Advanced Drug Delivery Reviews 53 (2001) 1–3www.elsevier.com/ locate /drugdeliv

Preface

Polymeric materials for advanced drug delivery

One of the enduring features of drug delivery biosynthetic principles and potential uses of PHAs istechnology is the central role that polymers play in provided here in a review by Zinn et al.control of drug release, and fabrication of drug Synthetic biodegradable polymers continue todelivery devices. The need for polymers with spe- develop, to allow finer control of biocompatibility,cific physical and biological properties has generated surface properties and drug release. In this issue,continuing interest in novel polymer synthesis, both Domb et al. describe the chemistry and uses of blockfrom academic and commercial environments. This copolymers with a biodegradable element. Typicalissue of Advanced Drug Delivery Reviews brings materials of interest are block polymers of poly(lac-together articles that reflect recent trends and ad- tide-co-glycolide) with polyoxyethylene (widelyvances in pharmaceutical polymer science. known as polyethylene glycol or PEG). The water–

Parenteral systems need to be biocompatible, and soluble nature of PEG confers useful physical prop-in many cases, are required to be biodegradable. The erties on the material, such as a reduction in extentmost well known class of biodegradable materials for of protein adsorption. Block copolymerisation offerscontrolled release are poly(lactide-co-glycolide)s, the opportunity to change the surface properties ofwhich were originally synthesised for use in manu- solid polymers, and hence the biological response tofacture of resorbable sutures. These copolymers have a polymer [4]. Using such strategies, prostheticbeen developed as commercial products for sustained devices or implants could be made more biocompat-delivery of therapeutic peptides by careful control of ible, or the technology could be used to control cellpolymer molecular weight, copolymer ratio, drug growth in tissue engineering applications. Surfaceloading and device fabrication (see for example modification also has the potential to modify biodis-[1,2]). A close chemical relative, polyhydrox- tribution of colloidal drug delivery systems, in aybutyrate (PHB) is a natural storage material in manner analogous to the changes brought about bysome bacteria. PHB has been produced in ton PEGylation of proteins [5,6]. There are also oppor-quantities by bulk biosynthesis as a potential bio- tunities to create structure within an aqueous en-degradable commodity polymer. This material has vironment. There is growing interest in polymericbeen available for several years and awaits the right micellization, which provides an example of how thesocio-economic conditions to fulfil its full potential chemistry of the polymer can be used to design thein bulk packaging, but its applications in biomedical morphology of the material in solution [7]. Onetechnology would certainly not be inhibited by cost. flexible group of biodegradable polymers which hasPHB is one of a broader group of polyhydroxy- received considerable attention since their intro-alkanoates (PHAs) which can be manufactured by duction in the 1970s is poly(orthoesters). Control ofbiosynthesis using a variety of microrganisms. chemistry allows viscous, injectable materials to beMedium chain length PHA copolymers are particu- synthesised. Their potential biomedical applicationslarly interesting candidates for drug delivery in view are reviewed in this issue by Gurny et al. Recentof their physical properties (lower melting point and developments have seen the introduction of ‘auto-lower degree of crystallinity) [3]. An update of the catalytic’ poly(orthoester)s with lactate residues

0169-409X/01/$ – see front matter 2001 Published by Elsevier Science B.V.PII : S0169-409X( 01 )00236-8

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within the polymer backbone. The mechanisms of of such particles by grafting functional groups ontobiodegradation have now been elucidated, which will their surfaces. It may be possible to regulate drugaid development of drug delivery systems with these release by including channel proteins or other pore-bioerodible materials. Ophthalmic applications are of forming agents within the capsule shell.particular interest, given the relative ease of adminis- The objective of producing polymeric systems thattration. are capable of responding to pH could be met by

One of the greatest contemporary challenges to utilizing polymers with a combination of alternatingdrug delivery science is to improve the efficiency of hydrophobic and charged units. Charged chains are‘non-viral’ gene delivery, which has great potential typically extended due to ionic repulsion, and loss offor pharmaceutical development but at present is charge mediated by a pH change can cause theextremely inefficient [8,9]. Polymers may well play a polymer to condense. Given that biological compart-role in future developments, either to promote par- ments vary in pH and that abnormal physiology mayticle escape from the endosome or to act as a generate a pH gradient, there is the potential forscaffold for DNA condensation and coupling of polymeric systems to be ‘bioresponsive’. Ultimatelybioactive ligands. Polyethyleneimine (PEI) is able to it may be possible to develop systems which mimiccondense DNA and promote endosomal escape the complex interactions which are typical of bio-because not all of its nitrogen atoms are protonated logical molecules, or alternatively produce hybridat neutral pH. PEI is sufficiently cationic to condense systems which couple polymers with bioactive com-DNA at neutral pH but is further protonated at the ponents [10,11]. Tonge and Tighe review the pro-lower endosomal pH, and this causes endsomal gress in this exciting field. One technique that mayescape by mechanisms which are not fully eluci- accelerate progress in design of novel polymers, isdated. An analogous effect can be achieved using combinatorial synthesis, which may allow an exami-copolymers which contain both lysine and histidine nation of the differences in properties within largeresidues, which is explained by the difference in pK groups of related copolymers. Brocchini has ad-a

of the two side chains. Midoux et al. review this dressed the potential of combinatorial chemistry, andapproach, which has the advantage that such poly- discussed methods that could be used for analysis ofmers will be biodegradable. The approach of this the polymeric products and high throughput screen-group has been to graft histidine onto polylysine to ing of their physicochemical properties.produce a copolymer which has both primary aminesand imidazole groups, and can function in an analo-gous manner to PEI. Additional attributes will need Acknowledgementsto be build into DNA delivery systems to enable theDNA payload to be transported within the cytoplasm As theme editor, I thank the authors for theirand delivered to the cell nucleus, but the core of a excellent contributions to this issue, which I am sureDNA delivery system could well include endosmal will stimulate further innovation in copolymer de-escape systems such as those described by Midoux et sign, and point the way towards new pharmaceuticalal. applications of polymers.

Construction of future gene delivery systems willrely on developments in the design of block poly-mers and advances in the understanding of sup- Referencesramolecular self-assembly, a technology which willhave an impact on many other biomedical applica- [1] R.A. Jain, The manufacturing techniques of various drugtions. Klok et al. review self-assembly of polymer loaded biodegradable poly(lactide-co-glycolide) (PLGA) de-

vices, Biomaterials 21 (2000) 2475–2490.micelles and discuss techniques for cross-linking[2] P. Johansen, Y. Men, H.P. Merkle, B. Gander, Revisitingmicelles to produce stable particles. By including

PLA/PLGA microspheres: an analysis of their potential indegradable components it is possible to engineer parenteral vaccination, Eur. J. Pharm. Biopharm. 50 (2000)hollow nanoparticles of defined size, and there are 129–146.opportunities for modifying the biological properties [3] C.W. Pouton, S. Akhtar, Biosynthetic polyhydroxyalkanoates

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and their potential in drug delivery, Adv. Drug Deliv. Rev. in the design of protein-based constructs: hybrid hydrogels18 (1996) 133–162. and epitope displays, J. Controlled Release 72 (2001) 57–70.

[4] P. Bures, Y. Huang, E. Oral, N.A. Peppas, Surface modi- [11] K. Kirshenbaum, R.N. Zuckermann, K.A. Dill, Designingfications and molecular imprinting of polymers in medical polymers that mimic biomolecules, Curr. Opin. Struct. Biol.and pharmaceutical applications, J. Controlled Release 72 9 (1999) 530–535.(2001) 25–33.

[5] F.M. Veronese, Peptide and protein PEGylation: a review of Colin W. Poutonproblems and solutions, Biomaterials 22 (2001) 405–417.

(Theme Editor)[6] A. Kozlowski, J.M. Harris, Improvements in proteinPEGylation: pegylated interferons for treatment of hepatitisC, J. Controlled Release 72 (2001) 217–224. Victorian College of Pharmacy

[7] V.P. Torchilin, Structure and design of polymeric surfactant- Monash University (Parkville Campus)based drug delivery systems, J. Controlled Release 73 (2001) 381 Royal Parade137–172.

Parkville[8] C.W. Pouton, L.W. Seymour, Key issues in gene delivery,Victoria 3052Adv. Drug Deliv. Rev. 34 (1998) 3–19.

[9] M.C. Garnett, Gene-delivery systems using cationic poly- Australiamers, Crit. Rev. Ther. Drug Carrier Syst. 16 (1999) 147– E-mail: colin.pouton@vcp.monash.edu.au207.

[10] A. Tang, C. Wang, R.J. Stewart, J. Kopecek, The coiled coils