Effective in chemotherapy of cancer and viral infections nucleoside analogues (NA) are actually 'prodrugs', which must be first converted in vivo into nucleoside 5'-monophosphates and, finally, into the drug's active form, nucleoside 5'-triphosphates. They efficiently terminate DNA synthesis and are cytotoxic for the proliferating cancer cells. However, therapeutic NAs in the form of 5'-triphosphates are considered too unstable as a drug form to be used directly in cancer chemotherapy. Based on preliminary data, the hypothesis being evaluated in this proposal is that encapsulation of 5'-triphosphates of antiproliferative NA in a submicron polymeric carrier with protective and targeting properties will result in a novel therapeutic form of the old drugs. The proposed formulation and delivery system is based on self-assembled polyionic complexes formed between nucleoside 5'-triphosphates and cationic carrier called 'Nanogel'. This carrier consists of a cross-linked network of cationic polyethylenimine and poly (ethylene glycol) or Poloxamer block copolymers. Nanogel loaded with triphosphate nucleotides in aqueous media forms small nanosized particles. Formulated into the particles for systemic administration, active triphosphates of NA can be conventionally stored in freeze-dried form and then readily dispersed before injection. Nanogel can protect triphosphate nucleotides in circulation against enzymatic degradation and drastically increase intracellular transport of anionic nucleotides, which otherwise is not effective.
Specific aims of the proposal are to: (1) formulate polymer-nucleotide complexes with increased dispersion stability and enzymatic resistance, (2) Determine whether the polymer-nucleotide complexes can increase the cytotoxic effects of nucleotide analogues, and (3) Examine how the polymer-nucleotide complexes can enhance the systemic therapy of tumors in vivo. A panel of representative NA and cancer cell lines will be studied, and a murine Lewis lung carcinoma model will be used to verify obtained in vitro results. The long circulating polymer-nucleotide complexes can display better tumor accumulation because of the 'enhanced permeability and retention' effect. They can also be modified by vector ligands with affinity to surface receptors on actively proliferating cancer cells in order to enhance selective accumulation of the cytotoxic NA in tumors or metastatic nodes. Application of the drug forms may help to prevent many of the known chemotherapy side effects. Data accumulated in these studies can be directly used for design of better systemic formulations of cytotoxic nucleotide drugs.
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