Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

A majority of nanoencapsulated drugs that have shown promise in cancer chemotherapy are administered intravenously. Development of effective oral nanoformulations presents a very challenging medical goal. Here, we describe successful applications of innovative polymeric nanogels in the form of conjugates with activated nucleoside analogs for oral administration in cancer chemotherapy. Previously, we reported the synthesis of amphiphilic polyvinyl alcohol and dextrin-based nanogel conjugates with the phosphorylated 5-FU nucleoside Floxuridine and demonstrated their enhanced activity against regular and drug-resistant cancers (T.H. Senanayake, G. Warren, S.V. Vinogradov, Novel anticancer polymeric conjugates of activated nucleoside analogs, Bioconjug. Chem. 22 (2011) 1983-1993). In this study, we synthesized and evaluated oral applications of nanogel conjugates of a protected Gemcitabine, the drug never used in oral therapies. These conjugates were able to quickly release an active form of the drug (Gemcitabine 5′-mono-, di- and triphosphates) by specific enzymatic activities, or slowly during hydrolysis. Gemcitabine conjugates demonstrated up to 127 times higher in vitro efficacy than the free drug against various cancer cells, including the lines resistant to nucleoside analogs. Surprisingly, these nanogel-drug conjugates were relatively stable in gastric conditions and able to actively penetrate through the gastrointestinal barrier based on permeability studies in Caco-2 cell model. In tumor xenograft models of several drug-resistant human cancers, we observed an efficient inhibition of tumor growth and extended the life-span of the animals by 3 times that of the control with orally treated Gemcitabine- or Floxuridine-nanogel conjugates. Thus, we have demonstrated a potential of therapeutic nanogel conjugates with the activated and stabilized Gemcitabine as a successful oral drug form against Gemcitabine-resistant and other drug-resistant tumors.

Original languageEnglish (US)
Pages (from-to)200-209
Number of pages10
JournalJournal of Controlled Release
Volume167
Issue number2
DOIs
StatePublished - Apr 28 2013

Fingerprint

gemcitabine
Nucleosides
Pharmaceutical Preparations
Neoplasms
Floxuridine
Therapeutics
NanoGel
Polyvinyl Alcohol
Drug Therapy
Caco-2 Cells
Heterografts
Fluorouracil
Oral Administration
Permeability
Stomach
Hydrolysis
Cell Line
Growth

Keywords

  • Drug-resistant animal tumor xenografts
  • Gemcitabine
  • Nanogel-drug conjugates
  • Oral drug administration
  • Phosphorylated nucleoside analogs

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates. / Senanayake, Thulani H.; Warren, Galya; Wei, Xin; Vinogradov, Serguei V.

In: Journal of Controlled Release, Vol. 167, No. 2, 28.04.2013, p. 200-209.

Research output: Contribution to journalArticle

Senanayake, Thulani H. ; Warren, Galya ; Wei, Xin ; Vinogradov, Serguei V. / Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates. In: Journal of Controlled Release. 2013 ; Vol. 167, No. 2. pp. 200-209.
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