Efficient overcoming of drug resistance to anticancer nucleoside analogs by nanodelivery of active phosphorylated drugs

Carlos M. Galmarini, Galya Warren, Madapathage T. Senanayake, Serguei V Vinogradov

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

One of the major problems in cancer chemotherapy is the fast development of drug resistance to most anticancer therapeutics. Thus, an important cause of the eventual decline in clinical efficacy of cytotoxic nucleoside analogs was the selection of resistant cancer cells with deficiencies in the expression of nucleoside transporters or nucleoside-activating kinases. Here, we present an efficient strategy of overcoming this type of drug resistance by tumor-specific delivery of nanogel-encapsulated active triphosphates of nucleoside analogs (NATP). The small particles of biodegradable cationic nanogels loaded with anionic NATP efficiently interacted with cancer cells and released active drug compounds into the cytoplasm. The potential of novel drug formulations was evaluated in the nucleoside transport-deficient (CEM/araC/C8) or nucleoside activation-deficient (RL7/G) lymphogenic cancer cells. Compared to nucleoside analogs, NATP-loaded nanogels demonstrated increased cytotoxicity, reducing the drug resistance index 250- to 900-fold in CEM/araC/C8 cells and 70- to 100-fold in RL7/G cells. The strong cytotoxic effect of nanoformulations was accompanied by characteristic cell cycle perturbations, usually observed in drug-treated sensitive cells, and resulted in the induction of apoptosis in all studied drug-resistant cells. Efficient cellular accumulation of nanogels and the consequent increase in intracellular levels of NATP were found to be the major factors determining cytotoxic efficacy of nanoformulations. Decoration of nanogels with multiple molecules of tumor lymphatic-specific peptide (LyP1) enhanced the binding efficacy of nanocarriers with lymphogenic cancer cells. The targeted nanoformulation of activated gemcitabine (LyP1-NG-dFdCTP), when injected in subcutaneous RL7/G xenograft tumor model, demonstrated 2-fold more efficient tumor growth inhibition than gemcitabine at a higher dose. Nanogel-drug formulations exhibited no systemic toxicity during the treatment, hence extending the versatility of nucleoside analogs in the treatment of drug-resistant lymphogenic tumors.

Original languageEnglish (US)
Pages (from-to)281-289
Number of pages9
JournalInternational Journal of Pharmaceutics
Volume395
Issue number1-2
DOIs
StatePublished - Aug 1 2010

Fingerprint

Nucleosides
Drug Resistance
Pharmaceutical Preparations
Neoplasms
gemcitabine
Drug Compounding
nucleoside phosphotransferase
Nucleoside Transport Proteins
Gastrin-Secreting Cells
Heterografts
NanoGel
Cell Cycle
Cytoplasm
Apoptosis
Drug Therapy
Peptides
Growth

Keywords

  • Cationic nanogels
  • Drug resistance
  • Nucleoside 5'-triphosphate
  • Nucleoside analogs
  • Tumor-targeting peptides
  • Xenograft tumor model

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Efficient overcoming of drug resistance to anticancer nucleoside analogs by nanodelivery of active phosphorylated drugs. / Galmarini, Carlos M.; Warren, Galya; Senanayake, Madapathage T.; Vinogradov, Serguei V.

In: International Journal of Pharmaceutics, Vol. 395, No. 1-2, 01.08.2010, p. 281-289.

Research output: Contribution to journalArticle

Galmarini, Carlos M. ; Warren, Galya ; Senanayake, Madapathage T. ; Vinogradov, Serguei V. / Efficient overcoming of drug resistance to anticancer nucleoside analogs by nanodelivery of active phosphorylated drugs. In: International Journal of Pharmaceutics. 2010 ; Vol. 395, No. 1-2. pp. 281-289.
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