HPMA copolymer delivery of chemotherapy and photodynamic therapy in ovarian cancer.

Our studies document a unique and unexpected advantage of the combination of HPMA copolymer bound doxorubicin with mesochlorin e6/photodynamic therapy in the treatment of ovarian cancer. Each drug's activity is individually enhanced when compared with free (low molecular weight) drugs, furthermore, in combination these HPMA copolymer bound agents act synergistically to create an unexpected biological effect. Figure 8 depicts the known activities of each agent which may play synergistic roles. HPMA copolymer-doxorubicin has been widely evaluated in preclinical and clinical studies. It demonstrates marked advantages over free doxorubicin: control of biodistribution and accumulation via molecular weight restrictions, biodegradability, minimal immunogenicity, subcellular localization, anticancer activity, enhanced permeability and retention, increased apoptosis, lipid peroxidation, DNA damage, and reduced nonspecific toxicity. Recent clinical trials in the UK provide "proof of principle" of the "enhanced permeability and retention effect" for solid tumors and the unique advantages of this novel drug delivery system for the treatment of ovarian cancer. With regards to photodynamic therapy using the photosensitizer mesochlorin e6, the preclinical evaluations thus far document: control of biodistribution and accumulation via molecular weight restrictions, biodegradability, subcellular localization, anticancer activity, enhanced permeability and retention, and reduced nonspecific toxicity. Ongoing microarray studies document unique cellular pathways and new pharmaceutical properties which are initiated by the HPMA copolymer delivery delivery of these agents, and predict an exciting future for this novel drug delivery system.

Design of novel bioconjugates for targeted drug delivery.

This paper summarizes recent work on the design and development of targeted polymeric bioconjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. Polymerizable antibody Fab' fragment (MA-Fab') has been developed and used in the preparation of targeted HPMA copolymer-mesochlorin e6 conjugates for the treatment of human ovarian carcinomas. The reactivity of the MA-Fab' in copolymerization with HPMA depended on the length of the spacer between the monomer double bond and the antibody Fab' fragment. The biological activity of the antibody Fab' fragment was maintained after incorporation into the HPMA copolymer. Novel aromatic azo spacers were designed and incorporated into HPMA copolymer-drug (cyclosporin A, 9-aminocamptothecin) conjugates for the colon-specific drug delivery and for the treatment of colon diseases. The colon-specific drug release from the conjugates was controlled by the structures of both drug and spacers. Lectins, wheat germ agglutinin (WGA) and peanut agglutinin (PNA), were conjugated to the colon-specific polymer drug conjugates to enhance specific adhesion onto colon tissues.