In this study we discuss the development of nanocarriers with covalently-linked cytotoxic nucleoside analogs which are capable of sustained release of drugs in the activated phosphorylated form. Nanogels were synthesized from cholesterol-modified mucoadhesive polyvinyl alcohols or biodegradable dextrin and nucleoside analog drugs were covalently attached to these polymers through biodegradable polyphosphate linker. Each polymer contained from 4 to 6 cholesterol moieties per molecule, and drug (5-fluoro-2'-deoxyuridine) loading was equal to 0.44-0.51 �mol/mg. Degradation of nanogel-drug conjugates were slow in acidic media and fast enzymatically in the presence of snake venom phosphodiesterase (SVPD). These nanogels showed efficient cytotoxicity against a panel of cancer cells including cell lines that are resistant to nucleoside analogs in vitro. They demonstrated 15-16 times enhanced cytotoxicity in human prostrate PC3 and breast MCF7 carcinoma cells, while 85-100 times higher cytotoxicity in drug-resistant human T-lymphoma (CEM/araC) and follicular lymphoma (RL7/G) cells, compared to free drug. In the initial in vivo screening, PC3 and RL7/G tumor xenograft models showed enhanced sensitivity to nanogels compared to the control group after peritumoral injections. These data demonstrate that nanogels covalently linked to activated nucleoside analogues have enhanced tumor specificity and are also remarkably efficient against drug-resistant tumors because of the sustained release of the activated phosphorylated form of nucleoside analogs.

Novel anticancer nanogel conjugates of activated nucleoside analogs

242nd National Meeting (2011)

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