Polymeric nanogels containing the triphosphate form of cytotoxic nucleoside analogues show antitumor activity against breast and colorectal cancer cell lines

Carlos M. Galmarini, Galya Warren, Ekta Kohli, Arin Zeman, Anton Mitin, Serguei V. Vinogradov

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The therapeutic efficiency of anticancer nucleoside analogues (NA) strongly depends on their intracellular accumulation and conversion into 5′-triphosphates. Because active NATP cannot be directly administrated due to instability, we present here a strategy of nanoencapsulation of these active drugs for efficient delivery to tumors. Stable lyophilized formulations of 5′-triphosphates of cytarabine (araCTP), gemcitabine (dFdCTP), and floxuridine (FdUTP) encapsulated in biodegradable PEG-cl-PEI or F127-cl-PEI nanogel networks (NGC and NGM, respectively) were prepared by a self-assembly procedure. Cellular penetration, in vitro cytotoxicity, and drug-induced cell cycle perturbations of these nano-formulations were analyzed in breast and colorectal cancer cell lines. Cellular accumulation and NATP release from nanogel was studied by confocal microscopy and direct high-performance liquid chromatography analysis of cellular lysates. Antiproliferative effect of dFdCTP nanoformulations was evaluated in human breast carcinoma MCF7 xenograft animal model. Nanoencapsulated araCTP, dFdCTP, and FdUTP showed similar to NA cytotoxicity and cell cycle perturbations. Nanogels without drugs showed very low cytotoxicity, although NGM was more toxic than NGC. Treatment by NATP nano-formulations induced fast increase of free intracellular drug concentration. In human breast carcinoma MCF7 xenograft animal model, i.v. dFdCTP-nanogel was equally effective in inhibiting tumor growth at four times lower administered drug dose compared with free gemcitabine. Active triphosphates of NA encapsulated in nanogels exhibit similar cytotoxicity and cell cycle perturbations in vitro and faster cell accumulation and equal tumor growth-inhibitory activity in vivo at much lower dose compared with parental drugs, illustrating their therapeutic potential for cancer chemotherapy.

Original languageEnglish (US)
Pages (from-to)3373-3380
Number of pages8
JournalMolecular cancer therapeutics
Volume7
Issue number10
DOIs
StatePublished - Oct 1 2008

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Nucleosides
Colorectal Neoplasms
Breast Neoplasms
gemcitabine
Cell Line
Pharmaceutical Preparations
Cell Cycle
UCON 50-HB-5100
Heterografts
Neoplasms
Arabinofuranosylcytosine Triphosphate
Animal Models
Floxuridine
Poisons
Growth
Confocal Microscopy
triphosphoric acid
NanoGel
Therapeutics
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Polymeric nanogels containing the triphosphate form of cytotoxic nucleoside analogues show antitumor activity against breast and colorectal cancer cell lines. / Galmarini, Carlos M.; Warren, Galya; Kohli, Ekta; Zeman, Arin; Mitin, Anton; Vinogradov, Serguei V.

In: Molecular cancer therapeutics, Vol. 7, No. 10, 01.10.2008, p. 3373-3380.

Research output: Contribution to journalArticle

Galmarini, Carlos M. ; Warren, Galya ; Kohli, Ekta ; Zeman, Arin ; Mitin, Anton ; Vinogradov, Serguei V. / Polymeric nanogels containing the triphosphate form of cytotoxic nucleoside analogues show antitumor activity against breast and colorectal cancer cell lines. In: Molecular cancer therapeutics. 2008 ; Vol. 7, No. 10. pp. 3373-3380.
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