associates have provided synthetic roots for improved appli- heir e in ph 1993).Griffit and I namic therapy diation of PEO star po of PEO th tec ast oiologicaldrug livery application rareports of the f olymers as templa nd thei mesh size in detail (St inge and Peppa 996).Micelles o may not be imm ause of the stealth nature of hom and c lyvinyl alc A)ha Peptide nd prote delivery app andom rates but graft on drug t th ally when山e PH-sensit promise ing applicatior of such sys been dis sed.Other hydr with alternative thod of targetn ery vehicle of PEC oas and Sahlin. 1996).Such tures (Kevs atal.199) th due to in pen Controlling drug phar macokineties and targeting PEG chains could be added t ntly 'sp (PEG)to 1997).Such systems,espe ly those 1994)that can no one week in humar ling application non-im which Research has also been ted by th corpo arge mo cule,the iodistrib of th is sitive hydr en used in cer chemotherapy.The con ent is that lo ta灯 gh cancer drug e the given int nd Peppas,19 St memb Thus the drug is istribute be om NIPAAmC-MAA hydro ith no Ho ed so th ange in lood the polymer-drug jugate for thods of deli hydrogels have been recent reported.For example various sugar-containing copolymer Be most nc tissues have intac eutic ae K ecek and s have or that has a bed (Dur an et for releas 99 last few yean there have be new methods of upled The conjugates an be cleav rs than in no blies for drug deliv (O free drug (Duncan et al,1996:Mur ami et al 1997) a large numb The injection of a styrene-maleic anhydride copolymer cou 2994 December 2003 Vol.49.No.12 AIChE Journal associates have provided synthetic roots for improved appli￾cation of such systems. For example, hydroxypropyl methacrylamide-based copolymers and hydrogels have been developed for use in photodynamic crosslinking Shen et al., Ž 1996 . Such polymers could potentially be used in photody- . namic therapy of tumors. Hydrogels of PEO have received significant attention in the last few years, especially because of their associated stealth characteristics in certain biological drug delivery applications. Radiation-crosslinked PEO hydrogels have been prepared and their mesh size and drug diffusional behavior have been analyzed in detail Stringer and Peppas, 1996 . Micelles of Ž . PEO with various other comonomers are promising systems for release of drugs because of the stealth nature of particles prepared from these polymers. Poly vinyl alcohol PVA has Ž .Ž . also received significant attention in recent studies. For ex￾ample, PVA hydrogels Peppas and Mongia, 1997 have been Ž . well characterized and various studies have been performed on drug transport through these structures. Of particular promise are PVA hydrogels prepared by a freezingrthawing process that creates crystallites and forms a physically-cross￾linked 3-D network. Bioadhesi®e Hydrogels. An alternative method of targeting drugs to specific sites is by the use of bioadhesive and mu￾coadhesive hydrogels Peppas and Sahlin, 1996 . Such sys- Ž . tems usually consist of hydrogen-bonded structures such as poly acrylic acid PAA -based hydrogels which adhere to the Ž .Ž . mucosa due to hydrogen bonding andror polymer chain pen￾etration into the mucosa or tissue. In one study Sahlin and Peppas indicated that linear PEG chains could be added to PAA-based mucoadhesives either as free chains or as teth￾ered structures to serve as mucoadhesion promoters Sahlin Ž and Peppas, 1997 . Such systems, especially those prepared . from PVA, can be promising for wound healing applications Ž . Mongia et al., 1996 . Glucose-Sensiti®e Hydrogels. Research has also been con￾ducted in the utilization of environmentally responsive hydro￾gels as glucose-sensitive systems. Typically, this is achieved by incorporation of glucose oxidase Podual et al., 2000a during Ž . or after the polymerization for the production of pH- or tem￾perature-sensitive hydrogels. Other Hydrogels. Environmentally-sensitive hydrogels have been reported as excellent agents for the release of fibri￾nolytic enzymes or heparin Brazel and Peppas, 1996 . Strep- Ž . tokinase can be released from P NIPAAm-co-MAA hydro- Ž . gels by a simple change of temperature and pH in a narrow range. New methods of delivery of chemotherapeutic agents using hydrogels have been recently reported. For example, biorecognition of various sugar-containing copolymers Ž . Putnam et al., 1996 can be used for the release of chemotherapeutic agents. Kopecek and associates have used poly N-2-hydroxypropyl methacrylamide carriers for release Ž . of a wide range of such agents. In the last few years there have been new methods of preparation of hydrophilic polymers and hydrogels that may be used in the future in drug delivery applications. For exam￾ple, novel biodegradable polymers include polyrotaxanes, which are considered potentially useful for molecular assem￾blies for drug delivery Ooya and Yui, 1997 . Dendrimers and Ž . star polymers are new materials that enable a large number of functional groups to be available in a very small volume. Merrill has offered a useful review of PEO star polymers and their applications in the biomedical and pharmaceutical fields Ž . Ž. Merrill, 1993 . Griffith and Lopina 1995 prepared gels of controlled structure and large biological functionality by irra￾diation of PEO star polymers. Such gels may be promising materials as carriers for drug delivery if combined with tech￾niques of molecular imprinting. Indeed, there have been sev￾eral reports of the use of crosslinked polymers as templates for drug imprinting and subsequent release Cheong et al., Ž 1997 . Still, this field is relatively new and its applications . may not be immediately forthcoming. Thus, new synthetic methods have been used to prepare homo- and copolymeric hydrogels for a wide range of drug, peptide, and protein delivery applications. Random copoly￾mers with balanced hydrophobicityrhydrophilicity can offer desirable release rates and dissolution profiles, but graft, block, and comb-like copolymers offer additional advantages, especially when they contain temperature- or pH-sensitive pendent groups. Several interesting applications of such sys￾tems in the treatment of diabetes, osteoporosis, cancer or thrombosis have been discussed. Other hydrogels with promise as drug delivery vehicles include neutral gels of PEO or PVA, and gels of star molecules and other complex struc￾tures Keys at al., 1998 . Ž . Controlling drug pharmacokinetics and targeting One approach for altering the drug’s pharmacokinetics and duration of action is to covalently couple polymers such as polyethylene glycol PEG to it. This has been used to Ž . lengthen the lifetime of proteins such as interferon Burn- Ž ham, 1994 that can now last up to one week in humans. . For tissue targeting, water-soluble non-immunogenic bio￾compatible polymers, which will either degrade or be elimi￾nated by the body, are chemically linked to drugs, ideally through bonds that are cleaved once they reach their target Ž . for example, a tumor . By changing the drug from a small to a large molecule, the biodistribution of the drug is altered Ž . Duncan et al., 1996; Putnam et al., 1995 . This approach has been used in cancer chemotherapy. The concept is that low molecular weight anticancer drugs when given intravenously will penetrate most tissues because they pass rapidly through cell membranes. Thus, the drug is quickly distributed throughout the body, with no tumor selectivity. However, if the polymer-drug linkages are designed so that they are sta￾ble in blood, the polymer-drug conjugate circulates for a longer time than just the drug itself because the high molecu￾lar weight polymer-drug can generally only gain entry to cells by endocytosis. Because most normal tissues have intact non-leaky microvasculature, the polymer-drug accumulates more in the tumor that has a leaky vascular bed Duncan et Ž al., 1996; Putnam and Kopecek, 1995 . One approach in- . volves N- 2-hydroxypropyl methacrylamide HPMA copoly- Ž. Ž mer coupled to doxorubicin. The conjugates can be cleaved . by thiol-dependent proteases in lysosomes. Nearly seventy times more doxorubicin accumulates in mouse melanoma tu￾mors than in normal tissues. Furthermore, the maximum tol￾erated dose of the polymer-drug is 510 times greater than the free drug Duncan et al., 1996; Murakami et al., 1997 . Ž . The injection of a styrene-maleic anhydride copolymer cou- 2994 December 2003 Vol. 49, No. 12 AIChE Journal