Novel anticancer polymeric conjugates of activated nucleoside analogues

Thulani H. Senanayake, Galya Warren, Serguei V. Vinogradov

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Inherent or therapy-induced drug resistance is a major clinical setback in cancer treatment. The extensive usage of cytotoxic nucleobases and nucleoside analogues in chemotherapy also results in the development of specific mechanisms of drug resistance, such as nucleoside transport or activation deficiencies. These drugs are prodrugs; and being converted into the active mono-, di-, and triphosphates inside cancer cells following administration, they affect nucleic acid synthesis, nucleotide metabolism, or sensitivity to apoptosis. Previously, we actively promoted the idea that the nanodelivery of active nucleotide species, e.g., 5?-triphosphates of nucleoside analogues, can enhance drug efficacy and reduce nonspecific toxicity. In this study, we report the development of a novel type of drug nanoformulations, polymeric conjugates of nucleoside analogues, which are capable of the efficient transport and sustained release of phosphorylated drugs. These drug conjugates have been synthesized, starting from cholesterol-modified mucoadhesive polyvinyl alcohol or biodegradable dextrin, by covalent attachment of nucleoside analogues through a tetraphosphate linker. Association of cholesterol moieties in aqueous media resulted in intramolecular polymer folding and the formation of small nanogel particles containing 0.5 mmol/g of a 5?-phosphorylated nucleoside analogue, e.g., 5-fluoro-2?-deoxyuridine (floxuridine, FdU), an active metabolite of anticancer drug 5-fluorouracyl (5-FU). The polymeric conjugates demonstrated rapid enzymatic release of floxuridine 5?-phosphate and much slower drug release under hydrolytic conditions (pH 1.0-7.4). Among the panel of cancer cell lines, all studied polymeric FdU-conjugates demonstrated an up to 50 - increased cytotoxicity in human prostate cancer PC-3, breast cancer MCF-7, and MDA-MB-231 cells, and more than 100 - higher efficacy against cytarabine-resistant human T-lymphoma (CEM/araC/8) and gemcitabine-resistant follicular lymphoma (RL7/G) cells as compared to free drugs. In the initial in vivo screening, both PC-3 and RL7/G subcutaneous tumor xenograft models showed enhanced sensitivity to sustained drug release from polymeric FdU-conjugate after peritumoral injections and significant tumor growth inhibition. All these data demonstrate a remarkable clinical potential of novel polymeric conjugates of phosphorylated nucleoside analogues, especially as new therapeutic agents against drug-resistant tumors.

Original languageEnglish (US)
Pages (from-to)1983-1993
Number of pages11
JournalBioconjugate Chemistry
Volume22
Issue number10
DOIs
StatePublished - Oct 19 2011

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Nucleosides
Pharmaceutical Preparations
Floxuridine
Tumors
Neoplasms
Cholesterol
gemcitabine
Nucleotides
Drug Resistance
Cells
Polyvinyl Alcohol
Deoxyuridine
Gastrin-Secreting Cells
Follicular Lymphoma
Oncology
Chemotherapy
Diphosphates
Polyvinyl alcohols
Cytarabine
Nucleic acids

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

Cite this

Novel anticancer polymeric conjugates of activated nucleoside analogues. / Senanayake, Thulani H.; Warren, Galya; Vinogradov, Serguei V.

In: Bioconjugate Chemistry, Vol. 22, No. 10, 19.10.2011, p. 1983-1993.

Research output: Contribution to journalArticle

Senanayake, TH, Warren, G & Vinogradov, SV 2011, 'Novel anticancer polymeric conjugates of activated nucleoside analogues', Bioconjugate Chemistry, vol. 22, no. 10, pp. 1983-1993. https://doi.org/10.1021/bc200173e
Senanayake, Thulani H. ; Warren, Galya ; Vinogradov, Serguei V. / Novel anticancer polymeric conjugates of activated nucleoside analogues. In: Bioconjugate Chemistry. 2011 ; Vol. 22, No. 10. pp. 1983-1993.
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