Poly (L-glutamic acid)-Paclitaxel Conjugates for Cancer Treatment

One of the effective approaches to develop new anticancer drugs is to prepare polymeranticancer drug conjugates. The polymer-anticancer drug conjugates include polymerprotein conjugates, polymer-drug conjugates and supramolecular drug-delivery systems. In 1975, the concept of a polymer-drug conjugate was first proposed by Ringsdorf (Ringsdorf, 1975). In his model, a bioactive anticancer agent was attached to a suitable polymeric carrier, directly or through a biodegradable linker. Currently developed delivery systems for anticancer agents encompass colloidal systems (liposomes, emulsions, nanoparticles and micelles), polymer implants and polymer conjugates. These delivery systems are able to provide enhanced therapeutic efficacy and reduce toxicity of anticancer agents mainly by altering the pharmacokinetics and biodistribution of the drugs (Kim & Lim, 2002). The idea is attractive and could form the basis of a new generation of anticancer agents (Sugahara et al., 2007). Many polymers have been investigated as carriers for conjugates, including poly(glutamic acid), poly(L-lysine), poly(malic acid), poly(aspartamides), poly((N-hydroxyethyl)-L glutamine), poly(ethylene glycol), poly(styrene-co-maleic acid/anhydride), poly(N-(2hydroxypropyl) methacrylamide) copolymer, poly(ethyleneimine), poly(acroloylmorpholine), poly(vinylpyrrolidone), poly(vinylalcohol), poly(amidoamines), divinylethermaleic anhydride/acid copolymer, dextran, pullulan, mannan, dextrin, chitosan, hyaluronic acid and proteins etc.. Coupling low molecular weight anticancer drugs to high or low molecular weight polymers is an effective method for improving the therapeutic index of clinically used agents. Several candidates have been evaluated in clinical trials, such as N-(2-hydroxypropyl) methacrylamide conjugates of doxorubicin, camptothecin, paclitaxel, and platinum (II) complexes (Haag & Kratz, 2006). The conjugation of cytotoxic agents to a hydrophilic polymer may convey several advantages, (1) increased water solubility; (2) protection from hydrolysis and proteolysis; (3) prolonged half-life and enhanced bioavailability of drug; (4) reduction of toxicity, immunogenicity and antigenicity; (5) controlled release or specific targeting through an enhanced permeability and retention (EPR) effect. In the chapter, we will focus on poly (L-glutamic acid)-paclitaxel (PG-PTX), which can improve the therapeutic index, pharmacokinetic properties, safety and efficacy of paclitaxel (PTX).