apps and bio properties

8/19/2019 Apps and Bio Properties

1/16

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/235648148

Expand classical drug administration ways by emerging routes using dendrimer drug delivery

systems: A concise overview

ARTICLE in ADVANCED DRUG DELIVERY REVIEWS · FEBRUARY 2013

Impact Factor: 15.04 · DOI: 10.1016/j.addr.2013.01.001 · Source: PubMed

CITATIONS

73

READS

260

4 AUTHORS, INCLUDING:

Saïd El Kazzouli

Euro-Mediterranean University of Fez

45 PUBLICATIONS 669 CITATIONS

SEE PROFILE

Mosto Bousmina

Euro-Mediterranean Université of Fez

219 PUBLICATIONS 5,562 CITATIONS

SEE PROFILE

Available from: Mosto Bousmina

Retrieved on: 07 March 2016

https://www.researchgate.net/profile/Said_El_Kazzouli?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_4https://www.researchgate.net/profile/Said_El_Kazzouli?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_4https://www.researchgate.net/profile/Mosto_Bousmina?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_4https://www.researchgate.net/profile/Mosto_Bousmina?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_4https://www.researchgate.net/?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_1https://www.researchgate.net/profile/Mosto_Bousmina?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_7https://www.researchgate.net/profile/Mosto_Bousmina?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_5https://www.researchgate.net/profile/Mosto_Bousmina?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_4https://www.researchgate.net/profile/Said_El_Kazzouli?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_7https://www.researchgate.net/profile/Said_El_Kazzouli?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_5https://www.researchgate.net/profile/Said_El_Kazzouli?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_4https://www.researchgate.net/?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_1https://www.researchgate.net/publication/235648148_Expand_classical_drug_administration_ways_by_emerging_routes_using_dendrimer_drug_delivery_systems_A_concise_overview?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_3https://www.researchgate.net/publication/235648148_Expand_classical_drug_administration_ways_by_emerging_routes_using_dendrimer_drug_delivery_systems_A_concise_overview?enrichId=rgreq-f655b7ef-3951-4327-9d03-80809f6e2767&enrichSource=Y292ZXJQYWdlOzIzNTY0ODE0ODtBUzoxMDAwMjYyNDgzMzUzNjhAMTQwMDg1OTUyNDQ5MQ%3D%3D&el=1_x_2


2/16

Expand classical drug administration ways by emerging routes usingdendrimer drug delivery systems: A concise overview☆

Serge Mignani a,⁎, Saïd El Kazzouli b, Mosto Bousmina c , Jean-Pierre Majoral d,⁎a Université Paris Descartes, PRES Sorbonne Paris Cité, CNRS UMR 860, Laboratoire de Chimie et de Biochimie pharmacologiques et toxicologique, 45, rue des Saints Pères, 75006 Paris, Franceb INANOTECH, (Institute of Nanomaterials and Nanotechnology), MAScIR (Moroccan Advanced Science, Innovation and Research Foundation), ENSET, Av. Armée Royale, Rabat, Moroccoc Hassan II Academy of Sciences and Technology, Avenue MVI, km4, 10222 Rabat, Moroccod Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France

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

Article history:

Accepted 30 January 2013Available online xxxx

Keywords:

DendrimersRoutes of administrationTransdermal diffusionOcular drug deliveryIntravenous routeOral routeNasal administrationInhalation administration

Drugs are introduced into the body by numerous routes such as enteral (oral, sublingual and rectum administra-tion), parenteral (intravascular, intramuscular, subcutaneous and inhalation administration), or topical (skin andmucosal membranes). Each route has specic purposes, advantages and disadvantages. Today, the oral route re-mains the preferred one for different reasons such as ease and compliance by patients. Several nanoformulateddrugs 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. Numer-ous biochemical studies, as well as biological and pharmacological applications of both dendrimer based products(dendrimers as therapeutic compounds per se, likeVivagel®) and dendrimers as drugcarriers(covalentconjugationor noncovalent encapsulation of drugs) were described. It is widely known that due to their outstanding physicaland chemical properties, dendrimers afforded improvement of corresponding carried-drugs as dendrimer–drugcomplexes or conjugates (versus plain drug) such as biodistribution and pharmacokinetic behaviors. The purposeof this manuscript is to review the recent progresses of dendrimers as nanoscale drug delivery systems for the de-livery of drugsusing enteral, parenteraland topicalroutes. In particular, we focus our attention on the emergingandpromising routes such as oral, transdermal, ocular and transmucosal routes using dendrimers as delivery systems.

© 2013 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02. M ain physic oc hemic al aspects o f dendrimers in medic ine: a co nc ise o verview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03. Main linear polymer–drug conjugates and dendrimer

therapeutic properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 04. Main dendrimer applications using different routes

of administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 04.1. Dendrimers in ocular drug molecule delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 04.2. Dendrimer mediated transdermal drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 04.3. Dendrimers for oral drug release system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 04.4. Dendrimers for other controlled drug release systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

1. Introduction

Drugs are introduced into the body by numerous routes such asenteral (oral, sublingual and rectum administration), parenteral (in-travascular, intramuscular, subcutaneous and inhalation administra-tion), or topical (skin and mucosal membranes). Each route hasspecic purposes, advantages and disadvantages [1–3]. Fundamentally,

Advanced Drug Delivery Reviews xxx (2013) xxx–xxx

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "25thAnniversary issue - Advanced Drug Delivery: Perspectives and Prospects.⁎ Corresponding authors.

E-mail addresses: [email protected] (S. Mignani),[email protected] (J.-P. Majoral).

ADR-12434; No of Pages 15

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

http://dx.doi.org/10.1016/j.addr.2013.01.001

Contents lists available at SciVerse ScienceDirect

Advanced Drug Delivery Reviews

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / a d d r

Please citethis articleas: S. Mignani, et al., Expand classical drugadministrationways 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

http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.addr.2013.01.001http://www.sciencedirect.com/science/journal/0169409Xhttp://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001http://www.sciencedirect.com/science/journal/0169409Xhttp://dx.doi.org/10.1016/j.addr.2013.01.001mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.addr.2013.01.001http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


3/16

the accessibility of drug molecules to their respective target site anddrug treatment is strongly dependent on the route of administrationused. Thus, the route of administration has a profound effect uponboth the speed and the ef ciency with which the drug acts. The rateat which a drug reaches it site of action depends on its absorption anddistributionproles. Importantly,everyone responds to drugsdifferent-ly,and many parameters affect drug response. No singleroute of admin-istration of drug is ideal for all drugs in all circumstances. In recent

years, development of oral controlled release drug delivery systemshas 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 molecularlevel, using engineered nanodevices and nanostructures [5–8]. As adriving change in R&D research, during the last twenty years, thepharmaceutical industry began to adopt nanotools to implement highthroughput screening of drug repositories, to nd Hits and leads, toidentify drug targetsand biomarkers for bothpreclinical andclinicalstud-ies, to develop of diagnostic and imaging agents, and nally to carry outnew nanotechnologies such as nanoformulations and nanocarriers asdrug delivery approaches. Futuristic scenario for personalized medicineincludes the development of nanoparticles that simultaneously monitorand treat disease called the theranostic approach [9,10].

Several nanoformulated drugs have been already approved by theFDA including generic reformulations such as Abelcet® (liposome-basedamphotericin B, anti-fungal activity, liposomal formulation) [11], Doxil/Caelyxl® (liposome-based doxorubicin, cancer, Pegylated liposomesagainstovarian cancer Kaposi'ssarcoma) [12] and Abraxane® (paclitaxel,anti-cancer activity, albumin-bound particles) [12,13].

Interestingly, various polymeric drugs have been described to treatdifferent diseases. For representative examples: polymeric micelle for-mulated paclitaxel (Genexol-PM®) with free of Cremophor EL reducingCremophor EL-related toxicities and increasing therapeutic ef cacy(PhaseII studies, breastand lung cancers), Adagen® which is a conjugateof monomethoxypolyethylene glycol (PEG) covalently attached to theadenosine deaminase (ADA) enzyme for the treatment of severe com-bined 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, theenzyme that depletes the amino acid asparagine. In 2006, the FAD ap-proved Oncaspar®for therst-linetreatment of patientswith acutelym-phoblastic leukemia. Commercialized Neulasta® which is a PEGylated-recombinant methionyl human granulocyte colony stimulating factor(G-CSF) stimulating the bone marrow and promoting the growthof white blood cells, prevents neutropenia. Neulasta® is given intrave-nously once for each cycle of high-dose chemotherapy [12,14].

In thedendrimer domain,in 2012, Starpharma(Melbourne,Australia)started two pivotal phase III for the treatment of bacterial vaginosis withVivagel® [12,15]. This anionic G4-poly(L -lysine)-type dendrimer hasthirty-two naphthalene disulfonate groups on the surface, and showedpotent topical vaginal microbicide activity [16].

The deeper analysis of other PEG, dendrimers and nanocarrierplatforms have been recently presented and discussed by R. Haagand coworkers [12].

Based on extensive biochemical studies, biological and pharmacolog-ical applications of both dendrimer based products (dendrimers as ther-apeutic compounds per se, like Vivagel®) and dendrimers, dendrons andpolyether based amphiphiles as drug carriers (covalent conjugation ornoncovalent encapsulation of drugs) were portrayed in review articles[17]. One of the major advantages of these nanometer-scale dendrimerbiomaterials is their outstanding capability to be used with differentroutes of administration. To the bestof our knowledge, few nanoparticlesas 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 transmucosalroutes using dendrimers as deliverysystems. Before we highlight the un-conventional 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 linearpolymer–drug 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 newdruggable cluster which is included in the vast volume of chemicalspace [18]. The boundariesof this cluster can be determined by topolog-ical properties as diverse routes of administration using dendrimers.This new approach affords a new vision of pharmaceutical science re-search, and opens new and promising avenues to nd newdrug-based dendrimers.

2. Main physicochemical aspects of dendrimers in medicine: a

concise overview

The dendrimer literature is huge, and extensive studies usingdendrimers were carried out. Dendrimer nanostructures representoutstanding nano-carriers in medicine [17]. Dendrimeric structuresare of particular interest in the eld of drug delivery due to theirpeculiar structural properties including controllable internal cavitiesbearing specic species for the encapsulation of guest drugs andexternal periphery with 3D multiple functional moeities for solubiliza-tion, conjugation of bioactive compounds and targeting molecules,and recognition purposes. The main successes of dendrimers resultedin their appropriate, reproducible and optimized design parametersaddressing physicochemical limitationsof classical drugs(e.g. solubility,specicity, stability, biodistribution and therapeutic ef ciency) andtheir ability to overcome biological issues to reach the right target(s)(e.g. rst-pass effect, immune clearance, cell penetration, off-targetinteractions, etc.). Improvement of pharmacokinetic (PK) and pharma-codynamic (PD) behaviors of both drug-dendrimer conjugates anddrug–dendrimer encapsulates versus plain drugs demonstrates theirstrong potentials in medicine as nano-carriers [17,19].

A schematic of typical dendritic structure is shown in Fig. 1 andillustrates four main regions: i) an initiator core scaffold, ii) interiorlayers composed of repeating branching units attached to the core(generation, Gn, where n can be 0 to 12), iii) terminal surface groupsattached to the outmost interior generation iv) void spaces.

The most commonly referenced dendrimers used in nanomedicineare polyamidoamines (PAMAM), poly(L -lysine) scaffold dendrimers(PLL), polyesters (PGLSA-OH), polypropylimines (PPI), poly(2,2-bis(hydroxymethyl)propionic acid scaffold dendrimers (bis-MPA) andaminobis(methylenephosphonic acid) scaffold dendrimer. Some of them are depicted in Fig. 2 and several are commercially availablefrom various suppliers. For instance, the main providers for PAMAMdendrimers (Starburst®),poly-etherhydroxyl-amine PEHAMdendrimers(Priostar®), PPI dendrimers (Astramol®) are Sigma Aldrich, National

Dendrimers & Nanotechnology, Dendritic Nanotechnologies and DSMFine Chemicals. Phosphorus based dendrimers are commercialized byBDI (BioDendrimer International).

Importantly, the dendrimers showed strong ability to escape fromthe uptake by the non specic ReticuloEndothelial System (calledRES). In addition, the nanomeric size of dendrimers induces the pas-sive targeting effects reducing the non-specic toxicity of the carrieddrugs. This effect is called Enhanced Permeability and Retention effect(EPR effect), and is observed, for instance, in tumor or inamedtissues [17,19].

Dendrimers can be included as specic delivery nano-systemswhich are able to specically target the carried drugs to cells by a sim-ple 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

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

Pleasecite this article as:S. Mignani, et al.,Expandclassical drug administrationways by emerging routesusing dendrimerdrug delivery systems:A concise overview, Adv. Drug Deliv. Rev. (2013), http://dx.doi.org/10.1016/j.addr.2013.01.001

http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


4/16

amides, esters, hydrazones, etc., which is activated by disease-specic signals like chemical/oxidation and change in the surround-ing pH or by external stimuli such as magnetic eld, light [20,21] orspecic enzymes (self immolative approach) [22]. In both passiveand active targeting approaches, dendrimers avoid their uptake bythe RES and consequently remain in plenty of time in the blood cir-culation increasing their biological potency in specic tissues suchas tumors. For instance, the extravasation of the tumor vasculature hasbeen proposed for the anti-tumor activity of several dendrimer-encapsulated or -conjugated drugs [23]. Stimuli-responsive polymericnanocarriers including dendrimers, dendrons etc. for the controlledtransport of active compounds (drugs, peptides, genes, etc.) have beenanalyzed by R. Haag et al. [24]. Interestingly, multi- and polyvalent inter-actions of organic materials including dendrimers playing a crucial rolein biological recognition and adhesion has been nicely highlighted [25].

In addition to the use of large polycationic dendrimers, differentgroups have described the delivery of genetic material into cells using

dendrons. Thus, very interestingly, R. Haag et al. published the develop-ment of original non viral vectors based on well-dened molecularstructure from multivalent polyglycerol dendrons. For instance, theG2-octaamine derivative bearing a hydrophobic alkyl chain at thecore promoting dendron self-assembly, acts as an ef cient vector todeliver FAM-siRNA into the cells [26]. The same team presented thesynthesis of biodegradable cationic self-assembly dendron basedon cholesterol-functionalized core unit. Based on cellular uptakestudies, these amphiphilic nanocarriers are highly effective intransporting DNA into cells but with low transgene expression [27].

3. Main linear polymer –drug conjugates and dendrimer

therapeutic properties

The comparison between dendrimers and the well known linearpolymer–drug conjugates is of real interest. Table 1 summarizes themain, but not exhaustive relevant comparative properties related to invitro and in vivo properties between dendrimers and linear polymer–drug conjugates [28].

Developmentof polymer–drugconjugates as ‘polymer therapeutics’with cleavable linkers to improve the therapeutic index of severaltoxic drugs especially in cancer chemotherapy, has been intensivelyportrayed [29]. The main copolymer described is HPMA (N -(2-hydroxypropyl)methacrylamide) but others such as, for instance, PEG,poly-L -glutamate, albumin, dextran, 6-maleinimodcaproyl hydrazonederivatives, etc. have been also pointed out.These polymer–drug conju-gates have shown several advantages versus plain drugs such as fewerside effects, improved therapeutic ef cacy, ease of drug administration,

and improved patient compliance [23,24].

Different cleavable linker types were employed, namely: Gly-Phe-Leu-Gly, Gly-6-aminohexanoyl-Gly, alanine ester, Gly-ester, ester andacid-sensitive hydrazone [24,29]. The Phase I and phase II clinical trialswith HPMA copolymers containing different drugs such as doxorubicin,paclitaxel, camptothecin, methotrexate and carboplatinate analog andDACH palatinate analogs are ongoing, completed or stopped. It is notedthat the use of HMPA copolymers in nanomedicine has been reviewedrecently in a special issue of Advanced Drug Delivery Reviews [30].PEG-camptothecin and PEG-SN38 have been also described to treatsolid tumors or lymphoma [31]. A broader range of other treatment of diseases excluding cancers using HPMA copolymers was described in-cluding, for instance, musculoskeletal diseases, infectious diseases andspinal cord injury. Within this issue, R. Duncan and M. J. Vicent empha-sized a critical overview of current status and future opportunities of HPMA copolymer conjugates in nanomedicines [32]. Thus the designand the development of HPMA copolymer–cyclic RGD conjugates fortargeting tumor angiogenesis have been described. The Phase I clinical

studies performed with HPMA copolymer conjugates containing pacli-taxel (PNU 166945) and camptothecin (PNU 166148) failed due toinadequate designs. Indeed, after administration, rapid cleavage of the ester linker afforded low drug loading and consequently no phar-macokinetic benet. No clinical evidence of antitumor activities hasbeen observed, and no polymer-related toxicity has been reportedin these studies. Recently HPMA–copolymer platinates (AP5280 andthen 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 copolymer–antitumorconjugates have been safely (minimal adverse reactions) administeredonly parenterally (intravenous administration), and this treatmentallowed very good quality of life of patients for a certain period of time. Nevertheless, the future objective will be to use HPMA copoly-

mer–drug conjugates in the treatment of life-threatening diseases re-quiring non-parenteral routes of administration such as oral or topical.The non-degradable polymeric carriers such as HPMA copolymerslimit their parenteral use (relatively short course of treatment)unlike non-parenteral routes for which the accumulation of thenon-degradable polymer is not a safety risk. Non-degradable poly-meric carriers improve the risk of their cellular accumulationthrough their sequestration in the lysosomal compartments, espe-cially after chronic administrations or at high doses [33–35].

4. Main dendrimer applications using different routes

of administration

It is widely known that due to their outstanding physical and chem-

ical properties, dendrimers afforded improvement of corresponding

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

3S. Mignani et al. / Advanced Drug Delivery Reviews xxx (2013) xxx– xxx


http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


5/16

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



http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001


6/16

carried-drugs as dendrimer–drug complexes or conjugates(versus plaindrug) such as biodistribution and pharmacokinetic behaviors.These pa-rameters are the main relevant factors in clinical trials [36]. Both,dendrimer–drug complexes (physical encapsulation or electrostatic in-teraction) 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 rationaldesign and the development of dendrimers for successful in vivoapplication and clinical translation. Thus, relationships between physico-chemical properties of dendrimers and pharmacokinetic parameterssuch as AUC (Area Under the Curve), hepatic and renal clearance, size,generation, charge, PEGylation, etc., after intravenous administration inmice, have been discussed. Interestingly, Therapeutic Availability (TA)based on the total drug amount as a function of the AUC at the targetsite has been used showing effectiveness of macromolecule-conjugateddrugs compared withplain drugs either afterintravenous, intraperitone-al, intratumoral, oral, transdermal or ocular administration. The thera-peutic applications studied are anticancer, anti-inammatory, anti-

thrombotic and antimalarial. The higher TA values were obtained forconjugation versus encapsulation/complexation. In addition, increaseof the multivalency of conjugated ligands on dendrimers induced im-provement in tumor targeting. Consequently, highly tumor-targeteddendrimers would enhance biodistribution proles. The main draw-backs of theencapsulationapproachare: a) fast anduncontrolled releaseof drugs, possibly before reaching the targeted cells; moreover, drug-encapsulated dendrimers could be unstable in different buffers and inplasma, b) critical clinical translation. This very important point wasoutlined and analyzed by M. A. Mintzer and M. W. Grinstaff [17].

Very interestingly, in a recent review, R. Haag et al. analyzed thecurrent status of nanomedicines such as advanced forms of liposomes,PEG based nanocarriers and dendritic polymer conjugates targetingcancer and inammation domains. Based on the main biophysical re-

quirements of nanoparticles for in vivo biocompatibility assessments,implications and rationale for effective nanodelivery systems havebeen presented and analyzed in-depth [12].

Nowadays, the preferred route for the delivery of drugs usingdendrimers is the intravenous route. The immense potential of dendrimers in medicinal chemistry results, for instance, in their routeof administration expansion versus conventional route as intravenous[37]. Thus, recently, other interesting routes have been portrayed suchas ocular, transdermal, oral, nasal, pulmonary and intravaginal. Table 2presents 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 tothe use of dendrimers (dendrimer–drug complexes or conjugates)usingnon-classical routesof 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 (vitreoushumor, retina, choroid, and optic nerve). Various drugs have beendeveloped to treat many eye disorders such as uveitis (which is theinammation of the middle layer of the eye, termed the uvea), con-

junctivitis and glaucoma. Systematic administration of ophthalmicdrugs by oral or intravenous ways cured some anterior segment dis-eases 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 theeye tissues. Consequently, accumulation of these drugs in differenttissues resulted in unwanted side effects. The main challenge in ocu-lar drug delivery is to improve the bioavailability of ophthalmic drugs,and consequently their residence time. Drug molecules can be mixedwith several inactive substances (polymeric formulation) to make aliquid or gel, which can be applied to the eye. Several side effectshave been observed including blurred vision and irritation. Liquid eye

drops are relatively easy to use but may run off the eye too quickly tobe well absorbed. Ideal ocular drug-delivery systems should be sterile,non-irritating, isotonic and biocompatible. Importantly, the eye droproute is a non invasive route of administration, but this route is nothighly effective for eye disease such as age-related macular degenera-tion, diabetic retinophathy, uveitis and retinis (glaucoma) which arelocated in the posterior segment of the eye [68].

Lucratively, various nanosized carriers in ocular drug deliverywere described such as micro/nano-suspensions, liposome, noi-some, nanoparticles, dendrimers, ocular inserts, implants, hydrogelsand prodrug approaches and were reviewed [69]. In addition,polyoxyethylated nonionic surfactants in topical ocular drug deliv-ery have been also described [70].

Dendrimers are useful for the delivery of drugs to the eyes as oph-

thalmic vehicles. The main advantage of using dendrimers as nano-carriers is their strong aptitude to improve the ophthalmic drug ef-fects due to the eye penetration enhancement through the cornea,and the sustained release of drugs. Up to now, several studies havebeen carried out with PAMAM, PPI and lipid-lysine dendrimers, andboth approaches were used: encapsulation, conjugation and electro-static interactions. One of the main advantages of dendrimers asocular drug delivery systems is their ability to release drugs in theposterior segment of the eye (vide supra).

In early studies, Vandamme and Brobeck investigated the develop-ment of surface-modied PAMAM dendrimers [71]. Thus, G1.5,G2-OH, G4-OH PAMAM dendrimers (in aqueous solution) signicantlyimproved the residence time and activities of both host–guests (encap-sulation) pilocarpine nitrate (parasympathomimetic alkaloid) and

tropicamide (pyridinylmethyl-benzeneacetamide) in miotic and

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 Polymer–drug conjugates

Structure Compact/globular (➩ predictable MW and monodispersity ➩ reproductiblepharmacokinetics)

Not compact and structural heterogeneity

Structural control Very high (➩ controlled branching (topology) and versatility in design andmodication of terminal end groups)

Medium

Aqueous solubility High (essential for drug candidates, good absorption, bioavailability and

pharmacokinetic)

Low (major obstacle to the development and

clinical application of drugs)Pro gramme d release of drugs Hig h (➩ reduced toxicity, increased bioavailability, simplied dosing schedule) Available within a specic period of timePenetration abilities High (high cell membrane penetrat ion➩ increased cellular uptake level of the

drugs complexed or conjugated)High/low

Penetration and retention (EPR a) effect Enhanced (➩ preferential uptake of the dendrimers by cancer tissues) YesRoutes of administration Intravenous, intraperitoneal, ocular, transdermal, oral, intranasal, pulmonary,

intravaginal …Mainly intravenously

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



http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


7/16

mydriatic activity tests,respectively. The testswere performed on rabbiteyes using topical route (eye drops). These dendrimers showed at leastcomparable potency and bioavailability than the 0.2% w/v bioadhesivepolymer Carbopo® solution or phosphate solution. The improvementsof ocular delivery ef ciency result of theslow release of these drugs en-capsulated 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 PAMAM-glucosamine (DG) and glucosamine-6-sulfate (DGS) conjugateddendrimers displayed together potent activities in a validated and clini-cally relevant wound healing glaucoma model in rabbit. DG is animmune-modulator (giving pro-inammatory response) and DGS an

anti-angiogenic compound, both were administrated by subconjunctival

injection. Interestingly, minimal scar tissue formation was observedversus placebo-treated animals, and hematological, biochemical toxicityor 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 cor-nea with that of a human donor (allograft cornea transplantation).Nevertheless, several challenges amounted such as patient waitinglists which are dramatically growing. Many patients are unsuitablefor this treatment or simply do not have donor tissue available, safetyof donor tissue, lack of corneal tissue, etc. Articial corneas offeropportunities to solve these issues.

Then, Duanand Sheardown havedesignated G2 PPI dendrimer which

was covalently conjugated to collagen [73]. This arti

cial biomaterial

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 Cisplatin Cancer [38]Folic acid-PAMAM Methotrexate Cancer [39]PEGylated-PAMAM Methotrexate Cancer [40,41]PPI Methotrexate Cancer [42]EGF-PAMAM (interperitoneal and intratumoral) Boron Cancer (boron neutron capture

therapy)

[43]

PEGylated-PAMAM 5-Fluorouracil Cancer and pharmacokinetic studies [44,41]Polyester bow-tie dendrimer Doxorubicin Cancer [45]Polyester bow-tie dendrimer Cancer and biodistribution studies [46]Polylysine dendrimers Cancer and biodistribution studies [47]PEGylated-poly(L -lysine) Camptothecin Cancer [48]PAMAM Flurbiprofen Inammation [49]PAMAM Indomethacin Inammation [50]Galactose-PPI Primaquine phosphate Liver targeting [51]PAMAM DNA Murine lung tissue targeting [52]Cyclodextrin(α-CDE conjugate)-PAMAM DNA Spleen, liver and kidney targeting [53]Mannosylated-PAMAM- α-cyclodextrinconjugates

DNA Kidney targeting [54]

PPI DNA Liver targeting [55]PEGylated-PPI DNA Effective transfection agents [56]cRGD pe ptide coated PAMAM Gd(III) (macromo lecular i mag ing ag ent) Angio genesis [57]Polylysine dendrimers Tubulysin analog Cancer [58]

Polysorbate-PPI Docetaxel Bain cancer [59]Intratumoral PAMAM DNA Inhibition of tumor growth andangiogenesis

[60]

Anti-EGF receptor monoclonal antibody(cetuximab)-PAMAM

Boron Cancer (boron neutron capturetherapy)

[61]

Intraperitoneal Monoclonal antibody immunoconjugate(MoAbIB16-6)-PAMAM

Boron Cancer (boron neutron capturetherapy

[62]

Glyco-PAMAM Glucosamine Cancer [63]5-Aminolaevulinic acid Porphyrin Photodynamic therapy [64]Avidin-PAMAM DNA Cancer [65]Avidin-PAMAM Indium-111 Cancer (internal radiation therapy) [66]Folic acid-PAMAM Indomethacin Arthritis [67]

Ocular PAMAM Pilocarpine nitrate and tropicamide Miotic activity and mydriaticactivity

[70]

PAMAM Glucosamine and glucosamine-6-sulfate Immunology and angiogenese [72]PPI Collagen Articial biomaterial [73]Phosphorus dendrimers Carteolol Hypertension [74]PAMAM Fluocinolone Inammation [75]

Lysine dendrimers ODN-1 oligonucleotide Ocular neovascularisation [76]Transdermal PAMAM Tamsulosin hydrochloride α1A-adrenoceptor antagonist [88]

PAMAM CAT reporter transgene Skin gene transfections [92]PAMAM Indomethacin Inammation [93]PAMAM Ketoprofen and Diunisal Improve oral bioavailability and

inammatory[94]

PAMAM 8-Methoxypsiralene Hyperproliferative skin disease(e.g. psoriasis, vitiligo …)

[96]

PAMAM Riboavin (B2 vitamin) Dermatological indication [97]Oral PAMAM Propanolol Improve oral bioavailability [105]

Fatty acid and phospholipid-PAMAM 5-Fluorouracil Cancer [107]PAMAM 5-Aminosalicylic acid Improve oral bioavailability [108]PAMAM Ketoprofen Improve oral bioavailability and

anti-inammatory[109]

PAMAM SN-38 (active metabolite of irinotecan (CPT-11)) Improve oral bioavailability andanti-cancer

[110]

PAMAM 5(6)-Carboxyuorescein, uorescein

isothiocyanate-dextran, calcitonin and insulin

Improve oral bioavailability [111]



http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


8/16

displayed very interesting properties versus natural human cornea, EDCand glutaraldehyde cross-linked collagen, suchas mechanical properties,adhesion ability, optical transparency, and glucose permeability. More-over, G2 PPI dendrimer showed no cell toxicity. The same authorsdescribed the synthesis of cell adhesion peptide (YIGSR) modied PPIbearing conjugated collagen. These peptide modied collagen gelswere used as corneal tissue engineering scaffolds, and promoted the ad-hesion and proliferation of human corneal epithelial cells as well as neu-

ritis extension from the dorsal root ganglia.Recently, one of us (J-P. Majoral), described the biological activityof water soluble G1-2-CO2H phosphorus-containing dendrimerscomplexed with carteolol which is an ocular anti-hypertensive drug(β-blocker) for the treatment of glaucoma. These dendrimers, in solu-tion in milliQ water, have been instilled in the eyes of rabbits. Thequantity of released carteolol from dendrimers, that penetrate insidethe eyes (aqueous humor), is larger than carteolol alone, highlightinggood biocompatibility of these phosphorus dendrimers. In this study,no irritation was observed [74].

Very recently also, dendrimer-uocinolone acetonide-G4-OHPAMAM conjugate has been prepared for attenuation of neuroin-ammation in the retina. Intravitreal administration of this nano-device induced in vivo ef cacy against retinal degeneration in two ratmodels, and arrest of retinal degeneration was fully observed. In factdendrimer-uocinolone conjugate is localized within activated outerretinalmicroglia, but not in the retina of healthy controls. The conjugatereleaseduocinolone was observed in a sustained mannerover 90 days[75].

Diseases complicated by vascular leakage and/or neovascularizationin the eye are responsible for the vast majority of visual morbidity andblindness in developed countries. It is known that suppression of ocularneovascularization had been done using siRNA targeting vascular endo-thelial growth factor (VEGF) receptor 1. Consequently, VEGF plays animportant role in ocular neovascularization. Wimmer et al. pointedout that lipid-lysine dendrimers improved the delivery of the sense ol-igonucleotideODN-1 into thenucleiof retinal cells and induceda reduc-tion in VEGF expression. Based on in vivo studies, dendrimer-ODN-1complex (electrostatic interactions) signicantly reduced choroidal

neovascularisation in rat model. The dendrimer-ODN-1 complex wasinjected into the vitreous of both eyes separately and remained activefor up to two months after injection. No major toxicity was observed[76].

4.2. Dendrimer mediated transdermal drug delivery

Very selective transdermal drug delivery route is a noninvasivemethod of administering drugs through the skin for both local andsystemic therapies [77]. The transdermal revolution has started as anovel epoch, which allowed the pharmaceutical industry to treat,for instance, bone diseases [78] and local immunosuppression usingcyclosporine A-loaded nanobers for cell-based therapy [79]. Howev-er, tremendous challenges in achieving effective transdermal delivery

of bioactives remain as for instance the penetration through the stra-tum corneum barrier, which is the outermost cover of the skin.Indeed, skin represents the largest (1–2 m2 for absorption) andmost easily accessible organ of the body, and the most successfulnon-oral systemic drug delivery system [77].

Several marketed therapeutic agents such as scopolamine, estradi-ol, nicotine, insulin, lidocaine, and testosterone are used in medicinevia this approach within a wide variety of therapeutic indications in-cluding hypertension, angina, female menopause, local pain control,nicotine dependence, etc. [77] Transdermal drug delivery system isnot suited for all drugs nor is it justied for all therapies. In particular,the stratum corneum shows protective barrier effect against com-pounds with molecular weights over 500 Da and/or with logPo/PBSless than 1 or greater than 3 [77]. LogPo/PBS represents the partition

coef cient 1-octanol versus PBS (phosphate buffered saline).

A very interesting review written by A. Naik et al. [77] highlightsthe main physicochemical parameters for both passive and iontopho-retic transdermal delivery approaches. The main ideal limits arethe following (passive versus iontophoretic): 1) aqueous solubility:>1 mg/ml for both approaches, 2) lipophilicity: 10 bKo/w b1000 forthe passive approach, 3) molecular weight: b500 Da for the passiveapproach, 4) melting point: b200 °C forthe passive approach,5) dose de-liverable: b10 mg/day vs 20–50 mg/day (MWb1000 Da), 2–5 mg/day

(1000 Dab

MWb

5000 Da) and b

1 mg/day for MW >5000 Da and6) charge: pKa pI b 4 (for acids) or >7.4 (for bases). Ko/w represents oil–water partition coef cient, whereas pKa and Pi represent ionization con-stant and isoelectric point, respectively.

In contrast to oral and intravenous administrations, transdermaldrug release presents some major advantages: a) it maintains quiteconstantly (prolonged/sustained delivery system) the low concentra-tion of the administered drug in the blood thus avoiding its potentialtoxicity (absence of high peaks), b) it allows the simplication of thedosing schedule and the high exibility of use, c) it permits bypassingof the hepatic rst-pass metabolism effect in the gastrointestinal tractfor drugs with poor oral bioavalability, and d) it improves patientcompliance thus avoiding frequent administration [77]. However,the slow rate of transdermal drug delivery permeation is one of itsmajor limitations due to the presence of the skin's intrinsic layerbarrier properties (tortuous lipoidal diffusion pathway and multiplelipid layers) of stratum corneum biomembrane against exogenousmolecules [77]. Skin irritation and high manufacturing costs can bealso mentioned as drawbacks.

To aid dermal passive absorption, various transdermal penetrationenhancers (CPEs) – based on chemical and physical approaches –were applied. Chemical penetration enhancers are present in a largenumber of transdermal, dermatological, and cosmetic products, anduse 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 enhancerssuch as iontophoresis, electroporation and ultrasound [80]. In addi-tion, different nanoparticle types were also described as transdermaldrug delivery systems such as polysaccharides [81] and dendrimers

(vide infra).To the best of our knowledge, only PAMAM dendrimers and den-

dritic PEGylated polyglycerol amine have been used for transdermaldelivery of bioactive molecules. Co-treatment or pre-treatment tech-niques have been carried out to deliver these bioactives using differ-ent vehicles such as water, chloroform, chloroform–water mixture,isopropyl myristate (IPM) or octanol/water emulsion. Three differentpossible mechanisms were, very recently reviewed and discussed byY. Zhao et al. [82]. The rst one involved dendrimers which act asdrug release modiers for which the biological activity of the drugis related to the drug concentration in the vehicle. The drug is encap-sulated in the dendrimer, and the dendrimer poorly penetrates the SC(stratum corneum) by itself. The drug must be released from thedendrimer into the vehicle prior to further penetrating/partitioning

into the SC. The high level of the free drug in the vehicle boosts thedriving force of drug permeation. The free drug ux increases withdendrimer concentration. The second possible mechanism implied avehicle-dependent penetration enhancement. This approach usedpotent skin penetration enhancers such as IPM acting as stratumcorneum lipids. The presence of this skin penetration enhancer im-proved the dendrimer–drug complex skin penetration. Free drug skinpenetration results of synergitic effect of the lipid behaviors of vehicleand dendrimer.Moreover, pre-treatment enhances drug skin diffusivityversus skin co-treatment. The unloaded dendrimers in the SC can func-tion as a depot and increase the solubility of drugs in the SC. The lastmechanism concerned dendrimer skin penetration via hair follicles onthe skin's surface (0.1%). To the best of our knowledge, no report hasbeen published showing the skin penetration by dendrimer using this

route. Up to now, only polystyrene nanoparticles have demonstrated



http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


9/16

their capability to penetrate the skin through the follicular route. Fig. 3shows 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 byS. Hong and coworkers [85], strongly sustained and completed the pre-

vious conclusions submitted by P. Perumal et al., and very helpfully,showed that 1-octanol/PBS partition coef cient can be manipulated asa predictor of skin permeation. The main goal of this study was tofully investigate the effects of generation PAMAM dendrimer size, mo-lecular weight, surface charge and hydrophobicity as key parametersfor skin penetration (Table 3). All these parameters (surface charge,molecular weight) dened ideal limits based on understanding of theinteraction between skin membrane layers and surface-engineereddendrimers, and can be used to design dendrimer-based nanocarriersfor drug delivery to skin.

In another similar study, P. Perumal et al. [86] showed the identi-cal ranking order, than PAMAM dendrimers alone, of pig skin perme-ation enhancement of the hydrophilic drug 5-uorouracil (5-FU)using PAMAM dendrimers as enhancers with IPM as vehicle, andpre-treatment approach: G4-NH2 >G4-OH>G3.5-CO2H. 5-FU is ahydrophilic drug (logP=−0.89) showing poor permeability throughthe skin. 5-FU is currently used in the treatment of psoriasis, prema-lignant and malignant skin diseases. In another work, the sameauthors 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 phosphatebuffer (PB), mineral oil (MO) and IPM. Pre-treatment with dendrimersincreased permeability coef cient of 5-FU ~2-4-folds in the lipophilicvehicles MO and IPM, but not in PB (Fig. 4). The same conclusion wasobserved in co-treatment. Notably, the decrease in skin resistance isdirectly correlated with the enhancement in skin penetration of 5-FU.The transdermaldrugpermeability coef cient wasinversely proportional

to the molecular weight of the dendrimer, suggesting that small PAMAMdendrimers are the most effective ones.Hereafter, among the quite few reports, we highlight the most

relevant studies related to skin permeation with dendrimers. Simul-taneous different studies done about dendrimeric architectures forboth transdermal and oral drug delivery (vide infra) have demon-strated that dendrimers take up both paracellular and transcellularroutes for crossing the epithelial barrier of the cells, and set up asupplementary itinerary for accessing systemic circulation [87].

In early studies, Wang and coworkers emphasized the utilization of ef cient pre-treatment transdermal drug delivery system based onpolyhydroxyalkanoate (PHA) matrix and G3-PAMAM dendrimer. PHAwas a mixture of 3-hydroxyhexanoic acid (8%) and 3-hydroxyoctanoicacid (92%). Tamsulosin hydrochloride, a charged compound (selectiveα1A-adrenoceptor antagonist) which cannot permeate the stratumcorneum showed good transdermal penetration ef ciency for 24 hwhen administered with PHA coadministrated with G3-PAMAM invitro in snake skin (Python reticulates) model (15.7 μ g/cm2/d for PHAversus 24 μ g/cm2/d for PAMAM dendrimers containing PHA matrices).

(stratum corneum)

VE

(viable epidermis)

DE

(dermis)

Vehicle

Dendrimer-drug

encapsulate Rapid drug

releaseDrug

Drug solubilisation

in the vehicle

Vehicle: skin

penetration enhancers

Dendrimer-drug

encapsulate

Drug

Drug release

Dendrimer-drugencapsulate

Drug release

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]).



http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


10/16

The authors concluded that PHA-dendrimer matrix achieved clinicalobjective, and is a very useful material for clinical transdermal drug de-livery system [88]. Then, taking this into consideration, the same au-thors studied the mechanism of the enhancement effect of G2.5-andG3-PAMAM dendrimers [89]. Only cationic dendrimers increased theskin penetration of tamsulosin hydrochloride. Interestingly, based onX-ray analysis, the authors found that tamsulosin crystals have highlyordered orientation in the dendrimer-PHA matrix promoting drug re-lease in contrario to drug crystallization effect in other transdermal

drug delivery system [90].Another example has been describedby thesame team regarding the

transdermal drug delivery of both ketoprofen and clonidine throughsnake skin from PHA matrix by co-treatment using G3-PAMAM andG2.5-PAMAM dendrimers and chloroform–methanol mixture as vehicle.No enhancement effect for the two drugs has been observed [91].

J. R. Baker and co-workers described the transdermal ability forthe delivery of gene, in a mice transfection assay, using solid supportcollagen-phosphatidyl glycerol membranes in the presence of PAMAMdendrimers [92]. In the absence of PAMAM dendrimers, no signicantexpression of chloramphenicol acetyltransferase (CAT) reporter wasobserved. Based on membrane-mediated gene transfection, the CATexpression reached 50–250 pg/mg of the skin homogenates in the pres-ence of dendrimers. Keratinocytes or dermalbroblasts are the primary

types of transfected cells. Consequently, these studies provide supportfor the use of transdermal diffusion system for in vitro and in vivo trans-fection of skin cells.

Non-steroidal anti-inammatory drugs (NSAIDs) are the mostfrequently used drugs in the world. A representative example is indo-methacin which is a hydrophobic drug (logP ~4.2). Chauhan et al.reported that G4-NH2, G4-OH and G-4.5-CO2H-PAMAM dendrimersenhanced indomethacin skin penetration in vitro in rat skin mem-brane model using co-treatment and water as vehicle [93]. Interest-ingly, the steady-state ux of indomethacin increased linearly withan increase in dendrimer concentration in the formulations versusthe plain drug, despite the non-linear increase in solubility. In addi-tion, based on this study, in vivo pharmacokinetic and pharmacody-namic 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 sus-pension. The [AUC]0–24h of G4-NH2 and G4-OH formulations arehigher than pure drug with a ratio of 2.27 times and 1.95 foldsrespectively. The G4-PAMAM dendrimers maintained the effective in-domethacin concentration in the blood for 24 h. Low improvementwas observed with G-4.5-PAMAM dendrimer formulation.

Another in vivo study has been performed by Y. Chen. et al. regard-ing the transdermal delivery of both ketoprofen and diunisal asmodel drugs [94]. From a general point of view, oral administration

of NSAIDs is effective, but their clinical use is often limited by severaladverse side effects such as adverse gastrointestinal and renal events,and hypersensitivity reactions [95]. Consequently, transdermaladministration represents an interesting alternative to these sideeffects. Thus, in vitro permeation studies – using excised rat skinmodel – indicated that PAMAM dendrimer suspension formulationsin water highly enhanced, by as much as 4-fold, the accumulative per-meated amount of both drugs after 24 h, in comparison with drugsuspensions without PAMAM dendrimers. The NSAIDs fraction inthe complex is estimated at 39% (w/w) and 27% (w/w) for ketoprofenand diunisal, respectively. Improvement of the water-solubility of these two drugs by their respective complexation with PAMAMdendrimers should explain the potency improvement. Interestingly,in in vivo antinociceptive studies in rats (acetic acid-induced writhing

model) a prolonged pharmacodynamic prole was observed aftertransdermal administration (abdominal skin, 2 mg of each NSAID in100 μ L of formulation), for both NSAIDs-PAMAM dendrimer com-plexes. Analysis of blood drug levels showed that the bioavailabilitywas 2.73 times higher for the ketoprofen-PAMAM dendrimer com-plex and 2.48 times higher for the diunisal-PAMAM dendrimer com-plex, respectively, versus pure drug suspensions. Going into moredetail, similar tmax (5–4 h) were observed for ketoprofen–dendrimercomplex, plain ketoprofen, diunisal–dendrimer complex and plaindiunisal, improvement of ~3 times of the Cmax for the NSAID–dendrimer complexes in comparison to plain NSAIDs, and ~3 timesincrease of the [AUC]0–8/12 h for the NSAID–dendrimer complexes incomparison to plain NSAIDs. Undeniably, this work opens the doorto the development of this new transdermal drug formulation using

dendrimers as skin penetration enhancers.

Table 3

Relationships of structure-skin permeability of PAMAM dendrimers.

P. Perumal et al. [83,84] S. Hong et al. [85]

Vehicle: water Vehicle: waterPAMAM dendrimers in water PAMAM dendrimers in 70% ethanol solutionSurface 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)

Surface charge modicationsa:Neutral G2-dendrimer (−NHAc) showed higher skin permeation than G2-anionicdendrimer (−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 retentionLogPo/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 timeIonotophoresis skin penetration enhancer increase the skin penetration

of cationic and neutral dendrimersSize modications:

Passive and iontophoretic skin penetration of cationic dendrimerswas 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)

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: rhodamineB isothiocyanate as a uorescent probe.



http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


11/16

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 andto host 8-methoxypsiralene (8-MOP). 8-MOP is a photosensitizer forPUVA therapy (treatment of hyperproliferative skin disease like pso-riasis, vitiligo, etc. by UVA irradiation after oral or topical administra-tion of psoralene). The higher water solubilization was obtained withG3- and G4-PAMAM dendrimers [96]. The maximum weight% load of

8-methoxypsiralene in full-generation dendrimers G3 and G4 were9.4% and 10.4% respectively. Any precipitation of the host–guest com-pound was observed after dilution of the concentrated solutions withwater. The co-treatment of 3:1 host–guest complexes with G3- andG4-dendrimers diffused slowly through both polyvinyldiuoride andpig ear skin membranes, when released from o/w (octanol/water)emulsion, with value of time of 10% transfer (τ 0.1) of ~6.5 and ~9,respectively.

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 enhancethe solubility (~7–10 folds) of riboavin (B2 vitamin) in methanolaccording to the following order: G2≫G2.5>G3≫G3.5>G4 [97]. Thein vitro transdermal ability of dendrimer-B2 complexes, from o/w emul-sions, wasstudied in pig earskin membranemodel by co-treatment. The

diffusion of B2, in pig ear skin membrane permeation model, affordedthe following ranking: G2> G3≫G2.5> G3.5> G4 (none). The best per-meation enhancer for B2 was hydrophilic, small-sized (29 Å hydrody-namic diameter) G2-PAMAM dendrimer. The authors suggested that,reasonably, the multicomponent tissue of pig ear skin including fattycomponents acts itself as slight solubilizer of riboavin.

Another representative example is the furfural permeation enhance-ment through rat skin model using G5-PAMAM dendrimers in water asvehicle by co- and pre-treatment [98].

K. D. Kramer and co-workers emphasized in a recent paper theskin penetration enhancement of Nile red incorporated in dendriticcore-multishell as nanotransporter (CMS) [99]. Nile red is a lipophilicstain which is commonly used for the detection of intracellularlipid 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 aC18-alkyl chain and PEG chains. Using co-treatment technique, dyeamounts increased eight-fold in the SC surface and thirteen-fold in theepidermis compared to the cream (Nile red cream 0.004%). Water wasthe vehicle used. Viable primary human keratinocytes showed aninternalization of the nanocarrier.

4.3. Dendrimers for oral drug release system

Despite strong advances in the injectable and transdermal routesof administration, the non-invasive oral drug delivery system remainswell ahead of the pack as the dominant delivery route.

To sum up, the main signicant advantages of oral drug moleculedelivery are: 1) low total dose, 2) low gastrointestinal side effects,3) reduced dosing frequency (dosing schedules), 4) good patient ac-ceptance and compliance, 5) less uctuation at plasma drug levels,6) more uniform drug effect, 7) improved ef cacy/safety ratio and8) low cost-effectiveness, versus the main defects which include:1) dose regiment, 2) immediate drug release causing toxicity in prac-tice, 3) reduced potential for accurate dose adjustment, 4) low drugsolubility in aqueous solutions and low penetration across intestinal

membranes issues and 5) stability problem [100]. Several attractivestrategies to overcome oral drug delivery issues (vide supra) suchas ab-sorption and distribution have been described focused on the develop-ment of different systems in which drugs are loaded into oral drugcarriers [101]. These systems are strongly related to physicochemicalproperties of macromolecular carriers. Some examples of nanocarriersused for oral drug delivery applications include micelles, liposomes,nanoemulsions, polymer therapeutics, dendrimers, etc. The main re-sults are the improvement of 1) drug solubility inducing good drug'spharmacokinetic/pharmacodynamic proles due to sustained drugconcentration within the therapeutic range at the injured regions and2) therapeutic index and the decrease of toxicity compared with freedrug [102].

Both dendrimer conjugating or encapsulating low-penetrating drug

molecules can easily penetrate through intestinal membranes– such as

(stratum corneum)

(viable epidermis)

(dermis)

2 2 2

7 14 17

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



http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


12/16

the epithelial barrier of the intestine – enhancing their oral absorption.Thus, designed highly water-soluble and biocompatible dendrimershave been shown to be able to improve important drug propertiessuch as solubility of orally administrated drugs and their stability in bi-ological environments. In addition, prolonged circulation half-life, in-creased concentration at the site action and decreased non-specictoxicity of loaded-drugs were highlighted [103]. Importantly, severalstudies showed the uptake of dendrimers through the lymphoid tissue

in the small intestine but not in the large intestine. These interesting re-sults 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 prep-aration of G3-NH2 and G3-Lauryl-PAMAM dendrimers conjugatingpropranolol which is a well-known competitive, but nonselective,β-adrenergic blocking agent that is used for treating high blood pres-sure, heart pain such as angina and abnormal rhythms of the heart[105]. The aim of this interesting study was to evaluate the effectson the transport of propranolol across monolayers of the humancolon adenocarcinoma cell line named Caco-2. Propranolol is a poorlysoluble drug and substrate of the P-glycoprotein (P-gp) ef ux trans-porter. The authors demonstrated that these dendrimers both wellsolubilized propanolol and signicantly evaded P-gp ef ux effect. Thus,interestingly, the apical (A) to basolateral (B) apparent permeability co-ef cient,Papp, of propranolol wasenhanced following conjugation to G3dendrimers or lauroyl-G3 dendrimers. In addition, theyalsoshowed thatthe A→B Papp of propranolol conjugates was reduced in the presence of the endocytosis inhibitor such as colchicine, suggesting that the en-hancement mechanism involves endocytosis-mediated transepithelialtransport. Very interestingly, the A→B Papp of conjugated propranololwas not altered in the presence of the P-gp inhibitor such as cyclosporinA. Consequently, the conjugation of drug to dendrimer allows thebypassing of the ef ux transporter. In addition, the decrease of cytotox-icity of PAMAM dendrimer conjugates, against Caco-2 cell lines, hasbeen observed with lipid chain–drug–dendrimer conjugates versusnon-modied dendrimer. Mechanistic studies, based on transepithelialelectrical resistance (TEER) measurements, conrmed that the en-hancement of the permeability through cell monolayer results in

the opening of the tight junctions by lipid chain–drug–dendrimerconjugates.

In in vivo studies, Florence et al. investigated the oral absorption(gavage) from rats (female Sprague Dawley) of G4-lysine dendrimerbearing 16 C12 linear alkyl chains on the surface (molecular weight:6300, clogPoctanol/water ~1.24) [106]. Oral administration of G4-dendrimer (single dose of 14 mg/kg), after 6 h following drug admin-istration, showed that the maximum levels of dendrimer observedwere 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, ~1–4% was absorbed throughPeyer's patches and small intestine enterocytes, versus 0.3% whichwas absorbed via Peyer's patches, and 4% via large intestine

enterocytes after 12 h. The total percentage of dendrimer absorbedthrough Peyer's patches, in the small intestine after 3 and 24 h, wasgreater than through normal enterocytes, but the opposite was ob-served in the large intestine. Interestingly, the authors compared theabsorption of PAMAM dendrimers with 50–3000 nm size polystyreneparticles. They highlighted that the levels of uptake and translocationfrom dendrimers are lower than those exhibited by 50 nm polystyreneparticles, suggesting that there is an optimum size for nanoparticulateuptake 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 water-soluble 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). Incuba-tion of these PAMAM dendrimer conjugates with rat homogenatecontents released 5-ASA with 45.6 and 57.0% of the dose after 24 h, re-spectively, while in the small intestine the release of 5-ASA, from bothdendrimer 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 orphosphate buffer, pH 1.2 and 6.8. The authors suggested that the drug

release from the dendrimer conjugate occurred through the cleavageof both amide bonds (between dendrimer and spacer) and azo bond(between spacer and 5-ASA). The last cleavage resulted in the cleavageof the azo bond by azoreductase enzyme in the colon. Consequently,these PAMAM dendrimer conjugates can be developed for use ascarriers for colon-specic drug delivery.

Prolonged delivery of ketoprofen-G5-PAMAM dendrimer complexin in vitro and in vivo (oral administration) studies has been describedby Na et al. [109]. The in vitro release of ketoprofen from the drug–dendrimer complex is signicantly slower compared with plainketoprofen. Interestingly, in acetic acid induced writhing model inKummingmice, sustainedpharmacodynamic behavior(anti-nociceptioneffect in acetic acid-induced writhing model) of ketoprofen–PAMAMdendrimer complex was observed after oral administration at the doseof 10 mg/kg weights. Blood level studies were investigated, andstrengthened the prolonged release of ketoprofen from ketoprofen–PAMAM dendrimer complex. The main pharmacokinetic parametersof plain ketoprofen versus ketoprofen-G5-PAMAM dendrimer complexare the following: tmax (h): 0.5 vs 1; Cmax (μ g/ml): 48.31 vs 51.58;[AUC]0–12 (μ g/ml/h): 137.23 vs 160.96.

Very interestingly, R. B. Kolhatkar et al. investigated the potentialapplication of G4-PAMAM dendrimer for improving the oral deliveryof SN-38. SN-38 is a potent topoisomerase I inhibitor and the activemetabolite of irinotecan hydrochloride (CPT-11) [110]. Stable andwater soluble complex between SN-38 and G4-PAMAM dendrimerincreased 10 folds the permeability across Caco-2 cell monolayersand more than hundred folds in cellular uptake with respect toplain drug.

Recently, the effects of G2-PAMAM dendrimer on the intestinal ab-

sorption of poorly absorbable drugs have been studied by an in situ closedloop 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 intestinewas signicantly enhanced in the presence of PAMAM dendrimers. Thesmall intestinal absorption of CF was concentration and generation de-pendent, and the maximum effect was obtained in the presence of 0.5%(w/v) of G2-PAMAM dendrimer. No effect was observed with FD10 andinsulin, and at G2-PAMAM dendrimer concentrations of 0.05% (w/v)and0.1%(w/v).Taken together, theincrease of thesmall intestine absorp-tion effects of G2-PAMAM dendrimer decreased as the molecular weightof drug increased. This effect is dendrimer concentration dependent. In-terestingly, G2-PAMAM dendrimer did notenhancethe intestinalabsorp-tionof these drugs withdifferent molecular weightsin the large intestine.

A myriad of in vitro studies have been performed concerning thetransepithelial transport and toxicity of dendrimers, mainly PAMAMdendrimers, and summarized in the S. Sadekar, H. Ghandehari [102],and V. Gajbhiye et al. [17] reviews. Thus, the penetration of dendrimersacross epithelial barrier depends upon several important parametershighlighted in Table 4.

4.4. Dendrimers for other controlled drug release systems

Other very interesting drug delivery systems using dendrimershave been explored recently, and are highlighted below.

In addition to Vivagel® (vide supra), in vitro intravaginal transportand biodistribution of G4-PAMAM dendrimer has been also describedusing intact fetal membrane (chorioamnion), and separated chorion

and amnion layers [116]. The dendrimer transport across all these



http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


13/16

three membranes was lower (b3%) for G4-PAMAM dendrimer versusG4-PAMAM dendrimer bearing conjugated uorescein (FITC) groupson the surface(> 49%). The permeabilityof FITC-G4-PAMAMdendrimer

was 7-fold higher than the permeability of G4-dendrimer through thechoriamnion membrane. Biodistribution studies showed that thesetwo dendrimers were largely present in interstitial spaces in the decid-ual stromal cells and chorionictrophoblast cells. Few amounts are pres-ent in nuclei (trophoblastand stromal cells). Theauthors suggestedthatpassive diffusion and paracellular transport are the major routes fordendrimer transport.

In early studies, C. A. Lemere and coworkers described theboosting effect with intranasal dendrimeric Aβ1-15 (16 copies of Aβ1-15 on a lysine tree) but not Aβ1-15 peptide affording immuneresponse following a single injection of Aβ1-40/42 in heterozygousAPP-tg mice [117]. In addition, good in vivo nasal absorption, in rats,of insulin and calcitonin using G3-PAMAM dendrimer was empha-sized 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-PAMAMdendrimer, showed good lung anti-inammation potency (associatedwith asthma) [119]. Thus, MP-G4-PAMAM dendrimer at the dose of 5 mg/kg (on a drug basis) improved the airway delivery in a pulmonaryinammatory murinemodel based on an 11-fold enhancement of eosin-ophil lung accumulation following ve daily inhalation exposures of sensitized mice to allergen ovalbumin. This study demonstrated thatMP-G4-PAMAM dendrimer enhances the ability of MP to decreaseallergen-induced inammation, probably by improving drug residencetime in thelung.Indeed,only 24%of a single dose of dendrimer deliveredto 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 respiratorytissues (release of protein and activities of LDH) [120]. PAMAMdendrimers increased the pulmonary absorption of both insulin and

calcitonin in rats. The absorption-enhancing effects were generationdependent with the following rank: G3>G2>G1>G0. In addition,for the same generation, this effect is concentration dependent. Inter-estingly, the absorption-enhancing effects of the protein-PAMAMdendrimers are linearly correlated with the positive charge of theprotein-PAMAM dendrimers which is determined by their zetapotential.

Enoxaparin–G2-(or G3)-PAMAM dendrimer complex is effective inpreventing deep vein thrombosis after pulmonary administration intothe lungs of anesthetized rats [121]. Enoxaparin is a low-molecularweight heparin. Positively charged dendrimers increased the relativebioavailability of enoxaparin by 40%, while a negatively chargeddendrimer had no effect. In addition, no adverse damage was observedto the lungs.

To sum up, importantly, the pulmonary route of administrationrepresentsa useful wayto treat specic lung diseases such as chronicinammatory disorders such as asthma. In this case, lung can beconsidered as the drug target. Dendrimers represent powerfulnanocarriers to target regional lung deposition. Note that two veryinteresting 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 docu-ments to build andoptimize new nanocarriers forthe delivery of bio-actives through the inhalation route. In addition, recently, J. K-W.Lam et al. reviewed the pulmonary delivery of therapeutic siRNAusing lipid-based delivery vectors (cationic lipoplexes and lipo-somes, PEGylated lipids, neutral lipids and lipids particles) andpolymer-based delivery vectors (synthetic polymer PEI, chitosan

and PLGA) [124].

Table 4

Main factors inuencing the permeability of dendrimers across the epithelial barriers.

Dendrimer effects on oralpermeability

Studies and results References

Generation sizeFITC 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.

[112]

Interaction and hole formation studies by G7-PAMAM dendrimers against KB and Ray2 cell membranes. G7-NH2PAMAM 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.

[113]

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.

[87]

Surface chargePermeability 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 dendrimersathwart Caco-2 cell monolayers.

[112]

G0-2-PAMAM dendrimers were non-toxic to the cells versus higher generations. Mannitol permeability increased withgeneration size (BA direction>AB direction).

112

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

[91]

ConcentrationPermeability coef cients (Papp) of G2-PAMAM dendrimer depends upon concentration of dendrimers across MDCK.a [112]Internalization of G5-PAMAM dendrimer in Rat2 cell lines increased with the dendrimer concentration. No effect withAc-G5-PAMAM dendrimer

[113]

Uptake rate of cationic G3- and G4-PAMAM dendrimers increased with their concentration. No effect with anionicG5.5-PAMAM dendrimer [83,84]

Ef ux transporterPermeability of paclitaxel across Caco-2 cell monolayers was higher in BA direction as compared to AB direction whereas thepermeability of G2-PAMAM dendrimer was identical in both directions➩ P-gp ef ux system does not affect dendrimer transport.

[114]

Surface modicationImprovement of the permeability coef cients (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 conjugateddendrimers. This lipid chain effect increased with the number of attached lipid chains.

[115]

a Madin–Darby Canine Kidney (same permeability characteristics than Caco-2 cell lines).



http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.addr.2013.01.001http://dx.doi.org/10.1016/j.addr.2013.01.001http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


14/16

5. Conclusion

The choice of the route of administration– related to delivery devicetechnologies – remains the utmost important challenge regarding bothdosing, frequency of dosing, dose volume, number of treatments, etc. Inan 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 thera-peutic ef cacy. Taken together, these ndings suggest the best routeof administration in order to maximize the therapeutic effect andminimize the toxicity effects.

It is well known, that polymeric drug delivery systems can highly en-hance bioavailabilities and therapeutic ef cacies (versus the plain drug)and decrease the side effects of drugs. In this direction, due to their tun-able physico-chemical properties, bio-compatible dendrimers – whichare unique in comparison with other classical nanoparticles– representoutstanding choice of nano-carriers of a large variety of drugs such assmall molecules, siRNA, antibodies, etc.Both, nonnoncovalent encapsu-lation o

apps and bio properties

Documents