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Mosto Bousmina
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ADR-12434; No of Pages 15
Advanced Drug Delivery Reviews xxx (2013) xxxxxx
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
d
Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France
b
c
a r t i c l e
i n f o
Article history:
Accepted 30 January 2013
Available online xxxx
Keywords:
Dendrimers
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.
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Main physicochemical aspects of dendrimers in medicine: a concise overview
Main linear polymerdrug conjugates and dendrimer
therapeutic properties
. . . . . . . . . . . . . . . . . . . . . . . . . .
4.
Main dendrimer applications using different routes
of administration
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Dendrimers in ocular drug molecule delivery
. . . . . . . . . . . .
4.2.
Dendrimer mediated transdermal drug delivery . . . . . . . . . . .
4.3.
Dendrimers for oral drug release system . . . . . . . . . . . . . . .
4.4.
Dendrimers for other controlled drug release systems
. . . . . . . .
5.
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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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: serge.mignani@parisdescartes.fr (S. Mignani),
majoral@lcc-toulouse.fr (J.-P. Majoral).
0169-409X/$ see front matter 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.addr.2013.01.001
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), http://dx.doi.org/10.1016/j.addr.2013.01.001
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), http://dx.doi.org/10.1016/j.addr.2013.01.001
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), http://dx.doi.org/10.1016/j.addr.2013.01.001
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), http://dx.doi.org/10.1016/j.addr.2013.01.001
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
Dendrimers
Polymerdrug conjugates
Structure
Structural control
Aqueous solubility
Programmed release of drugs
Penetration abilities
Penetration and retention (EPRa) effect
Routes of administration
a
Medium
Low (major obstacle to the development and
clinical application of drugs)
Available within a specic period of time
High/low
Yes
Mainly intravenously
Enhanced permeability and retention (passive drug targeting and specic tissue targeting).
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), http://dx.doi.org/10.1016/j.addr.2013.01.001
Table 2
Intravenous, intratumoral, intraperitoneal, ocular, transdermal, and oral routes for administration of dendrimers (non-exhaustive list of examples).
Routes of
delivery
Dendrimer types
Drug molecules
Therapeutic eld
References
Intravenous
PAMAM
Folic acid-PAMAM
PEGylated-PAMAM
PPI
EGF-PAMAM (interperitoneal and intratumoral)
Cisplatin
Methotrexate
Methotrexate
Methotrexate
Boron
[38]
[39]
[40,41]
[42]
[43]
PEGylated-PAMAM
Polyester bow-tie dendrimer
Polyester bow-tie dendrimer
Polylysine dendrimers
PEGylated-poly(L-lysine)
PAMAM
PAMAM
Galactose-PPI
PAMAM
Cyclodextrin(-CDE conjugate)-PAMAM
Mannosylated-PAMAM- -cyclodextrin
conjugates
PPI
PEGylated-PPI
cRGD peptide coated PAMAM
Polylysine dendrimers
Polysorbate-PPI
PAMAM
5-Fluorouracil
Doxorubicin
Cancer
Cancer
Cancer
Cancer
Cancer (boron neutron capture
therapy)
Cancer and pharmacokinetic studies
Cancer
Cancer and biodistribution studies
Cancer and biodistribution studies
Cancer
Inammation
Inammation
Liver targeting
Murine lung tissue targeting
Spleen, liver and kidney targeting
Kidney targeting
Intratumoral
Transdermal
Oral
Camptothecin
Flurbiprofen
Indomethacin
Primaquine phosphate
DNA
DNA
DNA
DNA
DNA
Gd(III) (macromolecular imaging agent)
Tubulysin analog
Docetaxel
DNA
Boron
Boron
Glucosamine
Porphyrin
DNA
Indium-111
Indomethacin
Pilocarpine nitrate and tropicamide
PAMAM
PPI
Phosphorus dendrimers
PAMAM
Lysine dendrimers
PAMAM
PAMAM
PAMAM
PAMAM
PAMAM
8-Methoxypsiralene
PAMAM
PAMAM
Fatty acid and phospholipid-PAMAM
PAMAM
PAMAM
PAMAM
PAMAM
5(6)-Carboxyuorescein, uorescein
isothiocyanate-dextran, calcitonin and insulin
Liver targeting
Effective transfection agents
Angiogenesis
Cancer
Bain cancer
Inhibition of tumor growth and
angiogenesis
Cancer (boron neutron capture
therapy)
Cancer (boron neutron capture
therapy
Cancer
Photodynamic therapy
Cancer
Cancer (internal radiation therapy)
Arthritis
Miotic activity and mydriatic
activity
Immunology and angiogenese
Articial biomaterial
Hypertension
Inammation
Ocular neovascularisation
1A-adrenoceptor antagonist
Skin gene transfections
Inammation
Improve oral bioavailability and
inammatory
Hyperproliferative skin disease
(e.g. psoriasis, vitiligo )
Dermatological indication
Improve oral bioavailability
Cancer
Improve oral bioavailability
Improve oral bioavailability and
anti-inammatory
Improve oral bioavailability and
anti-cancer
Improve oral bioavailability
[44,41]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[70]
[72]
[73]
[74]
[75]
[76]
[88]
[92]
[93]
[94]
[96]
[97]
[105]
[107]
[108]
[109]
[110]
[111]
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), http://dx.doi.org/10.1016/j.addr.2013.01.001
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), http://dx.doi.org/10.1016/j.addr.2013.01.001
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
Vehicle
Vehicle: skin
penetration enhancers
Dendrimer-drug
encapsulate
Drug
Dendrimer-drug
encapsulate
Rapid drug
release
Dendrimer-drug
encapsulate
Drug solubilisation
in the vehicle
( stratum
corneum)
Drug
Drug release
Drug release
VE
( viable epidermis)
DE
( 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]).
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), http://dx.doi.org/10.1016/j.addr.2013.01.001
Table 3
Relationships of structure-skin permeability of PAMAM dendrimers.
P. Perumal et al. [83,84]
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)]
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)
a
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.
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.
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), http://dx.doi.org/10.1016/j.addr.2013.01.001
10
14
17
( stratum
corneum)
( 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]).
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), http://dx.doi.org/10.1016/j.addr.2013.01.001
11
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), http://dx.doi.org/10.1016/j.addr.2013.01.001
12
Table 4
Main factors inuencing the permeability of dendrimers across the epithelial barriers.
Dendrimer effects on oral
permeability
References
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.
[112]
Generation size
[113]
[87]
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).
[112]
112
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.
[91]
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
[112]
[113]
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.
[114]
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.
[115]
Concentration
[83,84]
Efux transporter
Surface modication
MadinDarby Canine Kidney (same permeability characteristics than Caco-2 cell lines).
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), http://dx.doi.org/10.1016/j.addr.2013.01.001
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.
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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), http://dx.doi.org/10.1016/j.addr.2013.01.001