Targeted nanogel conjugate for improved stability and cellular permeability of curcumin: Synthesis, pharmacokinetics, and tumor growth inhibition

Xin Wei, Thulani H. Senanayake, Anna Bohling, Serguei V. Vinogradov

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Curcumin (CUR) is a unique natural compound with promising anticancer and anti-inflammatory activities. However, the therapeutic efficacy of curcumin was challenged in clinical trials, mostly due to its low bioavailability, rapid metabolism, and elimination. We designed a nanodrug form of curcumin, which makes it stable and substantially enhances cellular permeability and anticancer activity at standard oral administration. Curcumin was conjugated as an ester to cholesteryl-hyaluronic acid (CHA) nanogel that is capable of targeted delivery to CD44-expressing drug-resistant cancer cells. CHA-CUR nanogels demonstrated excellent solubility and sustained drug release in physiological conditions. It induced apoptosis in cancer cells, suppressing the expression of NF-κB, TNF-α, and COX-2 cellular targets similar to free curcumin. Pharmacokinetic/pharmacodynamic (PK/PD) studies also revealed improved circulation parameters of CHA-CUR at oral, i.p. and i.v. administration routes. CHA-CUR showed targeted tumor accumulation and effective tumor growth inhibition in human pancreatic adenocarcinoma MiaPaCa-2 and aggressive orthotropic murine mammary carcinoma 4T1 animal models. CHA-CUR treatment was well-tolerated and resulted in up to 13-fold tumor suppression, making this nanodrug a potential candidate for cancer prevention and therapeutic treatment.

Original languageEnglish (US)
Pages (from-to)3112-3122
Number of pages11
JournalMolecular Pharmaceutics
Volume11
Issue number9
DOIs
StatePublished - Sep 2 2014

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Keywords

  • Curcumin
  • NF-κB inhibition
  • PK/PD parameters
  • animal cancer models
  • nanogel-drug conjugate

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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