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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA102791-01A1
Application #
6778826
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$231,525
Indirect Cost
Name
University of Nebraska Medical Center
Department
Other Basic Sciences
Type
Schools of Pharmacy
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Vinogradov, Serguei V (2010) Nanogels in the race for drug delivery. Nanomedicine (Lond) 5:165-8
Kabanov, Alexander V; Vinogradov, Serguei V (2009) Nanogels as pharmaceutical carriers: finite networks of infinite capabilities. Angew Chem Int Ed Engl 48:5418-29
Vinogradov, Serguei V; Mitin, Anton; Warren, Galya (2008) FOLATE-TARGETED POLYFORMULATIONS OF CYTOTOXIC NUCLEOSIDE TRIPHOSPHATES AND PACLITAXEL. Polymer Prepr 49:1050-1051
Galmarini, Carlos M; Warren, Galya; Kohli, Ekta et al. (2008) Polymeric nanogels containing the triphosphate form of cytotoxic nucleoside analogues show antitumor activity against breast and colorectal cancer cell lines. Mol Cancer Ther 7:3373-80
Vinogradov, Serguei V (2007) Polymeric nanogel formulations of nucleoside analogs. Expert Opin Drug Deliv 4:5-17
Kohli, Ekta; Han, Huai-Yun; Zeman, Arin D et al. (2007) Formulations of biodegradable Nanogel carriers with 5'-triphosphates of nucleoside analogs that display a reduced cytotoxicity and enhanced drug activity. J Control Release 121:19-27
Vinogradov, Serguei V; Kohli, Ekta; Zeman, Arin et al. (2006) Chemical engineering of nanogel drug carriers: increased bioavailability and decreased cytotoxicity. Polymer Prepr 47:27-28
Vinogradov, Serguei V; Kohli, Ekta; Zeman, Arin D (2006) Comparison of nanogel drug carriers and their formulations with nucleoside 5'-triphosphates. Pharm Res 23:920-30
Vinogradov, Serguei V (2006) Colloidal microgels in drug delivery applications. Curr Pharm Des 12:4703-12
Vinogradov, Serguei V; Zeman, Arin D; Batrakova, Elena V et al. (2005) Polyplex Nanogel formulations for drug delivery of cytotoxic nucleoside analogs. J Control Release 107:143-57

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