Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer

Research output: Contribution to journal › Research article › Contributed › peer-review

Contributors

  • Xiaomeng Wan - , University of North Carolina at Chapel Hill (Author)
  • Yuanzeng Min - , University of North Carolina at Chapel Hill (Author)
  • Herdis Bludau - , Chair of Macromolecular Chemistry (Author)
  • Andrew Keith - , University of North Carolina at Chapel Hill (Author)
  • Sergei S. Sheiko - , University of North Carolina at Chapel Hill (Author)
  • Rainer Jordan - , Chair of Macromolecular Chemistry (Author)
  • Andrew Z. Wang - , University of North Carolina at Chapel Hill, TUD Dresden University of Technology, Xuzhou Medical University (Author)
  • Marina Sokolsky-Papkov - , University of North Carolina at Chapel Hill (Author)
  • Alexander V. Kabanov - , University of North Carolina at Chapel Hill, Lomonosov Moscow State University (Author)

Abstract

Nanoparticle-based systems for concurrent delivery of multiple drugs can improve outcomes of cancer treatments, but face challenges because of differential solubility and fairly low threshold for incorporation of many drugs. Here we demonstrate that this approach can be used to greatly improve the treatment outcomes of etoposide (ETO) and platinum drug combination ("EP/PE") therapy that is the backbone for treatment of prevalent and deadly small cell lung cancer (SCLC). A polymeric micelle system based on amphiphilic block copolymer poly(2-oxazoline)s (POx) poly(2-methyl-2-oxazoline-block-2-butyl-2-oxazoline-block-2-methyl-2-oxazoline) (P(MeOx-b-BuOx-b-MeOx) is used along with an alkylated cisplatin prodrug to enable co-formulation of EP/PE in a single high-capacity vehicle. A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50% wt. drug in dispersed phase is demonstrated. The highly loaded POx micelles have worm-like morphology, unprecedented for drug loaded polymeric micelles reported so far, which usually form spheres upon drug loading. The drugs co-loading in the micelles result in a slowed-down release, improved pharmacokinetics, and increased tumor distribution of both drugs. A superior antitumor activity of co-loaded EP/PE drug micelles compared to single drug micelles or their combination as well as free drug combination was demonstrated using several animal models of SCLC and non-small cell lung cancer.

Details

Original languageEnglish
Pages (from-to)2426-2439
Number of pages14
JournalACS nano
Volume12
Issue number3
Publication statusPublished - 27 Mar 2018
Peer-reviewedYes

External IDs

Scopus 85044537513
PubMed 29533606

Keywords

Sustainable Development Goals

Keywords

  • Cancer, chemotherapy, cisplatin, drug delivery, etoposide, nanomedicine, polymeric micelles