Improving Cancer Chemoradiotherapy Treatment by Dual Controlled Release of Wortmannin and Docetaxel in Polymeric Nanoparticles

Kin Man Au, Yuanzeng Min, Xi Tian, Longzhen Zhang, Virginia Perello, Joseph M. Caster, Andrew Z. Wang

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Combining molecularly targeted agents and chemotherapeutics is an emerging strategy in cancer treatment. We engineered sub-50 nm diameter diblock copolymer nanoparticles (NPs) that can sequentially release wortmannin (Wtmn, a cell signaling inhibitor) and docetaxel (Dtxl, genotoxic anticancer agent) to cancer cells. These NPs were studied in chemoradiotherapy, an important cancer treatment paradigm, in the preclinical setting. We demonstrated that Wtmn enhanced the therapeutic efficacy of Dtxl and increased the efficiency of radiotherapy (XRT) in H460 lung cancer and PC3 prostate cells in culture. Importantly, we showed that NPs containing both Wtmn and Dtxl release the drugs in a desirable sequential fashion to maximize therapeutic efficacy in comparison to administering each drug alone. An in vivo toxicity study in a murine model validated that NPs containing both Dtxl and Wtmn do not have a high toxicity profile. Lastly, we demonstrated that Dtxl/Wtmn-coencapsulated NPs are more efficient than each single-drug-loaded NPs or a combination of both single-drug-loaded NPs in chemoradiotherapy using xenograft models. Histopathological studies and correlative studies support that the improved therapeutic efficacy is through changes in signaling pathways and increased tumor cell apoptosis. Our findings suggest that our nanoparticle system led to a dynamic rewiring of cellular apoptotic pathways and thus improve the therapeutic efficiency.

Original languageEnglish (US)
Pages (from-to)8976-8996
Number of pages21
JournalACS Nano
Volume9
Issue number9
DOIs
StatePublished - Sep 22 2015
Externally publishedYes

Keywords

  • cancer
  • combination chemotherapy
  • concurrent chemoradiotherapy
  • diblock copolymer NPs
  • dual drug encapsulation
  • dynamic rewiring of cell apoptotic pathways

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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