,10].
Several nanoformulated drugs have been already approved by the
FDA including generic reformulations such as Abelcet (liposome-based
amphotericin B, anti-fungal activity, liposomal formulation) [11], Doxil/
Caelyxl (liposome-based doxorubicin, cancer, Pegylated liposomes
against ovarian cancer Kaposi's sarcoma) [12] and Abraxane (paclitaxel,
anti-cancer activity, albumin-bound particles) [12,13].
Interestingly, various polymeric drugs have been described to treat
different diseases. For representative examples: polymeric micelle formulated paclitaxel (Genexol-PM) with free of Cremophor EL reducing
Cremophor EL-related toxicities and increasing therapeutic efcacy
(Phase II studies, breast and lung cancers), Adagen which is a conjugate
of monomethoxypolyethylene glycol (PEG) covalently attached to the
adenosine deaminase (ADA) enzyme for the treatment of severe combined immunodeciency disease (SCID) associated with a deciency of
ADA) had received FDA approval in 1990 (intramuscular injection),
and Oncaspar which is a Pegylated formulation of L-asparaginase, the
enzyme that depletes the amino acid asparagine. In 2006, the FAD approved Oncaspar for the rst-line treatment of patients with acute lymphoblastic leukemia. Commercialized Neulasta which is a PEGylatedrecombinant methionyl human granulocyte colony stimulating factor
(G-CSF) stimulating the bone marrow and promoting the growth
of white blood cells, prevents neutropenia. Neulasta is given intravenously once for each cycle of high-dose chemotherapy [12,14].
In the dendrimer domain, in 2012, Starpharma (Melbourne, Australia)
started two pivotal phase III for the treatment of bacterial vaginosis with
Vivagel [12,15]. This anionic G4-poly(L-lysine)-type dendrimer has
thirty-two naphthalene disulfonate groups on the surface, and showed
potent topical vaginal microbicide activity [16].
The deeper analysis of other PEG, dendrimers and nanocarrier
platforms have been recently presented and discussed by R. Haag
and coworkers [12].
Based on extensive biochemical studies, biological and pharmacological applications of both dendrimer based products (dendrimers as therapeutic compounds per se, like Vivagel) and dendrimers, dendrons and
polyether based amphiphiles as drug carriers (covalent conjugation or
noncovalent encapsulation of drugs) were portrayed in review articles
[17]. One of the major advantages of these nanometer-scale dendrimer
biomaterials is their outstanding capability to be used with different
routes of administration. To the best of our knowledge, few nanoparticles
as dendrimers are suitable for a large variety of administration routes.
The purpose of this manuscript is to review the recent progresses of
dendrimers as nanoscale drug delivery systems using enteral, parenteral
and topical routes. In particular, we focus our attention on the emerging

and promising routes such as oral, transdermal, ocular and transmucosal

routes using dendrimers as delivery systems. Before we highlight the unconventional routes of administration of dendrimers, below, we present,
successively, a concise overview of the main physicochemical aspects of
dendrimers in nanomedicine, and then, we describe the main linear
polymerdrug conjugates and dendrimer therapeutic properties.
Recently, based on large number of biomedical applications of
dendrimers developed from a handful in the early 1990s, for the rst
time, we introduced the term of dendrimer space concept as a new
druggable cluster which is included in the vast volume of chemical
space [18]. The boundaries of this cluster can be determined by topological properties as diverse routes of administration using dendrimers.
This new approach affords a new vision of pharmaceutical science research, and opens new and promising avenues to nd new
drug-based dendrimers.
2. Main physicochemical aspects of dendrimers in medicine: a
concise overview
The dendrimer literature is huge, and extensive studies using
dendrimers were carried out. Dendrimer nanostructures represent
outstanding nano-carriers in medicine [17]. Dendrimeric structures
are of particular interest in the eld of drug delivery due to their
peculiar structural properties including controllable internal cavities
bearing specic species for the encapsulation of guest drugs and
external periphery with 3D multiple functional moeities for solubilization, conjugation of bioactive compounds and targeting molecules,
and recognition purposes. The main successes of dendrimers resulted
in their appropriate, reproducible and optimized design parameters
addressing physicochemical limitations of classical drugs (e.g. solubility,
specicity, stability, biodistribution and therapeutic efciency) and
their ability to overcome biological issues to reach the right target(s)
(e.g. rst-pass effect, immune clearance, cell penetration, off-target
interactions, etc.). Improvement of pharmacokinetic (PK) and pharmacodynamic (PD) behaviors of both drug-dendrimer conjugates and
drugdendrimer encapsulates versus plain drugs demonstrates their
strong potentials in medicine as nano-carriers [17,19].
A schematic of typical dendritic structure is shown in Fig. 1 and
illustrates four main regions: i) an initiator core scaffold, ii) interior
layers composed of repeating branching units attached to the core
(generation, Gn, where n can be 0 to 12), iii) terminal surface groups
attached to the outmost interior generation iv) void spaces.
The most commonly referenced dendrimers used in nanomedicine
are polyamidoamines (PAMAM), poly(L-lysine) scaffold dendrimers
(PLL), polyesters (PGLSA-OH), polypropylimines (PPI), poly(2,2-bis
(hydroxymethyl)propionic acid scaffold dendrimers (bis-MPA) and
aminobis(methylenephosphonic acid) scaffold dendrimer. Some of
them are depicted in Fig. 2 and several are commercially available
from various suppliers. For instance, the main providers for PAMAM
dendrimers (Starburst), poly-etherhydroxyl-amine PEHAM dendrimers
(Priostar), PPI dendrimers (Astramol) are Sigma Aldrich, National
Dendrimers & Nanotechnology, Dendritic Nanotechnologies and DSM
Fine Chemicals. Phosphorus based dendrimers are commercialized by
BDI (BioDendrimer International).
Importantly, the dendrimers showed strong ability to escape from
the uptake by the non specic ReticuloEndothelial System (called
RES). In addition, the nanomeric size of dendrimers induces the passive targeting effects reducing the non-specic toxicity of the carried
drugs. This effect is called Enhanced Permeability and Retention effect
(EPR effect), and is observed, for instance, in tumor or inamed
tissues [17,19].
Dendrimers can be included as specic delivery nano-systems
which are able to specically target the carried drugs to cells by a simple grafting of targeting molecules on the dendrimer surface termini.
This therapeutic approach is called active targeting approach, and
the drug delivery occurs via a conjugated cleavable linker such as

Please cite this article as: S. Mignani, et al., Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems:
A concise overview, Adv. Drug Deliv. Rev. (2013),

S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx

Fig. 1. 2D structural units of dendrimers for medicinal chemistry.

amides, esters, hydrazones, etc., which is activated by diseasespecic signals like chemical/oxidation and change in the surrounding pH or by external stimuli such as magnetic eld, light [20,21] or
specic enzymes (self immolative approach) [22]. In both passive
and active targeting approaches, dendrimers avoid their uptake by
the RES and consequently remain in plenty of time in the blood circulation increasing their biological potency in specic tissues such
as tumors. For instance, the extravasation of the tumor vasculature has
been proposed for the anti-tumor activity of several dendrimerencapsulated or -conjugated drugs [23]. Stimuli-responsive polymeric
nanocarriers including dendrimers, dendrons etc. for the controlled
transport of active compounds (drugs, peptides, genes, etc.) have been
analyzed by R. Haag et al. [24]. Interestingly, multi- and polyvalent interactions of organic materials including dendrimers playing a crucial role
in biological recognition and adhesion has been nicely highlighted [25].
In addition to the use of large polycationic dendrimers, different
groups have described the delivery of genetic material into cells using
dendrons. Thus, very interestingly, R. Haag et al. published the development of original non viral vectors based on well-dened molecular
structure from multivalent polyglycerol dendrons. For instance, the
G2-octaamine derivative bearing a hydrophobic alkyl chain at the
core promoting dendron self-assembly, acts as an efcient vector to
deliver FAM-siRNA into the cells [26]. The same team presented the
synthesis of biodegradable cationic self-assembly dendron based
on cholesterol-functionalized core unit. Based on cellular uptake
studies, these amphiphilic nanocarriers are highly effective in
transporting DNA into cells but with low transgene expression [27].
3. Main linear polymerdrug conjugates and dendrimer
therapeutic properties
The comparison between dendrimers and the well known linear
polymerdrug conjugates is of real interest. Table 1 summarizes the
main, but not exhaustive relevant comparative properties related to in
vitro and in vivo properties between dendrimers and linear polymer
drug conjugates [28].
Development of polymerdrug conjugates as polymer therapeutics
with cleavable linkers to improve the therapeutic index of several
toxic drugs especially in cancer chemotherapy, has been intensively
portrayed [29]. The main copolymer described is HPMA (N-(2hydroxypropyl)methacrylamide) but others such as, for instance, PEG,
poly-L-glutamate, albumin, dextran, 6-maleinimodcaproyl hydrazone
derivatives, etc. have been also pointed out. These polymerdrug conjugates have shown several advantages versus plain drugs such as fewer
side effects, improved therapeutic efcacy, ease of drug administration,
and improved patient compliance [23,24].

Different cleavable linker types were employed, namely: Gly-PheLeu-Gly, Gly-6-aminohexanoyl-Gly, alanine ester, Gly-ester, ester and
acid-sensitive hydrazone [24,29]. The Phase I and phase II clinical trials
with HPMA copolymers containing different drugs such as doxorubicin,
paclitaxel, camptothecin, methotrexate and carboplatinate analog and
DACH palatinate analogs are ongoing, completed or stopped. It is noted
that the use of HMPA copolymers in nanomedicine has been reviewed
recently in a special issue of Advanced Drug Delivery Reviews [30].
PEG-camptothecin and PEG-SN38 have been also described to treat
solid tumors or lymphoma [31]. A broader range of other treatment of
diseases excluding cancers using HPMA copolymers was described including, for instance, musculoskeletal diseases, infectious diseases and
spinal cord injury. Within this issue, R. Duncan and M. J. Vicent emphasized a critical overview of current status and future opportunities of
HPMA copolymer conjugates in nanomedicines [32]. Thus the design
and the development of HPMA copolymercyclic RGD conjugates for
targeting tumor angiogenesis have been described. The Phase I clinical
studies performed with HPMA copolymer conjugates containing paclitaxel (PNU 166945) and camptothecin (PNU 166148) failed due to
inadequate designs. Indeed, after administration, rapid cleavage of
the ester linker afforded low drug loading and consequently no pharmacokinetic benet. No clinical evidence of antitumor activities has
been observed, and no polymer-related toxicity has been reported
in these studies. Recently HPMAcopolymer platinates (AP5280 and
then AP5346-ProLindac) have entered Phase II clinical development
(as a single agent and combination) showing anti-tumor activities.
These clinical studies have shown that HPMA copolymerantitumor
conjugates have been safely (minimal adverse reactions) administered
only parenterally (intravenous administration), and this treatment
allowed very good quality of life of patients for a certain period of
time. Nevertheless, the future objective will be to use HPMA copolymerdrug conjugates in the treatment of life-threatening diseases requiring non-parenteral routes of administration such as oral or topical.
The non-degradable polymeric carriers such as HPMA copolymers
limit their parenteral use (relatively short course of treatment)
unlike non-parenteral routes for which the accumulation of the
non-degradable polymer is not a safety risk. Non-degradable polymeric carriers improve the risk of their cellular accumulation
through their sequestration in the lysosomal compartments, especially after chronic administrations or at high doses [3335].
4. Main dendrimer applications using different routes
of administration
It is widely known that due to their outstanding physical and chemical properties, dendrimers afforded improvement of corresponding

Please cite this article as: S. Mignani, et al., Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems:
A concise overview, Adv. Drug Deliv. Rev. (2013),

S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx

Fig. 2. Chemical structures of several commonly used dendrimers.

Please cite this article as: S. Mignani, et al., Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems:
A concise overview, Adv. Drug Deliv. Rev. (2013),

S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx

Table 1
Relevant properties related to in vitro and in vivo properties of dendrimers and polymer-drug conjugates.
Adapted from P. S. Narayan et al., see Ref. [28].
Main properties


Polymerdrug conjugates


Compact/globular ( predictable MW and monodispersity reproductible

Very high ( controlled branching (topology) and versatility in design and
modication of terminal end groups)
High (essential for drug candidates, good absorption, bioavailability and
High ( reduced toxicity, increased bioavailability, simplied dosing schedule)
High (high cell membrane penetration increased cellular uptake level of the
drugs complexed or conjugated)
Enhanced ( preferential uptake of the dendrimers by cancer tissues)
Intravenous, intraperitoneal, ocular, transdermal, oral, intranasal, pulmonary,

Not compact and structural heterogeneity

Structural control
Aqueous solubility
Programmed release of drugs
Penetration abilities
Penetration and retention (EPRa) effect
Routes of administration

Low (major obstacle to the development and
clinical application of drugs)
Available within a specic period of time
Mainly intravenously

Enhanced permeability and retention (passive drug targeting and specic tissue targeting).

carried-drugs as dendrimerdrug complexes or conjugates (versus plain

drug) such as biodistribution and pharmacokinetic behaviors. These parameters are the main relevant factors in clinical trials [36]. Both,
dendrimerdrug complexes (physical encapsulation or electrostatic interaction) and covalent conjugates have been evaluated in different
routes of administration.
Importantly, M. Hashida et al. emphasized, in a recent review [23],
the key role of pharmacokinetic considerations towards the rational
design and the development of dendrimers for successful in vivo
application and clinical translation. Thus, relationships between physicochemical properties of dendrimers and pharmacokinetic parameters
such as AUC (Area Under the Curve), hepatic and renal clearance, size,
generation, charge, PEGylation, etc., after intravenous administration in
mice, have been discussed. Interestingly, Therapeutic Availability (TA)
based on the total drug amount as a function of the AUC at the target
site has been used showing effectiveness of macromolecule-conjugated
drugs compared with plain drugs either after intravenous, intraperitoneal, intratumoral, oral, transdermal or ocular administration. The therapeutic applications studied are anticancer, anti-inammatory, antithrombotic and antimalarial. The higher TA values were obtained for
conjugation versus encapsulation/complexation. In addition, increase
of the multivalency of conjugated ligands on dendrimers induced improvement in tumor targeting. Consequently, highly tumor-targeted
dendrimers would enhance biodistribution proles. The main drawbacks of the encapsulation approach are: a) fast and uncontrolled release
of drugs, possibly before reaching the targeted cells; moreover, drugencapsulated dendrimers could be unstable in different buffers and in
plasma, b) critical clinical translation. This very important point was
outlined and analyzed by M. A. Mintzer and M. W. Grinstaff [17].
Very interestingly, in a recent review, R. Haag et al. analyzed the
current status of nanomedicines such as advanced forms of liposomes,
PEG based nanocarriers and dendritic polymer conjugates targeting
cancer and inammation domains. Based on the main biophysical requirements of nanoparticles for in vivo biocompatibility assessments,
implications and rationale for effective nanodelivery systems have
been presented and analyzed in-depth [12].
Nowadays, the preferred route for the delivery of drugs using
dendrimers is the intravenous route. The immense potential of
dendrimers in medicinal chemistry results, for instance, in their route
of administration expansion versus conventional route as intravenous
[37]. Thus, recently, other interesting routes have been portrayed such
as ocular, transdermal, oral, nasal, pulmonary and intravaginal. Table 2
presents an overview of the intravenous, intratumoral, intraperitoneal,
ocular, transdermal, and oral routes for administration of dendrimers.
Hereunder, we describe in more detail the main examples related to
the use of dendrimers (dendrimerdrug complexes or conjugates)
using non-classical routes of administration such as ocular, transdermal,
oral, nasal and pulmonary.

4.1. Dendrimers in ocular drug molecule delivery

The human eye can be anatomically divided into two segments:
anterior (cornea, iris, ciliary body, and lens) and posterior (vitreous
humor, retina, choroid, and optic nerve). Various drugs have been
developed to treat many eye disorders such as uveitis (which is the
inammation of the middle layer of the eye, termed the uvea), conjunctivitis and glaucoma. Systematic administration of ophthalmic
drugs by oral or intravenous ways cured some anterior segment diseases in clinical trials through reaching the retino-choroidal tissue,
but few amounts of administrated drugs can get across the cornea,
conjunctiva and sclera due to barriers between the blood and the
eye tissues. Consequently, accumulation of these drugs in different
tissues resulted in unwanted side effects. The main challenge in ocular drug delivery is to improve the bioavailability of ophthalmic drugs,
and consequently their residence time. Drug molecules can be mixed
with several inactive substances (polymeric formulation) to make a
liquid or gel, which can be applied to the eye. Several side effects
have been observed including blurred vision and irritation. Liquid eye
drops are relatively easy to use but may run off the eye too quickly to
be well absorbed. Ideal ocular drug-delivery systems should be sterile,
non-irritating, isotonic and biocompatible. Importantly, the eye drop
route is a non invasive route of administration, but this route is not
highly effective for eye disease such as age-related macular degeneration, diabetic retinophathy, uveitis and retinis (glaucoma) which are
located in the posterior segment of the eye [68].
Lucratively, various nanosized carriers in ocular drug delivery
were described such as micro/nano-suspensions, liposome, noisome, nanoparticles, dendrimers, ocular inserts, implants, hydrogels
and prodrug approaches and were reviewed [69]. In addition,
polyoxyethylated nonionic surfactants in topical ocular drug delivery have been also described [70].
Dendrimers are useful for the delivery of drugs to the eyes as ophthalmic vehicles. The main advantage of using dendrimers as nanocarriers is their strong aptitude to improve the ophthalmic drug effects due to the eye penetration enhancement through the cornea,
and the sustained release of drugs. Up to now, several studies have
been carried out with PAMAM, PPI and lipid-lysine dendrimers, and
both approaches were used: encapsulation, conjugation and electrostatic interactions. One of the main advantages of dendrimers as
ocular drug delivery systems is their ability to release drugs in the
posterior segment of the eye (vide supra).
In early studies, Vandamme and Brobeck investigated the development of surface-modied PAMAM dendrimers [71]. Thus, G1.5,
G2-OH, G4-OH PAMAM dendrimers (in aqueous solution) signicantly
improved the residence time and activities of both hostguests (encapsulation) pilocarpine nitrate (parasympathomimetic alkaloid) and
tropicamide (pyridinylmethyl-benzeneacetamide) in miotic and

Please cite this article as: S. Mignani, et al., Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems:
A concise overview, Adv. Drug Deliv. Rev. (2013),

S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx

Table 2
Intravenous, intratumoral, intraperitoneal, ocular, transdermal, and oral routes for administration of dendrimers (non-exhaustive list of examples).
Routes of

Dendrimer types

Drug molecules

Therapeutic eld



Folic acid-PAMAM
EGF-PAMAM (interperitoneal and intratumoral)



Polyester bow-tie dendrimer
Polyester bow-tie dendrimer
Polylysine dendrimers
Cyclodextrin(-CDE conjugate)-PAMAM
Mannosylated-PAMAM- -cyclodextrin
cRGD peptide coated PAMAM
Polylysine dendrimers


Cancer (boron neutron capture
Cancer and pharmacokinetic studies
Cancer and biodistribution studies
Cancer and biodistribution studies
Liver targeting
Murine lung tissue targeting
Spleen, liver and kidney targeting
Kidney targeting


Anti-EGF receptor monoclonal antibody

Intraperitoneal Monoclonal antibody immunoconjugate
5-Aminolaevulinic acid
Folic acid-PAMAM



Primaquine phosphate
Gd(III) (macromolecular imaging agent)
Tubulysin analog
Pilocarpine nitrate and tropicamide

Phosphorus dendrimers
Lysine dendrimers

Glucosamine and glucosamine-6-sulfate

ODN-1 oligonucleotide
Tamsulosin hydrochloride
CAT reporter transgene
Ketoprofen and Diunisal



Fatty acid and phospholipid-PAMAM

Riboavin (B2 vitamin)

5-Aminosalicylic acid


SN-38 (active metabolite of irinotecan (CPT-11))


5(6)-Carboxyuorescein, uorescein
isothiocyanate-dextran, calcitonin and insulin

mydriatic activity tests, respectively. The tests were performed on rabbit

eyes using topical route (eye drops). These dendrimers showed at least
comparable potency and bioavailability than the 0.2% w/v bioadhesive
polymer Carbopo solution or phosphate solution. The improvements
of ocular delivery efciency result of the slow release of these drugs encapsulated in the dendrimer's void spaces, and of several parameters of
dendrimers such as size, molecular weight and charge.
Shaunak and co-workers emphasized that G3.5-CO2H PAMAMglucosamine (DG) and glucosamine-6-sulfate (DGS) conjugated
dendrimers displayed together potent activities in a validated and clinically relevant wound healing glaucoma model in rabbit. DG is an
immune-modulator (giving pro-inammatory response) and DGS an
anti-angiogenic compound, both were administrated by subconjunctival

Liver targeting
Effective transfection agents
Bain cancer
Inhibition of tumor growth and
Cancer (boron neutron capture
Cancer (boron neutron capture
Photodynamic therapy
Cancer (internal radiation therapy)
Miotic activity and mydriatic
Immunology and angiogenese
Articial biomaterial
Ocular neovascularisation
1A-adrenoceptor antagonist
Skin gene transfections
Improve oral bioavailability and
Hyperproliferative skin disease
(e.g. psoriasis, vitiligo )
Dermatological indication
Improve oral bioavailability
Improve oral bioavailability
Improve oral bioavailability and
Improve oral bioavailability and
Improve oral bioavailability


injection. Interestingly, minimal scar tissue formation was observed

versus placebo-treated animals, and hematological, biochemical toxicity
or microbial infections were found in all animals [72].
It is well known that corneal blindness affecting millions of
patients worldwide is often treatable by replacing the diseased cornea with that of a human donor (allograft cornea transplantation).
Nevertheless, several challenges amounted such as patient waiting
lists which are dramatically growing. Many patients are unsuitable
for this treatment or simply do not have donor tissue available, safety
of donor tissue, lack of corneal tissue, etc. Articial corneas offer
opportunities to solve these issues.
Then, Duan and Sheardown have designated G2 PPI dendrimer which
was covalently conjugated to collagen [73]. This articial biomaterial

Please cite this article as: S. Mignani, et al., Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems:
A concise overview, Adv. Drug Deliv. Rev. (2013),

S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx

displayed very interesting properties versus natural human cornea, EDC

and glutaraldehyde cross-linked collagen, such as mechanical properties,
adhesion ability, optical transparency, and glucose permeability. Moreover, G2 PPI dendrimer showed no cell toxicity. The same authors
described the synthesis of cell adhesion peptide (YIGSR) modied PPI
bearing conjugated collagen. These peptide modied collagen gels
were used as corneal tissue engineering scaffolds, and promoted the adhesion and proliferation of human corneal epithelial cells as well as neuritis extension from the dorsal root ganglia.
Recently, one of us (J-P. Majoral), described the biological activity
of water soluble G1-2-CO2H phosphorus-containing dendrimers
complexed with carteolol which is an ocular anti-hypertensive drug
(-blocker) for the treatment of glaucoma. These dendrimers, in solution in milliQ water, have been instilled in the eyes of rabbits. The
quantity of released carteolol from dendrimers, that penetrate inside
the eyes (aqueous humor), is larger than carteolol alone, highlighting
good biocompatibility of these phosphorus dendrimers. In this study,
no irritation was observed [74].
Very recently also, dendrimer-uocinolone acetonide-G4-OH
PAMAM conjugate has been prepared for attenuation of neuroinammation in the retina. Intravitreal administration of this nanodevice induced in vivo efcacy against retinal degeneration in two rat
models, and arrest of retinal degeneration was fully observed. In fact
dendrimer-uocinolone conjugate is localized within activated outer
retinal microglia, but not in the retina of healthy controls. The conjugate
released uocinolone was observed in a sustained manner over 90 days
Diseases complicated by vascular leakage and/or neovascularization
in the eye are responsible for the vast majority of visual morbidity and
blindness in developed countries. It is known that suppression of ocular
neovascularization had been done using siRNA targeting vascular endothelial growth factor (VEGF) receptor 1. Consequently, VEGF plays an
important role in ocular neovascularization. Wimmer et al. pointed
out that lipid-lysine dendrimers improved the delivery of the sense oligonucleotide ODN-1 into the nuclei of retinal cells and induced a reduction in VEGF expression. Based on in vivo studies, dendrimer-ODN-1
complex (electrostatic interactions) signicantly reduced choroidal
neovascularisation in rat model. The dendrimer-ODN-1 complex was
injected into the vitreous of both eyes separately and remained active
for up to two months after injection. No major toxicity was observed
4.2. Dendrimer mediated transdermal drug delivery
Very selective transdermal drug delivery route is a noninvasive
method of administering drugs through the skin for both local and
systemic therapies [77]. The transdermal revolution has started as a
novel epoch, which allowed the pharmaceutical industry to treat,
for instance, bone diseases [78] and local immunosuppression using
cyclosporine A-loaded nanobers for cell-based therapy [79]. However, tremendous challenges in achieving effective transdermal delivery
of bioactives remain as for instance the penetration through the stratum corneum barrier, which is the outermost cover of the skin.
Indeed, skin represents the largest (12 m 2 for absorption) and
most easily accessible organ of the body, and the most successful
non-oral systemic drug delivery system [77].
Several marketed therapeutic agents such as scopolamine, estradiol, nicotine, insulin, lidocaine, and testosterone are used in medicine
via this approach within a wide variety of therapeutic indications including hypertension, angina, female menopause, local pain control,
nicotine dependence, etc. [77] Transdermal drug delivery system is
not suited for all drugs nor is it justied for all therapies. In particular,
the stratum corneum shows protective barrier effect against compounds with molecular weights over 500 Da and/or with logPo/PBS
less than 1 or greater than 3 [77]. LogPo/PBS represents the partition
coefcient 1-octanol versus PBS (phosphate buffered saline).

A very interesting review written by A. Naik et al. [77] highlights

the main physicochemical parameters for both passive and iontophoretic transdermal delivery approaches. The main ideal limits are
the following (passive versus iontophoretic): 1) aqueous solubility:
>1 mg/ml for both approaches, 2) lipophilicity: 10 bKo/w b1000 for
the passive approach, 3) molecular weight: b500 Da for the passive
approach, 4) melting point: b 200 C for the passive approach, 5) dose deliverable: b 10 mg/day vs 2050 mg/day (MWb 1000 Da), 25 mg/day
(1000 Dab MWb 5000 Da) and b 1 mg/day for MW >5000 Da and
6) charge: pKa pI b4 (for acids) or >7.4 (for bases). Ko/w represents oil
water partition coefcient, whereas pKa and Pi represent ionization constant and isoelectric point, respectively.
In contrast to oral and intravenous administrations, transdermal
drug release presents some major advantages: a) it maintains quite
constantly (prolonged/sustained delivery system) the low concentration of the administered drug in the blood thus avoiding its potential
toxicity (absence of high peaks), b) it allows the simplication of the
dosing schedule and the high exibility of use, c) it permits bypassing
of the hepatic rst-pass metabolism effect in the gastrointestinal tract
for drugs with poor oral bioavalability, and d) it improves patient
compliance thus avoiding frequent administration [77]. However,
the slow rate of transdermal drug delivery permeation is one of its
major limitations due to the presence of the skin's intrinsic layer
barrier properties (tortuous lipoidal diffusion pathway and multiple
lipid layers) of stratum corneum biomembrane against exogenous
molecules [77]. Skin irritation and high manufacturing costs can be
also mentioned as drawbacks.
To aid dermal passive absorption, various transdermal penetration
enhancers (CPEs) based on chemical and physical approaches
were applied. Chemical penetration enhancers are present in a large
number of transdermal, dermatological, and cosmetic products, and
use diverse compounds such as sulfoxides or analogs, pyrrolidones,
fatty acids essential oil, terpenes and terpenoids, oxazolidinones,
etc. The other delivery systems are gel, patch, and physical enhancers
such as iontophoresis, electroporation and ultrasound [80]. In addition, different nanoparticle types were also described as transdermal
drug delivery systems such as polysaccharides [81] and dendrimers
(vide infra).
To the best of our knowledge, only PAMAM dendrimers and dendritic PEGylated polyglycerol amine have been used for transdermal
delivery of bioactive molecules. Co-treatment or pre-treatment techniques have been carried out to deliver these bioactives using different vehicles such as water, chloroform, chloroformwater mixture,
isopropyl myristate (IPM) or octanol/water emulsion. Three different
possible mechanisms were, very recently reviewed and discussed by
Y. Zhao et al. [82]. The rst one involved dendrimers which act as
drug release modiers for which the biological activity of the drug
is related to the drug concentration in the vehicle. The drug is encapsulated in the dendrimer, and the dendrimer poorly penetrates the SC
(stratum corneum) by itself. The drug must be released from the
dendrimer into the vehicle prior to further penetrating/partitioning
into the SC. The high level of the free drug in the vehicle boosts the
driving force of drug permeation. The free drug ux increases with
dendrimer concentration. The second possible mechanism implied a
vehicle-dependent penetration enhancement. This approach used
potent skin penetration enhancers such as IPM acting as stratum
corneum lipids. The presence of this skin penetration enhancer improved the dendrimerdrug complex skin penetration. Free drug skin
penetration results of synergitic effect of the lipid behaviors of vehicle
and dendrimer. Moreover, pre-treatment enhances drug skin diffusivity
versus skin co-treatment. The unloaded dendrimers in the SC can function as a depot and increase the solubility of drugs in the SC. The last
mechanism concerned dendrimer skin penetration via hair follicles on
the skin's surface (0.1%). To the best of our knowledge, no report has
been published showing the skin penetration by dendrimer using this
route. Up to now, only polystyrene nanoparticles have demonstrated

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A concise overview, Adv. Drug Deliv. Rev. (2013),

S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx

their capability to penetrate the skin through the follicular route. Fig. 3
shows a schematic illustration of the three potential mechanisms of
drug penetration in the skin using dendrimers.
Remarkably, in two very interesting articles, P. Perumal et al. [83,84]
pointed out the importance of the physicochemical properties of
dendrimers per se in the control of their skin membrane permeation.
Recently, a very interesting additional systematic study published by
S. Hong and coworkers [85], strongly sustained and completed the previous conclusions submitted by P. Perumal et al., and very helpfully,
showed that 1-octanol/PBS partition coefcient can be manipulated as
a predictor of skin permeation. The main goal of this study was to
fully investigate the effects of generation PAMAM dendrimer size, molecular weight, surface charge and hydrophobicity as key parameters
for skin penetration (Table 3). All these parameters (surface charge,
molecular weight) dened ideal limits based on understanding of the
interaction between skin membrane layers and surface-engineered
dendrimers, and can be used to design dendrimer-based nanocarriers
for drug delivery to skin.
In another similar study, P. Perumal et al. [86] showed the identical ranking order, than PAMAM dendrimers alone, of pig skin permeation enhancement of the hydrophilic drug 5-uorouracil (5-FU)
using PAMAM dendrimers as enhancers with IPM as vehicle, and
pre-treatment approach: G4-NH2 > G4-OH > G3.5-CO2H. 5-FU is a
hydrophilic drug (logP = 0.89) showing poor permeability through
the skin. 5-FU is currently used in the treatment of psoriasis, premalignant and malignant skin diseases. In another work, the same
authors investigated the in vitro transdermal ability of G4-PAMAM


dendrimers in porcine ear skin permeation of 5-uorouracil (5-FU).

In this study, three different vehicles were used including phosphate
buffer (PB), mineral oil (MO) and IPM. Pre-treatment with dendrimers
increased permeability coefcient of 5-FU ~2-4-folds in the lipophilic
vehicles MO and IPM, but not in PB (Fig. 4). The same conclusion was
observed in co-treatment. Notably, the decrease in skin resistance is
directly correlated with the enhancement in skin penetration of 5-FU.
The transdermal drug permeability coefcient was inversely proportional
to the molecular weight of the dendrimer, suggesting that small PAMAM
dendrimers are the most effective ones.
Hereafter, among the quite few reports, we highlight the most
relevant studies related to skin permeation with dendrimers. Simultaneous different studies done about dendrimeric architectures for
both transdermal and oral drug delivery (vide infra) have demonstrated that dendrimers take up both paracellular and transcellular
routes for crossing the epithelial barrier of the cells, and set up a
supplementary itinerary for accessing systemic circulation [87].
In early studies, Wang and coworkers emphasized the utilization of
efcient pre-treatment transdermal drug delivery system based on
polyhydroxyalkanoate (PHA) matrix and G3-PAMAM dendrimer. PHA
was a mixture of 3-hydroxyhexanoic acid (8%) and 3-hydroxyoctanoic
acid (92%). Tamsulosin hydrochloride, a charged compound (selective
1A-adrenoceptor antagonist) which cannot permeate the stratum
corneum showed good transdermal penetration efciency for 24 h
when administered with PHA coadministrated with G3-PAMAM in
vitro in snake skin (Python reticulates) model (15.7 g/cm2/d for PHA
versus 24 g/cm2/d for PAMAM dendrimers containing PHA matrices).

Vehicle: skin
penetration enhancers


Rapid drug


Drug solubilisation
in the vehicle

( stratum
Drug release

Drug release

( viable epidermis)

( dermis)

Fig. 3. Schematic illustration of the three possible dendrimer-mediated drug delivery approaches to the skin.
Adapted from Y. Zhao et al., see Ref. [82]).

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A concise overview, Adv. Drug Deliv. Rev. (2013),

S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx

Table 3
Relationships of structure-skin permeability of PAMAM dendrimers.
P. Perumal et al. [83,84]

S. Hong et al. [85]

Vehicle: water
PAMAM dendrimers in water
Surface charge modications:
Cationic dendrimer (NH3+) showed higher skin permeation than
neutral (OH, weak ionization of the surface) and anionic (CO2H):
G4-NH3+ >G4-OH > G3.5-CO2H (pH7.4)

Vehicle: water
PAMAM dendrimers in 70% ethanol solution
Surface charge modicationsa:
Neutral G2-dendrimer (NHAc) showed higher skin permeation than G2-anionic
dendrimer (CO-CH2-CH2-CO2H) and for G2-cationic dendrimer (NH3+):
G2 (NHAc) > G2 (CO-CH2-CH2-CO2H) > G2 (NH3+) (pH7.4)
Hydrophobic modications:
Skin deposition and retention ranking order: oleic acid-G2-dendrimer
(OA2.7) > Oleic acid-G2-dendrimer (OA2.3) > G2 (NHAc) > G2
(NH3+) > G2 (CO-CH2-CH2-CO2H)
Conjugation of oleic acid (OA) to G2-PAMAM dendrimers increases their LogPo/PBS,
resulting in increased skin absorption and retention
LogPo/PBS: 1.4 [oleic acid-G2-dendrimer (OA2.7)]> 1.2 [Oleic acid-G2-dendrimer
(OA2.3)] > 0.9 [G2 (NH3+)] > 1 [G2 (NHAc] > 1.3 [G2 (CO-CH2-CH2-CO2H)]

Cationic skin penetration increased linearly with increase in treatment time

Ionotophoresis skin penetration enhancer increase the skin penetration
of cationic and neutral dendrimers
Size modications:
Passive and iontophoretic skin penetration of cationic dendrimers
was inversely related to their molecular weight:
G2 >G3 > G4 > G5 > G6

Size modications:
G2-cationic dendrimer (NH3+) showed higher skin penetration than G4-cationic dendrimer:
G2 > G4
G2 (NH3+) was internalized into the individual cells in both epidermal and dermal layers
(SC, VE and DE) versus G2 (NHAc) and G2 (CO-CH2-CH2-CO2H)

G2-NH2: 15 NH2 groups and 1 NHRITC group, G2-NHAc: 15 NHAc groups and 1 NHRITC group, G2-(CO-CH2-CH2-CO2H): 15 CO-CH2-CH2-CO2H groups and 1
NHRITC group, G2-(OA2.7): 2.7 OA groups, 1 NHRITC group and 12.3 NH2 groups, G2-(OA2.3): 2.3 OA groups, 1 NHRITC group and 12.7 NH2 groups); NITC: rhodamine
B isothiocyanate as a uorescent probe.

The authors concluded that PHA-dendrimer matrix achieved clinical

objective, and is a very useful material for clinical transdermal drug delivery system [88]. Then, taking this into consideration, the same authors studied the mechanism of the enhancement effect of G2.5-and
G3-PAMAM dendrimers [89]. Only cationic dendrimers increased the
skin penetration of tamsulosin hydrochloride. Interestingly, based on
X-ray analysis, the authors found that tamsulosin crystals have highly
ordered orientation in the dendrimer-PHA matrix promoting drug release in contrario to drug crystallization effect in other transdermal
drug delivery system [90].
Another example has been described by the same team regarding the
transdermal drug delivery of both ketoprofen and clonidine through
snake skin from PHA matrix by co-treatment using G3-PAMAM and
G2.5-PAMAM dendrimers and chloroformmethanol mixture as vehicle.
No enhancement effect for the two drugs has been observed [91].
J. R. Baker and co-workers described the transdermal ability for
the delivery of gene, in a mice transfection assay, using solid support
collagen-phosphatidyl glycerol membranes in the presence of PAMAM
dendrimers [92]. In the absence of PAMAM dendrimers, no signicant
expression of chloramphenicol acetyltransferase (CAT) reporter was
observed. Based on membrane-mediated gene transfection, the CAT
expression reached 50250 pg/mg of the skin homogenates in the presence of dendrimers. Keratinocytes or dermal broblasts are the primary
types of transfected cells. Consequently, these studies provide support
for the use of transdermal diffusion system for in vitro and in vivo transfection of skin cells.
Non-steroidal anti-inammatory drugs (NSAIDs) are the most
frequently used drugs in the world. A representative example is indomethacin which is a hydrophobic drug (logP ~ 4.2). Chauhan et al.
reported that G4-NH2, G4-OH and G-4.5-CO2H-PAMAM dendrimers
enhanced indomethacin skin penetration in vitro in rat skin membrane model using co-treatment and water as vehicle [93]. Interestingly, the steady-state ux of indomethacin increased linearly with
an increase in dendrimer concentration in the formulations versus
the plain drug, despite the non-linear increase in solubility. In addition, based on this study, in vivo pharmacokinetic and pharmacodynamic assays in rats showed that the blood concentration of
indomethacine, applied to shaved abdominal skin of rats, highly

increased with PAMAM dendrimers versus pure indomethacin suspension. The [AUC]024h of G4-NH2 and G4-OH formulations are
higher than pure drug with a ratio of 2.27 times and 1.95 folds
respectively. The G4-PAMAM dendrimers maintained the effective indomethacin concentration in the blood for 24 h. Low improvement
was observed with G-4.5-PAMAM dendrimer formulation.
Another in vivo study has been performed by Y. Chen. et al. regarding the transdermal delivery of both ketoprofen and diunisal as
model drugs [94]. From a general point of view, oral administration
of NSAIDs is effective, but their clinical use is often limited by several
adverse side effects such as adverse gastrointestinal and renal events,
and hypersensitivity reactions [95]. Consequently, transdermal
administration represents an interesting alternative to these side
effects. Thus, in vitro permeation studies using excised rat skin
model indicated that PAMAM dendrimer suspension formulations
in water highly enhanced, by as much as 4-fold, the accumulative permeated amount of both drugs after 24 h, in comparison with drug
suspensions without PAMAM dendrimers. The NSAIDs fraction in
the complex is estimated at 39% (w/w) and 27% (w/w) for ketoprofen
and diunisal, respectively. Improvement of the water-solubility of
these two drugs by their respective complexation with PAMAM
dendrimers should explain the potency improvement. Interestingly,
in in vivo antinociceptive studies in rats (acetic acid-induced writhing
model) a prolonged pharmacodynamic prole was observed after
transdermal administration (abdominal skin, 2 mg of each NSAID in
100 L of formulation), for both NSAIDs-PAMAM dendrimer complexes. Analysis of blood drug levels showed that the bioavailability
was 2.73 times higher for the ketoprofen-PAMAM dendrimer complex and 2.48 times higher for the diunisal-PAMAM dendrimer complex, respectively, versus pure drug suspensions. Going into more
detail, similar tmax (54 h) were observed for ketoprofendendrimer
complex, plain ketoprofen, diunisaldendrimer complex and plain
diunisal, improvement of ~ 3 times of the Cmax for the NSAID
dendrimer complexes in comparison to plain NSAIDs, and ~ 3 times
increase of the [AUC]08/12 h for the NSAIDdendrimer complexes in
comparison to plain NSAIDs. Undeniably, this work opens the door
to the development of this new transdermal drug formulation using
dendrimers as skin penetration enhancers.

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A concise overview, Adv. Drug Deliv. Rev. (2013),


S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx



( stratum

( viable epidermis)

( dermis)

Fig. 4. Schematic representation of the internalization mode of PAMAM dendrimers with different surface attachments.
Adapted from Y. Yang et al., see Ref. [85]).

S. Wolowiec et al. reported the use of G2.5-CO2H, G3.5-CO2H,

G3-NH2 and G4-NH2 PAMAM dendrimers to solubilize in water and
to host 8-methoxypsiralene (8-MOP). 8-MOP is a photosensitizer for
PUVA therapy (treatment of hyperproliferative skin disease like psoriasis, vitiligo, etc. by UVA irradiation after oral or topical administration of psoralene). The higher water solubilization was obtained with
G3- and G4-PAMAM dendrimers [96]. The maximum weight% load of
8-methoxypsiralene in full-generation dendrimers G3 and G4 were
9.4% and 10.4% respectively. Any precipitation of the hostguest compound was observed after dilution of the concentrated solutions with
water. The co-treatment of 3:1 hostguest complexes with G3- and
G4-dendrimers diffused slowly through both polyvinyldiuoride and
pig ear skin membranes, when released from o/w (octanol/water)
emulsion, with value of time of 10% transfer (0.1) of ~6.5 and ~9,
Also, in a recent paper, S. Wolowiec et al. reported the use of
G2-4-NH2 and G2.5-3.5-CO2H PAMAM dendrimers, to weakly enhance
the solubility (~710 folds) of riboavin (B2 vitamin) in methanol
according to the following order: G2 G2.5>G3G3.5>G4 [97]. The
in vitro transdermal ability of dendrimer-B2 complexes, from o/w emulsions, was studied in pig ear skin membrane model by co-treatment. The
diffusion of B2, in pig ear skin membrane permeation model, afforded
the following ranking: G2>G3G2.5>G3.5>G4 (none). The best permeation enhancer for B2 was hydrophilic, small-sized (29 hydrodynamic diameter) G2-PAMAM dendrimer. The authors suggested that,
reasonably, the multicomponent tissue of pig ear skin including fatty
components acts itself as slight solubilizer of riboavin.
Another representative example is the furfural permeation enhancement through rat skin model using G5-PAMAM dendrimers in water as
vehicle by co- and pre-treatment [98].
K. D. Kramer and co-workers emphasized in a recent paper the
skin penetration enhancement of Nile red incorporated in dendritic
core-multishell as nanotransporter (CMS) [99]. Nile red is a lipophilic
stain which is commonly used for the detection of intracellular
lipid droplets by uorescence microscopy and ow cytouorometry.
CMS was built from hyperbranched polymeric cores composed of

polyglycerol surrounded by a double-layered shell consisting of a

C18-alkyl chain and PEG chains. Using co-treatment technique, dye
amounts increased eight-fold in the SC surface and thirteen-fold in the
epidermis compared to the cream (Nile red cream 0.004%). Water was
the vehicle used. Viable primary human keratinocytes showed an
internalization of the nanocarrier.
4.3. Dendrimers for oral drug release system
Despite strong advances in the injectable and transdermal routes
of administration, the non-invasive oral drug delivery system remains
well ahead of the pack as the dominant delivery route.
To sum up, the main signicant advantages of oral drug molecule
delivery are: 1) low total dose, 2) low gastrointestinal side effects,
3) reduced dosing frequency (dosing schedules), 4) good patient acceptance and compliance, 5) less uctuation at plasma drug levels,
6) more uniform drug effect, 7) improved efcacy/safety ratio and
8) low cost-effectiveness, versus the main defects which include:
1) dose regiment, 2) immediate drug release causing toxicity in practice, 3) reduced potential for accurate dose adjustment, 4) low drug
solubility in aqueous solutions and low penetration across intestinal
membranes issues and 5) stability problem [100]. Several attractive
strategies to overcome oral drug delivery issues (vide supra) such as absorption and distribution have been described focused on the development of different systems in which drugs are loaded into oral drug
carriers [101]. These systems are strongly related to physicochemical
properties of macromolecular carriers. Some examples of nanocarriers
used for oral drug delivery applications include micelles, liposomes,
nanoemulsions, polymer therapeutics, dendrimers, etc. The main results are the improvement of 1) drug solubility inducing good drug's
pharmacokinetic/pharmacodynamic proles due to sustained drug
concentration within the therapeutic range at the injured regions and
2) therapeutic index and the decrease of toxicity compared with free
drug [102].
Both dendrimer conjugating or encapsulating low-penetrating drug
molecules can easily penetrate through intestinal membranes such as

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the epithelial barrier of the intestine enhancing their oral absorption.

Thus, designed highly water-soluble and biocompatible dendrimers
have been shown to be able to improve important drug properties
such as solubility of orally administrated drugs and their stability in biological environments. In addition, prolonged circulation half-life, increased concentration at the site action and decreased non-specic
toxicity of loaded-drugs were highlighted [103]. Importantly, several
studies showed the uptake of dendrimers through the lymphoid tissue
in the small intestine but not in the large intestine. These interesting results reinforced the use of dendrimers to enhance the absorption of
low-penetration drugs in the small intestine tissue [104].
In an early study, D'Emanuele and colleagues described the preparation of G3-NH2 and G3-Lauryl-PAMAM dendrimers conjugating
propranolol which is a well-known competitive, but nonselective,
-adrenergic blocking agent that is used for treating high blood pressure, heart pain such as angina and abnormal rhythms of the heart
[105]. The aim of this interesting study was to evaluate the effects
on the transport of propranolol across monolayers of the human
colon adenocarcinoma cell line named Caco-2. Propranolol is a poorly
soluble drug and substrate of the P-glycoprotein (P-gp) efux transporter. The authors demonstrated that these dendrimers both well
solubilized propanolol and signicantly evaded P-gp efux effect. Thus,
interestingly, the apical (A) to basolateral (B) apparent permeability coefcient, Papp, of propranolol was enhanced following conjugation to G3
dendrimers or lauroyl-G3 dendrimers. In addition, they also showed that
the AB Papp of propranolol conjugates was reduced in the presence of
the endocytosis inhibitor such as colchicine, suggesting that the enhancement mechanism involves endocytosis-mediated transepithelial
transport. Very interestingly, the A B Papp of conjugated propranolol
was not altered in the presence of the P-gp inhibitor such as cyclosporin
A. Consequently, the conjugation of drug to dendrimer allows the
bypassing of the efux transporter. In addition, the decrease of cytotoxicity of PAMAM dendrimer conjugates, against Caco-2 cell lines, has
been observed with lipid chaindrugdendrimer conjugates versus
non-modied dendrimer. Mechanistic studies, based on transepithelial
electrical resistance (TEER) measurements, conrmed that the enhancement of the permeability through cell monolayer results in
the opening of the tight junctions by lipid chaindrugdendrimer
In in vivo studies, Florence et al. investigated the oral absorption
(gavage) from rats (female Sprague Dawley) of G4-lysine dendrimer
bearing 16 C12 linear alkyl chains on the surface (molecular weight:
6300, clogPoctanol/water ~ 1.24) [106]. Oral administration of G4dendrimer (single dose of 14 mg/kg), after 6 h following drug administration, showed that the maximum levels of dendrimer observed
were 15%, 5% and 3% in small intestine, large intestine and blood,
respectively. Only 1.5% reached the liver, 0.1% the spleen and 0.5%
the kidneys. In a parallel study, using a higher dose of dendrimer
(28 mg/kg), after 3 h administration, ~ 14% was absorbed through
Peyer's patches and small intestine enterocytes, versus 0.3% which
was absorbed via Peyer's patches, and 4% via large intestine
enterocytes after 12 h. The total percentage of dendrimer absorbed
through Peyer's patches, in the small intestine after 3 and 24 h, was
greater than through normal enterocytes, but the opposite was observed in the large intestine. Interestingly, the authors compared the
absorption of PAMAM dendrimers with 503000 nm size polystyrene
particles. They highlighted that the levels of uptake and translocation
from dendrimers are lower than those exhibited by 50 nm polystyrene
particles, suggesting that there is an optimum size for nanoparticulate
uptake by the gut intestine.
N. K. Jain et al. reported the stability as well in vivo studies of
5-uorouracil (5-FU) entrapped in PAMAM dendrimer [107].
Wiwattanapatapee et al. designated and evaluated watersoluble G3-PAMAM dendrimer conjugates for colonic delivery of
5-aminosalicylic acid (5-ASA [108]). 5-ASA was grafted to the
dendrimer using two different spacers containing either an azo-bond:


p-aminobenzoic acid (PABA) or a p-aminohippuric acid (PAH). Incubation of these PAMAM dendrimer conjugates with rat homogenate
contents released 5-ASA with 45.6 and 57.0% of the dose after 24 h, respectively, while in the small intestine the release of 5-ASA, from both
dendrimer conjugates, was lower, with a percentage average of ~6%
after 12 h. In addition, no 5-ASA was detected from the incubation of
these dendrimer conjugates with the homogenate of the stomach or
phosphate buffer, pH 1.2 and 6.8. The authors suggested that the drug
release from the dendrimer conjugate occurred through the cleavage
of both amide bonds (between dendrimer and spacer) and azo bond
(between spacer and 5-ASA). The last cleavage resulted in the cleavage
of the azo bond by azoreductase enzyme in the colon. Consequently,
these PAMAM dendrimer conjugates can be developed for use as
carriers for colon-specic drug delivery.
Prolonged delivery of ketoprofen-G5-PAMAM dendrimer complex
in in vitro and in vivo (oral administration) studies has been described
by Na et al. [109]. The in vitro release of ketoprofen from the drug
dendrimer complex is signicantly slower compared with plain
ketoprofen. Interestingly, in acetic acid induced writhing model in
Kumming mice, sustained pharmacodynamic behavior (anti-nociception
effect in acetic acid-induced writhing model) of ketoprofenPAMAM
dendrimer complex was observed after oral administration at the dose
of 10 mg/kg weights. Blood level studies were investigated, and
strengthened the prolonged release of ketoprofen from ketoprofen
PAMAM dendrimer complex. The main pharmacokinetic parameters
of plain ketoprofen versus ketoprofen-G5-PAMAM dendrimer complex
are the following: tmax (h): 0.5 vs 1; Cmax (g/ml): 48.31 vs 51.58;
[AUC]012 (g/ml/h): 137.23 vs 160.96.
Very interestingly, R. B. Kolhatkar et al. investigated the potential
application of G4-PAMAM dendrimer for improving the oral delivery
of SN-38. SN-38 is a potent topoisomerase I inhibitor and the active
metabolite of irinotecan hydrochloride (CPT-11) [110]. Stable and
water soluble complex between SN-38 and G4-PAMAM dendrimer
increased 10 folds the permeability across Caco-2 cell monolayers
and more than hundred folds in cellular uptake with respect to
plain drug.
Recently, the effects of G2-PAMAM dendrimer on the intestinal absorption of poorly absorbable drugs have been studied by an in situ closed
loop method in rats [111]. The model drugs are 5(6)-carboxyuorescein
(CF), uorescein isothiocyanate-dextran (FDs), calcitonin and insulin.
The absorption of CF, FD4 and calcitonin from the rat small intestine
was signicantly enhanced in the presence of PAMAM dendrimers. The
small intestinal absorption of CF was concentration and generation dependent, and the maximum effect was obtained in the presence of 0.5%
(w/v) of G2-PAMAM dendrimer. No effect was observed with FD10 and
insulin, and at G2-PAMAM dendrimer concentrations of 0.05% (w/v)
and 0.1% (w/v). Taken together, the increase of the small intestine absorption effects of G2-PAMAM dendrimer decreased as the molecular weight
of drug increased. This effect is dendrimer concentration dependent. Interestingly, G2-PAMAM dendrimer did not enhance the intestinal absorption of these drugs with different molecular weights in the large intestine.
A myriad of in vitro studies have been performed concerning the
transepithelial transport and toxicity of dendrimers, mainly PAMAM
dendrimers, and summarized in the S. Sadekar, H. Ghandehari [102],
and V. Gajbhiye et al. [17] reviews. Thus, the penetration of dendrimers
across epithelial barrier depends upon several important parameters
highlighted in Table 4.
4.4. Dendrimers for other controlled drug release systems
Other very interesting drug delivery systems using dendrimers
have been explored recently, and are highlighted below.
In addition to Vivagel (vide supra), in vitro intravaginal transport
and biodistribution of G4-PAMAM dendrimer has been also described
using intact fetal membrane (chorioamnion), and separated chorion
and amnion layers [116]. The dendrimer transport across all these

Please cite this article as: S. Mignani, et al., Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems:
A concise overview, Adv. Drug Deliv. Rev. (2013),


S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx

Table 4
Main factors inuencing the permeability of dendrimers across the epithelial barriers.
Dendrimer effects on oral

Studies and results


FITC labeled G0-4-PAMAM dendrimers against MDCKa cell lines. Permeability rank-order: G4 G1 ~ G0 > G3 >G2.
Nine fold permeability increase for conjugated mannitol with dendrimers was obtained versus plain drug.
Interaction and hole formation studies by G7-PAMAM dendrimers against KB and Ray2 cell membranes. G7-NH2
PAMAM dendrimers but not G5-NH2 or Ac-G5 dendrimers were observed to form holes. Cytotoxicity effects
were obtained with G5-NH2 but not with G5-Ac dendrimers in both cell lines.
Transport across adult rat intestine using in vitro everted rat intestinal sac model. Rank-order of serosal transfer rate:
anionic G5.5-PAMAM dendrimer >cationic G3-PAMAM and G4-PAMAM >anionic G2.5- and G3.5-PAMAM dendrimers.
These three anionic dendrimers have a single amino group.


Generation size



Surface charge
Permeability of G0-4-PAMAM dendrimers across MDCKa cell lines showed the following rank order: G4 G1 ~ G0 >G3 > G2.
This is due to the high positive charge which interacts with negative cell surface. Permeability of G0-4-PAMAM dendrimers
athwart Caco-2 cell monolayers.
G0-2-PAMAM dendrimers were non-toxic to the cells versus higher generations. Mannitol permeability increased with
generation size (BA direction > AB direction).



Incubation time
AB permeability of G2-PAMAM dendrimer, through Caco-2 monolayers, increased with amplied incubation times. Adsorptive
endocytosis contribution in transport mechanism has been proposed.


Permeability coefcients (Papp) of G2-PAMAM dendrimer depends upon concentration of dendrimers across MDCK.a
Internalization of G5-PAMAM dendrimer in Rat2 cell lines increased with the dendrimer concentration. No effect with
Ac-G5-PAMAM dendrimer
Uptake rate of cationic G3- and G4-PAMAM dendrimers increased with their concentration. No effect with anionic
G5.5-PAMAM dendrimer


Permeability of paclitaxel across Caco-2 cell monolayers was higher in BA direction as compared to AB direction whereas the
permeability of G2-PAMAM dendrimer was identical in both directions P-gp efux system does not affect dendrimer transport.


Improvement of the permeability coefcients (Papp), through Caco-2 cell monolayers, of mannitol in the presence of
simple dendrimers (G3-5-PAMAM dendrimers) which was more pronounced in the presence of lauryl conjugated
dendrimers. This lipid chain effect increased with the number of attached lipid chains.




Efux transporter

Surface modication

MadinDarby Canine Kidney (same permeability characteristics than Caco-2 cell lines).

three membranes was lower (b 3%) for G4-PAMAM dendrimer versus

G4-PAMAM dendrimer bearing conjugated uorescein (FITC) groups
on the surface (>49%). The permeability of FITC-G4-PAMAM dendrimer
was 7-fold higher than the permeability of G4-dendrimer through the
choriamnion membrane. Biodistribution studies showed that these
two dendrimers were largely present in interstitial spaces in the decidual stromal cells and chorionictrophoblast cells. Few amounts are present in nuclei (trophoblast and stromal cells). The authors suggested that
passive diffusion and paracellular transport are the major routes for
dendrimer transport.
In early studies, C. A. Lemere and coworkers described the
boosting effect with intranasal dendrimeric A1-15 (16 copies of
A1-15 on a lysine tree) but not A1-15 peptide affording immune
response following a single injection of A1-40/42 in heterozygous
APP-tg mice [117]. In addition, good in vivo nasal absorption, in rats,
of insulin and calcitonin using G3-PAMAM dendrimer was emphasized by A. Yamamoto et al. without any membrane damage to the
nasal tissues [118].
In vivo pulmonary delivery, in mice, of the corticosteroid derivative
methylprednisolone (MP), which was conjugated with G4-OH-PAMAM
dendrimer, showed good lung anti-inammation potency (associated
with asthma) [119]. Thus, MP-G4-PAMAM dendrimer at the dose of
5 mg/kg (on a drug basis) improved the airway delivery in a pulmonary
inammatory murine model based on an 11-fold enhancement of eosinophil lung accumulation following ve daily inhalation exposures of
sensitized mice to allergen ovalbumin. This study demonstrated that
MP-G4-PAMAM dendrimer enhances the ability of MP to decrease
allergen-induced inammation, probably by improving drug residence
time in the lung. Indeed, only 24% of a single dose of dendrimer delivered
to the peripheral lung is lost over a 3-day period.
Similarly, in vivo pulmonary absorption studies of insulin and
calcitonin in rats using G0-G3-PAMAM dendrimers were outlined by

A. Yamamoto et al. without any membrane damage to the respiratory

tissues (release of protein and activities of LDH) [120]. PAMAM
dendrimers increased the pulmonary absorption of both insulin and
calcitonin in rats. The absorption-enhancing effects were generation
dependent with the following rank: G3 > G2 > G1 > G0. In addition,
for the same generation, this effect is concentration dependent. Interestingly, the absorption-enhancing effects of the protein-PAMAM
dendrimers are linearly correlated with the positive charge of the
protein-PAMAM dendrimers which is determined by their zeta
EnoxaparinG2-(or G3)-PAMAM dendrimer complex is effective in
preventing deep vein thrombosis after pulmonary administration into
the lungs of anesthetized rats [121]. Enoxaparin is a low-molecular
weight heparin. Positively charged dendrimers increased the relative
bioavailability of enoxaparin by 40%, while a negatively charged
dendrimer had no effect. In addition, no adverse damage was observed
to the lungs.
To sum up, importantly, the pulmonary route of administration
represents a useful way to treat specic lung diseases such as chronic
inammatory disorders such as asthma. In this case, lung can be
considered as the drug target. Dendrimers represent powerful
nanocarriers to target regional lung deposition. Note that two very
interesting review papers have been written by T. C. Carvalho et al.
[122] and H. S. Choi et al. [123] on the inuence of particle size,
charge, coating, etc. on lung deposition and represent pedestal documents to build and optimize new nanocarriers for the delivery of bioactives through the inhalation route. In addition, recently, J. K-W.
Lam et al. reviewed the pulmonary delivery of therapeutic siRNA
using lipid-based delivery vectors (cationic lipoplexes and liposomes, PEGylated lipids, neutral lipids and lipids particles) and
polymer-based delivery vectors (synthetic polymer PEI, chitosan
and PLGA) [124].

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S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx

5. Conclusion
The choice of the route of administration related to delivery device
technologies remains the utmost important challenge regarding both
dosing, frequency of dosing, dose volume, number of treatments, etc. In
an ideal world, for chronic human diseases, a single pill administration,
one time, is currently a dream.
Pharmacokinetics (PK), exposure-response relationship, and the
PK/pharmacodynamic (PD) index are predictive of maximum therapeutic efcacy. Taken together, these ndings suggest the best route
of administration in order to maximize the therapeutic effect and
minimize the toxicity effects.
It is well known, that polymeric drug delivery systems can highly enhance bioavailabilities and therapeutic efcacies (versus the plain drug)
and decrease the side effects of drugs. In this direction, due to their tunable physico-chemical properties, bio-compatible dendrimers which
are unique in comparison with other classical nanoparticles represent
outstanding choice of nano-carriers of a large variety of drugs such as
small molecules, siRNA, antibodies, etc. Both, non noncovalent encapsulation or covalent attachment to dendrimer termini of various drugs
have been intensively pointed out.
Indeed signicant advances and innovations regarding the development of dendrimer platforms have been directed towards specic
organs, tissues, cells and various biological targets. To date, the main
ways of administration of dendrimers involve intravenous and, to a
lesser extent, intraperitoneal routes. Recently, other routes have
been described such as ocular, transdermal, oral, intranasal, pulmonary and intravaginal for the treatment of life-threatening diseases
requiring parenteral and non-parenteral routes of administration. To
the best of our knowledge, only dendrimer nanoparticles are suitable
for a large variety of administration routes from intravenous to intranasal routes through transdermal route. So, as research progresses, newer
applications of dendrimers to enlarge their therapeutic applications,
representing needle-free injection devices, are, for instance, the transdermal delivery to improve vaccine administration, or non-viral nanovectors for gene delivery of RNA-ligands such as siRNAs or miRNAs
alone or in combination. Currently, the antiepileptic drugs are commonly given orally, but the treatment of this disease strongly requires multiple types of formulations for both acute and chronic treatments [125].
Consequently, there is a signicant need for non-oral formulations of
antiepileptic drugs. Dendrimers may play this role.
[1] Committee on Drugs, Alternative routes of drug administration advantages and
disadvantages, Pediatrics 100 (1997) 143152(and references cited therein).
[2] Available at:
pdf (Accessed on November 2012).
[3] P. Philip Jevon, Chapter 12. Miscellaneous routes of medication administration,
medicines management, Wiley-HC2010.
[4] I. Chugh, N. Seth, A.C. Rana, S. Gupta, Oral sustained release drug delivery system:
an overview, Int. Res. J. Pharm. 3 (2012) 5761.
[5] R.A. Freitas, What is nanomedicine? Nanomed. Nanotechnol. Biol. Med. 1 (2005)
29(and references cited therein).
[6] S.D. Caruthers, S.A. Wickline, G.M. Lanza, Nanotechnological applications in medicine,
Curr. Opin. Biotechnol. 18 (2007) 2630(and references cited therein).
[7] J. Ogier, T. Arnauld, E. Doris, Recent advances in the eld of nanometric drug
carriers, Futur. Med. Chem. 1 (2009) 693711(and references cited therein).
[8] R. Duncan, R. Gaspar, Nanomedicine(s) under the microscope, Mol. Pharm. 8
(2011) 21012141(and references cited therein).
[9] L.K. Wolf, Personalizing nanomedicine, C&ENSeptember 26 2011, pp. 2932.
[10] A.K. Singh, M.A. Hahn, L.G. Gutwein, M.C. Rule, J.A. Knapik, B.M. Moudgil, S.R.
Grobmyer, S.C. Brown, Multi-dye theranostic nanoparticle platform for
bioimaging and cancer therapy, Int. J. Nanomedicine 7 (2012) 27392750(and
references cited therein).
[11] P.O. Gubbins, E. Anaissie, Overview of antifungal agents, Pharm. Pract. News
Spec. Ed. (2006) 5964.
[12] a) P.G. Tardi, N.L. Bomam, P.R. Cullis, Liposomal doxorubicin, J. Drug Target. 4
(1996) 129140;
b) J. Khandare, M. Calderon, N.M. Dagia, R. Haag, Multifunctional dendritic polymers
in nanomedicine: opportunities and challenges, Chem. Soc. Rev. 41 (2012)
28242848(and references cited therein).


[13] M.R. Green, G.M. Manikhas, S. Orlov, B. Afanasyev, A.M. Makhson, P. Bhar, M.J.
Hawkins, Abraxane, a novel Cremophor-free, albumin-bound particle form
of paclitaxel for the treatment of advanced non-small-cell lung cancer, Ann.
Oncol. 14 (2006) 12631268.
[14] J.M. Harris, R.B. Chess, The dawning era of polymer therapeutics, Rev. Drug
Discov. 2 (2003) 214221.
[15] Available at on November 2012).
[16] T.D. McCarthy, P. Karellas, S.A. Henderson, M. Giannis, D.F. O'Keefe, G. Heery, J.R.A.
Paull, B.R. Matthews, G. Holan, Dendrimers as drugs: discovery and preclinical and
clinical development of dendrimer-based microbicides for HIV and STI prevention,
Mol. Pharm. 2 (2005) 312318.
[17] a) V. Gajbhiye, V.K. Palanirajan, R. Tekade, N.K. Jain, Dendrimers as therapeutic agents: a systematic review, J. Pharm. Pharmacol. 61 (2009)
b) S. Gupta, R. Tyagi, V.S. Parmar, S.K. Sharma, R. Haag, Polyether based amphiphiles for delivery of active compounds, Polymer 53 (2012) 30533078(and
references cited therein);
c) M.A. Mintzer, M.W. Grinstaff, Biomedical applications of dendrimers: a tutorial,
Chem. Soc. Rev. 40 (2010) 173190;
d) D. Astruc, E. Boisselier, C. Omelas, Dendrimers designed for functions: from
physical, photophysical, and supramolecular properties to applications in
sensing, catalysis, molecular electronics, photonics and nanomedicine,
Chem. Soc. Rev. 110 (2010) 18571959;
e) A.R. Menjoge, R.M. Kannan, D.A. Tomalia, Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications, Drug
Discov. Today 15 (2010) 171185;
f) S. El Kazzouli, S. Mignani, M. Bousmina, J.-P. Majoral, Dendrimer therapeutics: covalent and ionic attachments, New J. Chem. 36 (2012) 227240;
g) J.B. Wolinsky, W. Mark, M. Grinstaff, Therapeutic and diagnostic applications of dendrimers for cancer treatment, Adv. Drug Deliv. Rev. 60 (2008)
h) R.K. Tekade, P.V. Kumar, N.K. Jain, dendrimers in oncology: an expanding
horizon, Chem. Soc. Rev. 109 (2009) 4987(and references cited therein).
[18] S. Mignani, S. El Kazzouli, M. Bousmina, J.-P. Majoral, Dendrimer space concept
for innovative nanomedicine: a futuristic vision in medicinal chemistry, Progress in Polymer Science, in press.
[19] a) C.C. Anajwala, G.K. Jani, S.M.V. Swamy, Current trends of nanotechnology for
cancer therapy, Int. J. Pharm. Sci. Nanotechnol. 3 (2010) 10431056;
b) O.C. Farokhzad, R. Langer, Impact of nanotechnology on drug delivery,
ACSNano 3 (2009) 1620;
c) D.A. Tomalia, L.A. Reyna, S. Svenson, Biochem. Soc. Trans. 35 (2007) 6167;
d) N.K. Jain, U. Gupta, Application of dendrimer-drug complexation in the
enhancement of drug solubility and bioavailability, Expert. Opin. Drug
Discov. 4 (2008) 10351051;
e) L.M. Kaminskas, V.M. McLeod, C.J.H. Porter, B.J. Boyd, Association of
chemotherapeutic drugs with dendrimer nanocarriers: an assessment of
the merits of covalent conjugation compared to noncovalent encapsulation,
Mol. Pharm. 9 (2012) 355373(and references cited therein);
f) A.-M. Caminade, C.O. Turrin, J.-P. Majoral, Biological properties of phosphorus dendrimers, New J. Chem. 34 (2010) 15121524.
[20] C. Kojima, Design of stimuli-responsive dendrimers, Expert. Opin. Drug Discov. 7
(2010) 307319.
[21] R.R. Ramireddy, K.R. Raghupathi, D.A. Torres, S. Thayumanavan, Stimuli sensitive
amphiphilic dendrimers, New J. Chem. 36 (2012) 340349.
[22] M. Avital-Shmilovici, D. Shabat, Self-immolative dendrimers: a distinctive
approach to molecular amplication, Soft Matter 6 (2010) 10731080(and references
cited therein).
[23] a) W. Wijagkanalan, S. Kawakami, M. Hashida, Designing dendrimers for drug
delivery and imaging: pharmacokinetic considerations, Pharm. Res. 28 (2011)
b) C.C. Lee, J.A. MacKay, J.M. Frchet, F.C. Szoka, Designing dendrimers for biological applications, Nat. Biol. 23 (2005) 15171526;
c) L.M. Kaminska, V.M. McLeod, C.J.H. Porter, B.J. Boyd, Association of chemotherapeutic drugs with dendrimer nanocarriers: an assessment of the merits of covalent conjugation compared to noncovalent encapsulation, Mol. Pharm. 9 (2012)
355373(and references cited therein).
[24] E. Fleige, M.A. Quadir, R. Haag, Stimuli-responsive polymeric nanocarriers for
the controlled transport of active compounds: concepts and applications, Adv.
Drug Deliv. Rev. 64 (2012) 866884.
[25] C. Fasting, C.A. Schalley, M. Weber, O. Seltz, S. Hecht, B. Koksch, J. Demedde, C.
Graf, E.-W. Knapp, R. Haag, Multivalency as a chemical organization and action
principle, Angew. Chem. Int. Ed. 51 (2012) 1047210498.
[26] S. Malhotra, H. Bauer, A. Tschiche, A.M. Staedtler, A. Mohr, M. Calderon, V.S.
Parma, L. Hoeke, S. Sharbati, R. Einspanier, R. Haag, Glycine-terminated dendritic
amphiphiles for nonviral gene delivery, Biomacromolecules 13 (2012)
[27] A. Banard, P. Posocco, S. Pricl, M. Calderon, R. Haag, M.E. Hwang, V.W.T. Shum,
D.W. Pack, D.K. Smith, Degradable self-assembling dendrons for gene delivery:
experimental and theoritical insights into barriers to cellular uptake, J. Am.
Chem. Soc. 133 (2011) 2028820300.
[28] a) P.S. Narayan, S. Pooja, A. Khushboo, T. Diwakar, S. Ankit, A.K. Singhai, Dendrimers
as a novel drug delivery systemNov. 2010, pp. 382388, (;
b) M. Ina, Dendrimer a a novel drug delivery system, J. Drug Deliv. Syst. 1
(2011) 7074.
[29] a) R. Haag, F. Kratz, Polymer therapeutics: concepts and applications, Angew.
Chem. Int. Ed. 45 (2006) 11981215;

Please cite this article as: S. Mignani, et al., Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems:
A concise overview, Adv. Drug Deliv. Rev. (2013),




















S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx

b) R. Satchi-Fainaro, R. Duncan, C.M. Barnes, Polymer therapeutics for cancer:
current status and future challenges, Adv. Polym. Sci. 193 (2006) 165(and
references cited therein).
T. Lammers, K. Ulbrich, HPMA copolymers: 30 years of advances, Adv. Drug
Deliv. Rev. 62 (2010) 119121.
D. Gaikwad, S. Dhawale, J. Khandare, M. Patil, T. KHade, B. Gavitre, K. Bobe, V.
Kulkarni, U. Gaikwad, Polymerdrug conjugates: recent achievements, Res. J.
Pharm. Biol. Chem. Sci. 2 (2011) 200208.
R. Duncan, M.J. Vicent, Do HPMA copolymer conjugates have a future as clinically
useful nanomedicines? A critical overview of current status and future opportunities, Adv. Drug Deliv. Rev. 62 (2010) 272282(and references cited therein).
Kopeek J., P. Kopekov, HPMA copolymers: origins, early developments, present, and future, Adv. Drug Deliv. Rev. 62 (2010) 122149(and references cited
X.-M. Liu, S.C. Miller, D. Wang, Beyond oncology application of HPMA copolymers
in non-cancerous diseases, Adv. Drug Deliv. Rev. 62 (2010) 258271(and references
cited therein).
D.B. Pike, H. Ghandehari, HPMA copolymercyclic RGD conjugates for tumor
targeting, Adv. Drug Deliv. Rev. 62 (2010) 167183(and references cited therein).
B.G. Katzung, Basic and Clinical Pharmacology, in: Appleton & Lange (Ed.), 1998,
Stamford, Connecticut.
Y. Cheng, Z. Xu, M. Ma, T. Xu, Dendrimers as drug carriers: applications in different
routes administration, J. Pharm. Sci. 97 (2008) 123143.
N. Malik, E.G. Evagorou, R. Duncan, Dendrimer-platinate: a novel approach to
cancer chemotherapy, Anticancer Drugs 10 (1999) 767776.
a) J.F. Kukowska-Latallo, K.A. Candido, Z.Y. Cao, S.S. Nigavekar, I.J. Majoros, T.P.
Thomas, L.P. Balogh, M.K. Khan, J.R. Baker, Nanoparticle targeting of anticancer
drug improves therapeutic response in animal model of human epithelial
cancer, Cancer Res. 65 (2005) 53175532;
b) L. van Haandel, J.F. Stobaugh, Bioanalytical method development for a generation 5 polyamidoamine folic acid methotrexate conjugated nanoparticle, Anal.
Bioanal. Chem. 397 (2010) 18411852.
Y.-Y. Jiang, G.-T. Tang, L.H. Zhang, S.-Y. Kong, S.-J. Zhu, Y.-Y. Pei, PEGylated
PAMAM dendrimers as a potential drug delivery carrier: in vitro and in vivo
comparative evaluation of covalently conjugated drug and noncovalent drug
inclusion complex, J. Drug Target. 18 (2010) 389403.
P. Singh, U. Gupta, A. Asthana, N.K. Jain, Folate and folatePEGPAMAM
Dendrimers: synthesis, characterization, and targeted anticancer drug delivery
potential in tumor bearing mice, Bioconjug. Chem. 11 (2008) 22392252.
B.D. Kurmi, V. Gajbhiye, J. Kayat, N.K. Jain, Lactoferrin-conjugated dendritic
nanoconstructs for lung targeting of methotrexate, J. Pharm. Sci. 100 (2011)
a) W.L. Yang, R.F. Barth, D.M. Adams, A.H. Soloway, Intratumoral delivery of
boronated epidermal growth factor for neutron capture therapy of brain
tumors, Cancer Res. 57 (1997) 43334339;
b) W.L. Yang, R.F. Barth, G. Wu, A.K. Bandyopadhya, B.T.S. Thirumamagal, W.
Tjarks, P.J. Binns, K. Riley, H. Patel, J.A. Codere, Boronated epidermal growth
factor as a delivery agent for neutron capture therapy of EGF receptor positive gliomas, Appl. Radiat. Isot. 61 (2004) 981985;
c) R.F. Barth, D.M. Adams, A.H. Soloway, F. Alam, M.V. Darby, Boronated starburst
dendrimer-monoclonal antibody immunoconjugates: evaluation as a potential
delivery system for neutron capture therapy, Bioconjug. Chem. 5 (1994) 5866;
d) W.L. Yang, R.F. Barth, D.M. Adams, M.J. Ciessielski, R.A. Fenstermaker, S. Shukla,
TjarksW. , M.A. Caligiuri, Convection-enhanced delivery of boronated epidermal growth factor for molecular targeting of EGF receptor-positive gliomas,
Cancer Res. 62 (2002) 65526558.
D. Bhadra, S. Bhara, N.K. Jain, A PEGylated dendritic nanoparticulate carrier of
uorouracil, Int. J. Pharm. 257 (2003) 111124.
C.C. Lee, E.R. Gillies, M.E. Fox, S.J. Guilaudeu, J.M. Frchet, E.E. Dy, F.C. Szoka, A
single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing
C-26 colon carcinomas, PNAS 7 (2006) 1664916654.
E.R. Gillies, E. Dy, J.M. Frchet, F.C. Szoka, Biological evaluation of polyester
dendrimer: poly(ethylene oxide) bow-tie hybrids with tunable molecular
weight and architecture, Mol. Pharm. 2 (2005) 129138.
L.M. Kaminskas, D.B. Kelly, V.M. McLeod, G. Sberna, D.J. Owen, B.J. Boyd, C.J.H.
Porter, Characterisation and tumour targeting of PEGylated polylysine
dendrimers bearing doxorubicin via a pH labile linker, J. Control. Release 152
(2011) 241248.
M.E. Fox, S. Guillaudeu, J.M.J. Frchet, K. Jerger, N. Macaraeg, F.C. Szoka, Synthesis and
in vivo antitumor efcacy of PEGylated poly(L-lysine) dendrimer-camptothecin
conjugates, Mol. Pharm. 6 (2009) 15621572.
A. Asthana, A.S. Chauhan, P.V. Diwan, N.K. Jain, Poly(amidoamine) (PAMAM)
dendritic nanostructures for controlled site-specic delivery of acidic antiinammatory active ingredient, AAPS PharmSciTech 6 (2005) E536E542.
A.S. Chauhana, N.K. Jain, P.V. Diwana, A.J. Khopadec, Solubility enhancement of
indomethacin with poly(amidoamine) dendrimers and targeting to inammatory
regions of arthritic rats, J. Drug Target. 12 (2004) 575583.
D. Bhadra, A.K. Yadav, S. Bhadra, N.K. Jain, Glycodendrimeric nanoparticulate
carriers of primaquine phosphate for liver targeting, Int. J. Pharm. 295 (2005)
J.F. Kukowska-Latallo, C. Chen, E. Raczka, A. Qunintana, M. Rymaszewski, J.R.
Baker, Intravascular and endobronchial DNA delivery to murine lung tissue
using a novel, nonviral vector, Hum. Gene Ther. 11 (2000) 13851395.
F. Kihara, H. Arima, T. Tsutsumi, F. Hirayama, K. Uekama, In vitro and in vivo gene
transfer by an optimized alpha-cyclodextrin conjugate with polyamidoamine
dendrimer, Bioconjug. Chem. 14 (2003) 342350.

[54] K.H. Wada, H. Arima, T. Tsutsumi, Y. Chihara, K. Hattori, F. Hirayama, K. Uekama, Improvement of gene delivery mediated by mannosylated dendrimer/-cyclodextrin
conjugates, J. Control. Release 104 (2005) 397413.
[55] C. Dufes, W.N. Keith, A. Bilsland, I. Proutski, I.F. Uchegbu, A.G. Schatzlein, Synthetic anticancer gene medicine exploits intrinsic antitumor activity of cationic
vector to cure established tumors, Cancer Res. 65 (2005) 80798084.
[56] F. Tack, A. Bakker, S. Maes, N. Dekeyser, M. Bruining, C. Elissen-Roman, M.
Janicot, M. Brewster, H.M. Janssen, B.F.M. Waal, P.M. Fransen, X. Lou, E.W.
Meijer, Modied poly(propylene imine) dendrimers as effective transfection
agents for catalytic DNA enzymes (DNAzymes), J. Drug Target. 14 (2006) 6986.
[57] C.A. Boswell, P.K. Eck, C.A.S. Regino, M. Bernardo, K.J. Wrong, D.E. Milenic, P.L.
Choyke, M.W. Brechbiel, Synthesis, characterization, and biological evaluation
of integrin v3-targeted PAMAM dendrimers, Mol. Pharm. 5 (2008) 527539.
[58] W.C. Floyd, G.K. Datta, S. Imamura, H.M. Kieler-Ferguson, K. Jerger, A.W.
Patterson, M.E. Fox, F.C. Szoka, J.M.J. Frchet, J.A. Ellman, Chemotherapeutic
evaluation of a synthetic tubulysin analoguedendrimer conjugate in C26
tumor bearing mice, ChemMedChem 6 (2011) 4953.
[59] V. Gajbhiye, N.K. Jain, The treatment of glioblastoma xenografts by surfactant
conjugated dendritic nanoconjugates, Biomaterials 32 (2011) 62136225.
[60] L. Vincent, J. Varet, J.Y. Pille, H. Bompais, P. Opolon, A. Maksimenko, C. Malvy, M.
Mirshahi, H. Lu, J.P.V.C. Soria, H. Li, Efcacy of dendrimer-mediated angiostatin
and TIMP-2 gene delivery on inhibition of tumor growth and angiogenesis: in
vitro and in vivo studies, Int. J. Cancer 105 (2003) 419429.
[61] G. Wu, R.F. Barth, W.L. Yang, M. Chatterjee, W. Tjarks, M.J. Ciesielski, R.A.
Fenstermaker, Site-specic conjugation of boron-containing dendrimers to
anti-EGF receptor monoclonal antibody cetuximab (IMC-C225) and its evaluation as a potential delivery agent for neutron capture therapy, Bioconjug.
Chem. 15 (2004) 185194.
[62] R.F. Barth, D.M. Adams, A.H. Soloway, F. Alam, M.V. Darby, Boronated starburst
dendrimer-monoclonal antibody immunoconjugates: evaluation as a potential
delivery system for neutron capture therapy, Bioconjug. Chem. 5 (1994) 5866.
[63] L. Vannucci, A. Fiserova, K. Sadalapure, T.K. Lindhorst, M. Kuldova, P. Rossmann,
O. Horvath, V. Kren, P. Krist, K. Bezouska, M. Luptovcova, F. Mosca, M. Pospisil,
Effects of N-acetyl-glucosamine-coated glycodendrimers as biological modulators in the B16F10 melanoma model in vivo, Int. J. Oncol. 23 (2003) 285296.
[64] G. Di Venosa, A. Casas, S. Battah, P. Dobbin, H. Fukuda, A. Macrobert, A. Battle,
Investigation of a novel dendritic derivative of 5-aminolaevulinic acid for photodynamic therapy, Int. J. Biochem. Cell Biol. 38 (2006) 8291.
[65] N. Sato, H. Kobayashi, T. Saga, Y. Nakamoto, T. Ishimori, K. Togashi, Y.
Fujibayashi, J. Konishi, M.W. Brechbiel, Tumor targeting and imaging of intraperitoneal tumors by use of antisense oligo-DNA complexed with dendrimers
and/or avidin in mice, Clin. Cancer Res. 7 (2001) 36063612.
[66] M. Mamede, T. Saga, H. Kobayashi, T. Ishimori, T. Higashi, N. Sato, M.W.
Brechbiel, J. Konishi, Radiolabeling of avidin with very high specic activity for
internal radiation therapy of intraperitoneally disseminated tumors, Clin.
Cancer Res. 9 (2003) 37563762.
[67] A.S. Chauhan, N.K. Jain, P.V. Diwan, Pre-clinical and behavioural toxicity prole of
PAMAM dendrimers in mice, Proc. R. Soc. A 3 (2009),
[68] a) N. Kuno, S. Fujii, Recent advances in ocular drug delivery systems, Polymers
3 (2011) 193221;
b) R.K. Khar, G.K. Jain, M.H. Warsi, N.M. Mallick, S. Akhter, S.A. Pathan, F.J.
Ahmad, Nano-vectors for ocular delivery of nucleic acid-based therapeutics,
Indian J. Pharm. Sci. 72 (2010) 675688;
c) R.R. Thakur, M. Kashiv, Modern delivery systems for ocular drug formulations:
a comparative overview W.R.T. conventional dosage form, Intl. J. Biomed.
Pharma. Sci. 2 (2011) 818;
d) A.C. Amrite, U.B. Kompella, Nanoparticles for ocular drug delivery, in: R.B.
Gupta, U.B. Kompella (Eds.), Nanoparticle Technology for Drug Delivery,
Taylor & Francis2006, (and references cited therein).
[69] S. Wadhwa, R. Paliwal, S.R. Paliwal, S.P. Vyas, Nanocarriers in ocular drug delivery:
an update review, Curr. Pharm. Des. 15 (2009) 27242750(and references cited
[70] J. Jiao, Polyoxyethylated nonionic surfactants and their applications in topical
ocular drug delivery, Adv. Drug Deliv. Rev. 60 (2008) 16631673(and references
cited therein).
[71] Th.F. Vandamme, L. Brobeck, Poly(amidoamine) dendrimers as ophthalmic
vehicles for ocular delivery of pilocarpine nitrate and tropicamide, J. Control.
Release 102 (2005) 2338.
[72] S. Shaunak, S. Thomas, E. Gianasi, A. Godwin, E. Jones, I. Teo, K. Mireskandari, P.
Luthert, R. Duncan, S. Patterson, P. Khaw, S. Brocchini, Polyvalent dendrimer
glucosamine conjugates prevent scar tissue formation, Nat. Biotechnol. 22
(2004) 977984.
[73] X. Duan, H. Sheardown, Dendrimer crosslinked collagen as a corneal tissue engineering scaffold: mechanical properties and corneal epithelial cell interactions,
Biomaterials 27 (2006) 46084617.
[74] G. Spataro, F. Malecaze, C.-O. Turrin, V. Soler, C. Duhayon, P.-P. Elena, J.-P.
Majoral, A.-M. Caminade, Designing dendrimers for ocular drug delivery, Eur.
J. Med. Chem. 45 (2010) 326334.
[75] R. Iezzi, B.R. Guru, I.V. Glybina, M.K. Mishra, A. Kennedy, R.M. Kannan,
Dendrimer-based targeted intravitreal therapy for sustained attenuation of
neuroinammation in retinal degeneration, Biomaterials 33 (2012) 979988.
[76] R.J. Marano, N. Wimmer, P.S.b Kearns, B.G. Thomas, I. Toth, M. Brankova, P.E.
Rakoczy, Inhibition of in vitro VEGF expression and choroidal neovascularization
by synthetic dendrimer peptide mediated delivery of a sense oligonucleotide,
Exp. Eye Res. 79 (2004) 525535.

Please cite this article as: S. Mignani, et al., Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems:
A concise overview, Adv. Drug Deliv. Rev. (2013),

S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxxxxx

[77] a) A. Naik, Y.N. Kalia, R.H. Guy, Transdermal drug delivery: overcoming the
skin-barrier function, Pharm. Sci. Technol. Today 3 (2000) 318326;
b) M.R. Prausnitz, R. Langer, Transdermal drug delivery, Nat. Biotechnol. 26
(2008) 12611268;
c) B.J. Thomas, B.C. Finnin, The transdermal revolution, Drug Discov. Today 9
(2004) 697703;
d) G.T. Tolia, H.H. Choi, The role of dendrimers in topical drug delivery, Pharm.
Technol. 32 (2008) 8898(and references cited therein).
[78] C. Ramachandran, R.D. Fleisher, Transdermal delivery of drugs for the treatment
of bone diseases, Adv. Drug Deliv. Rev. 42 (2000) 197223.
[79] V. Holana, M. Chudickova, P. Trosan, E. Svobodova, M. Krulova, S. Kubinova, E.
Sykova, J. Sirc, J. Michalek, M. Juklickova, M. Munzarova, A. Zajicova, Cyclosporine A-loaded and stem cell-seeded electrospun nanobers for cell-based therapy
and local immunosuppression, J. Control. Release 156 (2011) 406412.
[80] a) For representative examples, see:A.I. Shembale, D.K. Borole, R.T. Lohiya,
Useful permeation enhancers for transdermal drug delivery: a review, Int.
J. Pharm. Res. Dev. 2 (2012) 16;
b) I.B. Pathan, C.M. Setty, Chemical penetration enhancers for transdermal drug
delivery systems, Trop. J. Pharm. Res. 8 (2009) 173179;
P. Karande, A. Jain, K. Ergun, V. Kispersky, S. Mitragotri, Design principles of
chemical penetration enhancers for transdermal drug delivery, PNAS 102
(2005) 46884693.
[81] M.J. Santander-Ortega, T. Stauner, B. Loretz, J.L. Ortega-Vinuesa, D. BastosGonzalez, G. Wenz, U.F. Schaefer, C.M. Lehr, Nanoparticles made from novel
starch derivatives for transdermal drug delivery, J. Control. Release 141 (2010)
[82] M. Sun, A. Fan, Z. Wang, Y. Zhao, Dendrimer-mediated drug delivery to the skin,
Soft Matter 8 (2012) 43014305.
[83] V.V.K. Venuganti, O.P. Perumal, Poly(amidoamine) dendrimers as skin penetration enhancers: inuence of charge, generation and concentration, J. Pharm. Sci.
98 (2009) 23452356.
[84] V.V.K. Venuganti, P. Sahdev, M. Hildreth, X. Guan, O. Perumal, Structure-skin
permeability relationship of dendrimers, Pharm. Res. 28 (2011) 22462260.
[85] Y. Yang, S. Sunoqrot, C. Stowell, J. Ji, C.-W. Lee, J.W. Kim, S.A. Khan, S. Hong, The
effect of size, surface charge and hydrophobicity of poly(amidoamine) dendrimers
on their skin penetration, Biomacromelecules 13 (2012) 21542162.
[86] V.V.K. Venuganti, O.P. Perumal, Effect of poly(amidoamine) (PAMAM) dendrimer
on skin permeation of 5-uorouracil, Int. J. Pharm. 361 (2008) 230238.
[87] a) R. Wiwattanapatapee, B. Carreno-Gomez, N. Malik, R. Duncan, Anionic
PAMAM dendrimers rapidly cross adult rat intestine in vitro: a potential
oral delivery system? Pharm. Res. 17 (2000) 991998;
b) R. Jevprasesphant, J. Penny, D. Attwood, A. D'Emanuele, Transport of
dendrimer nanocarriers through epithelial cells via the transcellular route,
J. Control. Release 97 (2004) 259267.
[88] Z. Wang, Y. Ito, Y. Hosaka, I. Kobayashi, Y. Nakano, I. Maeda, F. Umeda, J.
Yamakawa, M. Kawase, K. Yagi, Novel transdermal drug delivery system with
polyhydroxyalkanoate and Starburst polyamidoamine dendrimer, J. Biosci.
Bioeng. 95 (2003) 541543.
[89] Z. Wang, Y. Itoh, Y. Hosaka, I. Kobayashi, Y. Nakano, I. Maeda, F. Umeda, J.
Yamakawa, M. Nishimine, T. Suenobu, S. Fukuzumi, M. Kawase, K. Yagi, Mechanism of enhancement effect of dendrimer on transdermal drug permeation
through polyhydroxyalkanoate matrix, J. Biosci. Bioeng. 95 (2003) 537540.
[90] H. Kim, H.K. Choi, Effect of additives on the crystallization and the permeation of
ketoprofen from adhesive matrix, Int. J. Pharm. 236 (2002) 8185.
[91] Z. Wang, Y. Itoh, Y. Hosaka, I. Kobayashi, Y. Nakano, I. Maeda, F. Umeda, J.
Yamakawa, M. Kawase, K. Yagi, J. Biosci. Bioeng. 95 (2003) 541543.
[92] A.U. Bielinska, A. Yen, H.L. Wu, K.M. Zahos, R. Sun, N.D. Weiner, J.R. Baker, B.J.
Roesslezer, Application of membrane-based dendrimer/DNA complexes for
solid phase transfection in vitro and in vivo, Biomaterials 21 (2000) 877887.
[93] A.S. Chauban, S. Sridevi, K.B. Chalasani, A.K. Jain, S.K. Jain, N.K. Jain, P.V.
Diwan, Dendrimer-mediated transdermal delivery: enhanced bioavailability
of indomethacin, J. Control. Release 90 (2003) 335343.
[94] Y. Cheng, N. Man, T. Xu, R. Fu, X. Wang, X. Wang, L. Wen, Transdermal delivery of
nonsteroidal anti-inammatory drugs mediated by polyamidoamine (PAMAM)
dendrimers, J. Pharm. Sci. 96 (2007) 595602.
[95] W.H. Hrl, Nonsteroidal anti-inammatory drugs (NSAIDs) and the kidney,
Pharmaceuticals 3 (2010) 22912321.
[96] K. Borowska, B. Laskowska, A. Magon, Mysliwiec, M. Pyda, S. Wolowiec, PAMAM
dendrimers as solubilizers and hosts for 8-methoxypsoralene enabling transdermal diffusion guest, Int. J. Pharm. 398 (2010) 185189.
[97] A. Filipowicz, S. Wolowiec, Solubility and in vitro transdermal diffusion of riboavin assisted by PAMAM dendrimers, Int. J. Pharm. 408 (2011) 152156.
[98] H.R. Moghimi, R. Varshochian, F. Kobarfard, M. Erfan, Reduction of percutaneous absorption of toxic chemicals by dendrimers, Cutan. Ocul. Toxicol. 29 (2010) 3440.
[99] S. Kchler, M.R. Radowski, T. Blaschke, M. Dathe, J. Plendl, R. Haag, M.
Schfer-Korting, K.D. Kramer, Nanoparticles for skin penetration enhancement
a comparison of a dendritic core-multishell-nanotransporter and solid lipid
nanoparticles, Eur. J. Pharm. 71 (2009) 243250.


[100] A. Hillery, A.W. Lloyd, J. Swarbrick, Drug Delivery and Targeting, in: Taylor &
Francis (Ed.), 2001, (London and New York, and references cited therein).
[101] a) C. Kojima, K. Kono, K. Maruyama, T. Takagishi, Synthesis of polyamidoamine
dendrimers having poly(ethylene glycol) grafts and their ability to encapsulate anticancer drugs, Bioconjugate 11 (2000) 910917;
b) I. Lambkin, C. Pinilla, Targeting approaches to oral drug delivery, Expert.
Opin. Biol. Ther. 2 (2002) 6773.
[102] a) For very interesting review/article, see:S. Sadekar, H. Ghandehari, Transepithelial
transport and toxicity of PAMAM dendrimers: implications for oral drug delivery,
Adv. Drug Deliv. Rev. 64 (2012) 571588;
b) R. Duncan, F. Spreaco, Polymer conjugates. Pharmacokinetic considerations
for design and development, Clin. Pharmacokinet. 27 (1994) 290306.
[103] R. Duncan, Polymer conjugates as anticancer nanomedicines, Nat. Rev. Cancer 6
(2006) 688701(and references cited therein).
[104] T. Sakthivel, I. Toth, A.T. Florence, Distribution of a lipidic 2.5 nm diameter
dendrimer carrier after oral administration, Int. J. Pharm. 183 (1999) 5155.
[105] A. D'Emanuele, R. Jevprasesphant, J. Penny, D. Attwood, The use of a
dendrimer-propranolol prodrug to bypass efux transporters and enhance oral
bioavailability, J. Control. Release 95 (2004) 447453.
[106] A.T. Florence, T. Sakthivel, I. Toth, Oral uptake and translocation of a polylysine
dendrimer with a lipid surface, J. Control. Release 65 (2000) 253259.
[107] P.K. Tripathi, A.J. Khopade, S. Nagaich, S. Shrivastava, S. Jain, N.K. Jain, Dendrimer
grafts for delivery of 5-uorouracil, Pharmazie 57 (2002) 261264.
[108] R. Wiwattanapatapee, L. Lomlim, K. Saramunee, Dendrimers conjugates for
colonic delivery of 5-aminosalicylic acid, J. Control. Release 88 (2003) 19.
[109] M. Na, C. Yiyun, X. Tongwen, D. Yang, W. Xiaomin, L. Zhenwei, C. Zhichao, H.
Guanyi, S. Yunyu, W. Longping, Dendrimers as potential drug carriers. Part II.
Prolonged delivery of ketoprofen by in vivo and in vitro studies, Eur. J. Med.
Chem. 41 (2006) 670674.
[110] R.B. Kolhatkar, P. Swaan, H. Ghandehari, Potential oral delivery of 7-ethyl-10hydroxy-camptothecin (SN-38) using poly(amidoamine) dendrimers, Pharm. Res.
25 (2008) 17231729.
[111] Y. Lin, T. Fujimari, N. Kawaguchi, Y. Tsujimoto, M. Nishimi, Z. Dong, H. Katsumi,
T. Sakane, A. Yamamoto, Polyamidoamine dendrimers as novel potential
absorption enhancers for improving the small intestinal absorption of poorly absorbable drugs in rats, J. Control. Release 149 (2011) 2128.
[112] F. Tajarobi, M. El-Sayed, B.D. Rege, J.E. Polli, H. Ghandehari, Transport of poly
amidoamine dendrimers across MadinDarby canine kidney cells, Int. J. Pharm.
215 (2001) 263267.
[113] S. Hong, A.U. Bielinska, A. Mecke, J.L. Beals, X. Shi, L.B.G. Orr, J.R. Baker, M.M.B.
Holl, Interaction of poly(amidoamine) dendrimers with supported lipid bilayers
and cells: hole formation and the relation to transport, Bioconjug. Chem. 15
(2004) 774782.
[114] M. El-Sayed, C.A. Rhodes, M. Ginski, H. Ghandehari, Transport mechanism(s) of
poly (amidoamine) dendrimers across Caco-2 cell monolayers, Int. J. Pharm. 265
(2003) 151157.
[115] J. Jevprasesphant, J. Penny, D. Attwood, N.B. McKeown, A. D'Emanuele, Engineering
of dendrimer surfaces to enhance transepithelial transport and reduce cytotoxicity, Pharm. Res. 20 (2003) 15431550.
[116] A.R. Menjoge, R.S. Navath, A. Asad, S. Kannan, C.J. Kim, R. Romero, R.M. Kannan,
Transport and biodistribution of dendrimers across human fetal membranes:
implications for intravaginal administration of dendrimer-drug conjugates, Biomaterials 31 (2010) 50075021.
[117] T.J. Seabrook, L. Jiang, K. Thomas, C.A. Lemere, Boosting with intranasal dendrimeric
A115 but not A115 peptide leads to an effective immune response following a
single injection of A140/42 in APP-tg mice, J. Neuroinammation 3 (2006) 110.
[118] Z. Dong, H. Katsumi, T. Sakane, A. Yamamoto, Effects of polyamidoamine
(PAMAM) dendrimers on the nasal absorption of poorly absorbable drugs in
rats, Int. J. Pharm. 30 (2010) 244252.
[119] R. Inapagolla, B.R. Guru, Y.E. Kurtoglu, X. Gao, M. L.ieh-Lai, D.J.P. Bassett, R.M.
Kannan, In vivo efcacy of dendrimer-methylprednisolone conjugate formation
for the treatment of lung inammation, Int. J. Pharm. 339 (2010) 140147.
[120] Z. Dong, K.A. Hamid, Y. Gao, Y. Lin, H. Katsumi, T. Sakane, A. Yamamoto,
Polyamidoamine dendrimers can improve the pulmonary absorption of insulin
and calcitonin in rats, J. Pharm. Sci. 100 (2011) 18661878.
[121] S. Bai, C. Thomas, F. Ahsan, Dendrimers as a carrier for pulmonary delivery of
enoxaparin, a low-molecular weight heparin, J. Pharm. Sci. 96 (2007) 20902106.
[122] T.C. Carvalho, J.I. Peters, R.O.W. Ill, Inuence of particle size on regional lung
deposition what evidence is there? Int. J. Pharm. 406 (2011) 110.
[123] H.S. Choi, Y. Ashitate, J.H. Lee, S.H. Kim, A. Matsui, N. Insin, M.G. Bawendi, M.
Semmler-Behnke, J. Frangioni, A. Tsuda, Rapid translocation of nanoparticles
from lung airspaces to the body, Nat. Biotechnol. 28 (2010) 13001304.
[124] J.K.-W. Lam, W. Liang, H.-K. Chan, Adv. Drug Deliv. Rev. 64 (2012) 115.
[125] G.D. Anderson, R.P. Saneto, Current oral and non-oral routes of antiepileptic
drug delivery, Adv. Drug Deliv. Rev. 64 (2012) 911918.

Please cite this article as: S. Mignani, et al., Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems:
A concise overview, Adv. Drug Deliv. Rev. (2013),