Hydrogel nanoparticles(7)

was235.5with the drug encapsulation ef?ciencies of70–90%,80–90%, and88–95%for INH,RIF,and EMB,respectively.The bioavailability of all drugs encapsulated in alginate NPs were signi?cantly higher than those with free drugs.Moreover,local administration of inhalable alginate-based NPs bearing the same drugs except for EMB has been attempted by Ahmad et al.[202]with both loading capacity and sizes comparable to the previous study.Recently,another study has been published by the same research group,dealing with the chemother-apeutic evaluation of alginate NP-encapsulated azol antifungal and antitubercular drugs against murine tuberculosis[201].A series of other studies involving NPs of alginate origin is currently available in the literature[204–206].

3.3.Poly(vinyl alcohol)-based hydrogel nanoparticles

Poly(vinyl alcohol),PVA,is the product of free radical polymerization of vinyl acetate with subsequent hydrolysis of acetate groups to hydroxyl moieties resulting in a wide molecular weight distribution.The molecular weight distribution is an important characteristic due to its roles in determining polymer properties including crystallizability, adhesion,mechanical strength,and diffusivity.PVA is among the most promising polymer candidates for hydrogel studies.Crosslinking of PVA polymeric chains is carried out using chemical(e.g.,crosslinking agents, electron beam,γ-irradiation)as well as physical(e.g.,freezing/thawing) methods,with the crosslinks being critical for PVA in order to be useful for various applications in medical and pharmaceutical?elds[207].

In late1990s,PVA NPs were prepared with the aim of protein/peptide drug delivery using a water-in-oil emulsion/cyclic freezing–thawing procedure[208].In this study,the emulsion was kept frozen at?20°C followed by a thawing phase at ambient temperature and no emulsi?er involved.The average diameter of PVA NPs obtained was675.5±42.7nm with a skewed or log-normalized size distribution.Bovine serum albumin, BSA,was loaded in this study in nanogels with a notable loading ef?ciency of96.2±3.8%and a diffusion-controlled release trend.In another study, three separate production methods,including salting-out,emulsi?cation diffusion,and nanoprecipitation,have been used by Galindo-Rodriguez et al.as a comparative scale-up production evaluation to reach PVA-based NPs loaded with ibuprofen[209].The pilot-scale stirring rates of790–2000rpm led to mean sizes ranging from174to557nm for salting-out and from230to565nm for emulsi?cation diffusion.

Heterogeneously structured composites involving PVA have been interested in the?eld of hydrogel nanoparticles.Biodegradable polyesters consisting of short poly(lactone)chains grafted to PVA or charge-modi?ed sulfobutyl-PVA(SB-PVA)were prepared and used as a novel class of water soluble comb-like polyesters.These polymers undergo spontaneous self-assembling to produce NPs,which form stable complexes with a number of proteins such as human serum albumin,tetanous toxoid and cytochrom C[210].However,the development of NPs from such polymers does not require the use of solvents or surfactants[211–213].

Preparation of PVA-based NPs encapsulated by poly(lactide-co-glycolic acid)(PLGA)microspheres[214],preparation and release kinetic evaluation of poly(N-vinyl caprolactone)NPs loaded by nandolo,propranolol,and tacrine[215],attempts to aerosol therapy using the biodegradable NPs prepared by branched polyesters diethylaminopropyl amine-poly(vinyl alcohol)-grafted-poly(lactide-co-glycolide)(DEAPA-PVA-g-PLGA)[216],DNA nanocarriers formed by a modi?ed solvent displacement method[217],and the study on local delivery of paclitaxel via drug-loaded PVA-g-PLGA NPs for the treatment of restenosis[218]have all been reported in recent years using PVA or its derivatives as a basis for hydrogel formation.

3.4.Poly(ethylene oxide)and poly(ethyleneimine)-based hydrogel nanoparticles

A new family of nanoscale materials on the basis of dispersed networks of crosslinked poly(ethylene oxide)(PEO)and poly(ethyle-neimine)(PEI),PEO-cl-PEI,has been developed[219].Interaction of anionic/amphiphilic molecules or oligonucleotides with PEO-cl-PEI results in formation of nanocomposite materials in which the hydro-phobic regions from polyion complex are joined by the hydrophilic PEO chain[220].Formation of polyion complex leads to the collapse of the dispersed gel particles.However,the complexes form stable aqueous dispersions due to the stabilizing effect of the PEO chain.These systems allow for immobilization of negatively charged biologically active compounds such as retinoic acid,indomethacin[221],and oligonucleo-tides(bound to polycation chains)or hydrophobic molecules(incorpo-rated into nonpolar regions of polyion–surfactant complexes)[219].The nanogel particles carrying biologically active compounds have been modi?ed with polypeptide ligands to enhance receptor-mediated delivery.Ef?cient cellular uptake and intracellular release of oligonu-cleotide immobilized in PEO-cl-PEI nanogel have been demonstrated [222].Antisense activity of an oligonucleotide in a cell model was enhanced as a result of formation of oligonucleotide-nanogel associa-tion.This delivery system has a potential of enhancing oral[220]and brain[223–225]bioavailability of oligonucleotides as demonstrated using polarized epithelial and brain mircrovessel endothelial cell monolayers.PEO-cl-PEI nanogels were synthesized by crosslinking of branched PEI with bis-activated PEO molecules[220].When conducted in a homogenous aqueous solution,the reaction between amino groups of PEI and imidazolylcarbonyl ends of activated PEO proceeded very rapidly,resulting in formation of transparent hydrogels in only3–5min. These bulk hydrogels retained large quantities of water reaching approximately50-fold by weight,compared to the dried substance. Rigid hydrogels could be produced at the minimal PEO/PEI molar ratio of 6or higher.To obtain?ne disperse systems,the crosslinking reaction was performed by a modi?ed solvent emulsi?cation/evaporation method[226].According to this method,activated PEO solution in dichloromethane was emulsi?ed in the aqueous solution of PEI by sonication.The organic solvent was removed from the mixture in vacuo resulting in formation of a clear suspension.Most of the nanogel particles have had a very low density and could not be fractioned by ultracentrifugation.Therefore,crude suspension of nanogel particles was partitioned using gel-permeation chromatography.Several frac-tions could be separated by particle size from300to400nm,with a major fraction having average particle diameters between150and 240nm.

3.5.Poly(vinyl pyrrolidone)-based hydrogel nanoparticles

Poly(vinyl pyrrolidone),PVP,is a hydrophilic polymer generally known and approved by FDA as a biocompatible and non-antigenic compound[227]and is therefore safe for biological experiments. Baharali et al.have described a procedure for preparation PVP-based hydrogel NPs with?nal diameter less than100nm,using the aqueous cores of reverse micellar droplets as nanoreactors[228].Since the reverse micellar droplets are highly monodispersed and the droplet sizes can be well-controlled,the NPs prepared using a reverse micellar medium are ideally monodispersed with narrow size distribution. Moreover,their size can be modulated by controlling the size of the reverse micellar droplets[229].

Guowie et al.[230]have synthesized and characterized a magnetic micromolecular delivery system based on PVP hydrogel with PVA as crosslinker.The PVP hydrogel magnetic nanospheres exhibited passive drug release that could be exploited to enhance therapeutic ef?cacy.The results indicated that hydrogel PVP-based magnetic nanospheres have the potential as drug carriers in magnetically guided chemotherapeutic drug delivery.

3.6.Poly-N-isopropylacrylamide-based hydrogel nanoparticles

Poly-N-isopropylacrylamide(PNIPAM)is perhaps the most well known member of the class of responsive polymers.Free chains of

1644M.Hamidi et al./Advanced Drug Delivery Reviews60(2008)1638–1649

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