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Our studies document a unique and unexpected advantage of the combination of HPMA copolymer bound doxorubicin with mesochlorin /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 [10,16,35,37,45], biodegradability [16-19,24,25,39,42], minimal immunogenicity [17-19, 25,38-44], subcellular localization [15-20], anticancer activity [33-36,43-46,54,55,57], enhanced permeability and retention [9,14,57,58], increased apoptosis [36], lipid peroxidation [57], DNA damage [57], and reduced nonspecific toxicity [14,33-35,43-46]. 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. [35,43-46]

With regards to photodynamic therapy using the photosensitizer mesochlorin the preclinical evaluations thus far document: control of biodistribution and accumulation via molecular weight restrictions [10,11,16,33], biodegradability [14,43], subcellular localization [15-19], anticancer activity [33,55,56], enhanced permeability and retention [55], and reduced nonspecific toxicity [33].

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.

Figure 8. (see next page) Proposed mechanisms of the unexpected biological activity and reduced nonspecific toxicity associated with the combination of HPMA copolymer doxorubicin and mesochlorin ej in the treatment of ovarian cancer.

HPMA copolymer delivery of doxorubicin and mesochlorin requires internalization within membrane limited organelles (lysosomes) via pinocytosis. Because the rate of pinocytosis is slow the polymer drug conjugates are effectively confined to the blood stream. The HPMA copolymer design feature, which allows control of the molecular weight

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a to insure the size is less than the renal threshold as well as control of the degradability of the tetrapeptide (G-F-L-G) side chains, effectively avoids long term accumulation and reduces toxicity. These features are considered the primary level of selectivity- systemic in nature-which controls systemic biodistribution and reduces nonspecific toxicity. The abnormal vasculature of solid tumors, such as noted in ovarian cancer, results in an increased uptake of macromolecular drugs in tumor tissues compared to free drugs. This secondary level of selectivity or tissue selectivity is attributed to the "enhanced permeability and retention effect (EPR) of solid tumors" characterized by Maeda [23]. The EPR effect is caused by; a) abnormal vascular architecture and angiogenesis; b) increased vascular permeability due to vasoactive substances including VEGF, bFGF, bradykinin, nitric oxide, peroxynitrite, prostaglandins, cytokines, and uPA; and finally, poor lymphatic drainage.

The tetrapeptide attachment and release site (or spacer) represents the third or subcellular level of targeting. The peptide spacer (Gly- Phe- Leu- Gly-) or (G-F-L-G) has been designed to allow HPMA copolymer drug conjugates to maintain their stability in the circulation and yet maintain susceptibility to enzymatic hydrolysis in the lysozomal compartment. This subcellular delivery system overcomes the P-glycoprotein efflux pump found in multi-drug resistant ovarian carcinoma cell lines. The spacer also reduces the nonspecific toxicity of the HPMA copolymer bound doxorubicin by limiting its release to a subcellular location. While HPMA copolymer bound mesochlorin e6 is active whenever and wherever it is exposed to light the quantum yield of singlet oxygen is greater when bound to HPMA copolymer via the spacer. New approaches for enhanced targeting include the addition of antibodies or folic acid as targeting agents. These, and other molecules, will function as tissue and subcellular localizing properties of the drug delivery system.

Finally on a subcellular/molecular level, HPMA copolymer delivered agents demonstrate a unique selectivity for various structures, signaling pathways and genes. HPMA copolymer bound doxorubicin in comparison to free drug: overcomes the MDR 1 ATP driven efflux pump and down regulates the MRP gene; suppresses or activates to a lesser degree than free drug HSP-70, GST-Jt, BUDP, Topo II a and Topo II [J genes; activates p53, Apaf-1, Caspase 9, c-fos, genes; and, inhibits the bcl-2 gene. In the case of HPMA copolymer bound mesochlorin e6, the administration of light results in the creation of singlet oxygen 'C^, and the free radicals and Within a 40 nm radius of the photosensitizer complex, membrane structures and/or DNA may be damaged. Specifically, the following membrane activities are inactivated: cytochrome c oxidase, succinate dehydrogenase, respiration, acyl coenzyme A, Cai+/ATPase, Na7K+ ATPase. A cascade of events leads to vascular endothelial damage resulting in hemorrhage, stasis-thrombosis, arteriolar constriction and microcirculatory collapse. Some of the pathways which participate in these processes include the phospholipase a and c, arachidonic acid and prostaglandin synthesis, apoptotic endonuclease, multiple inflammatory mediators, heat shock proteins, and glucose-regulated proteins. The combination of HPMA copolymer doxorubicin and mesochlorin eg thus results in a myriad of effects which result in the significant potentiation and unexpected biological activity of the combination compared to a simple combination of the effects of the HPMA copolymer bound agents alone.

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