Journal article
Improving Cancer Chemoradiotherapy Treatment by Dual Controlled Release of Wortmannin and Docetaxel in Polymeric Nanoparticles
ACS nano, Vol.9(9), pp.8976-8996
09/22/2015
DOI: 10.1021/acsnano.5b02913
PMCID: PMC4990743
PMID: 26267360
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.
Details
- Title: Subtitle
- Improving Cancer Chemoradiotherapy Treatment by Dual Controlled Release of Wortmannin and Docetaxel in Polymeric Nanoparticles
- Creators
- Kin Man Au - Laboratory of Nano- and Translational Medicine, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, North Carolina 27599, United StatesYuanzeng Min - Laboratory of Nano- and Translational Medicine, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, North Carolina 27599, United StatesXi Tian - Laboratory of Nano- and Translational Medicine, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, North Carolina 27599, United StatesLongzhen Zhang - Department of Radiation Oncology, Xuzhou Medical School, Xuzhou, ChinaVirginia Perello - Laboratory of Nano- and Translational Medicine, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, North Carolina 27599, United StatesJoseph M Caster - Laboratory of Nano- and Translational Medicine, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, North Carolina 27599, United StatesAndrew Z Wang - Laboratory of Nano- and Translational Medicine, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, North Carolina 27599, United States
- Resource Type
- Journal article
- Publication Details
- ACS nano, Vol.9(9), pp.8976-8996
- DOI
- 10.1021/acsnano.5b02913
- PMID
- 26267360
- PMCID
- PMC4990743
- NLM abbreviation
- ACS Nano
- ISSN
- 1936-0851
- eISSN
- 1936-086X
- Grant note
- name: University Cancer Research Fund, University of North Carolina at Chapel Hill; DOI: 10.13039/100000054, name: National Cancer Institute, award: R01CA178748, U54-CA151652
- Language
- English
- Date published
- 09/22/2015
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984046828302771
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