Drug-polymer conjugates

Pasut G, Veronese FM (2007) Polymer-drug conjugation, recent achievements and general strategies. Progr Polym Sci 32 933-961... 

A phase I clinical and pharmacokinetic study of PKl comprising doxorubicin covalently bound to N-(2-hydroxypropyl)-methacrylamide copolymer by a peptidyl linker, was carried out in 36 patients with refractory or resistant cancers [94], PKl demonstrated anti-tumour activity, and that polymer-drug conjugation decreased doxorubicin dose-limiting toxicities. Phase II studies are in progress. 

Fig. I. Endocytic pathways used by cells to internalize soluble macromolecules [25] fluid-phase pinocytosis (1), adsorptive pinocytosis (2), and receptor-mediated endocytosis (pinocytosis) (6). Each of these processes involves a formation of a sealed vesicle formed from the plasma membrane which encloses part of the extracellular medium. The internalization of a polymer-drug conjugate (P-D), and targeted polymer-drug conjugate ( => —P-D) is shown. Other abbreviations — = cell surface receptor/antigen 1 = clathrin molecule X = lysosomal enzyme. Fluid-phase pinocytosis (1) and adsorptive pinocytosis (2) are nonspecific processes which direct the macromolecule into the lysosomal compartment of the cell. Once P-D is internalized, whether by (1) or (2), the resulting endosome (3) is ultimately fused with a primary lysosome (4) forming a secondary lysosome (5). In the latter compartment P-D is in contact with several types of lysosomal enzymes. The membrane of (5) is impermeable to macromolecules. Consequently, the structure of P-D may be designed in such...

Duncan, R., S. Gac-Breton, R. Keane, R. Musila, Y. N. Sat, R. Satchi, and F. Searle. 2001. Polymer-drug conjugates, PDEPT and PELT basic principles for design and transfer from the laboratory to clinic. 

Drug absorption enhancers have been intensively studied over the past three decades [190— 192] in order to increase the oral availability of poorly absorbed drugs (BSC classes II-IV) [193,194]. Much attention has been paid to the synthesis and evaluation of new absorption enhancer molecules. Excluding the preparation of polymer drug conjugates less awareness was focused on the delivery rate of the molecules tested that is, the concomitant input of the poorly soluble drug together with its enhancer, so that maximal area of the small intestine would be exploited for absorption. The differences between the dimensions of the GI tract in... 

Duncan, R., M,J. Vicent, F. Greco, and R.I. Nicholson. 2005. Polymer-drug conjugates Towards a novel approach for the treatment of endocrine-related cancer. Endocr Relat Cancer 12(Suppl. 1) S189. 

Modi, S., Jain, P. J., and Kumar, N. Polymer-drug conjugates Recent development for anticancer drugs. CRIPS 5 2-8, 2004. 

Polymer-based delivery systems (Fig. 11.1) include polymer-protein conjugates, polymer-drug conjugates, micelles consisting of polymeric surfactants, and complexes of cationic polymers and DNA (polyplexes).26... 

Figure 11.2 Structure of pHPMA-based polymer-drug conjugates.

Thanou, M., and Duncan, R. Polymer-protein and polymer-drug conjugates in cancer therapy. Curr. Opin. Invest. Drugs 4(6) 701—709. 2003. 

Kwon, G. S., Yokoyama, M., Okano, T., et al. Biodistribution of micelle-forming polymer-drug conjugates. Pharm. Res. 10 970-974. 1993. 

Polymer-drug conjugate X Degradative lysosomal enzymes... 

Fig. 3 A tumor-targeted polymer-drug conjugate. The major elements include (i) a polymeric drug-carrier that is water-soluble, bicompatible or biodegradable, non-immunogenic (ii) targeting moieties (iii) a linker between a drug and the carrier. The linker can be a) a chemical bond such as ester or amide. An ester bond is more stable at lysosomal pH than at plasma pH (7.4) while an amide bond is stable at both lysosomal and plasma pH b) an oligopeptide linker that is degradable by specific enzymatic hydrolysis and c) an acid labile linker that is degradable at lysosomal pH but stable at plasma pH.

Cytoplasmic drug release using liposomes [170-172], polymer-drug conjugates [173-176], and micellar nanoparticles [99, 100, 177-180] have been shown to bypass the P-gp-based mnltidrug resistance, probably becanse cells take np drugs in the carriers via endocytosis rather than diffnsion throngh the cell membrane, where P-gp is located. 

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