Nanoparticle delivery of chemosensitizers improve chemotherapy efficacy without incurring additional toxicity

Joseph M Caster; Manish Sethi; Sonya Kowalczyk; Edina Wang; Xi Tian; Sayed Nabeel Hyder; Kyle T Wagner; Ying-Ao Zhang; Chintan Kapadia; Kin Man Au; Andrew Z Wang

doi:10.1039/C4NR07102F

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Nanoparticle delivery of chemosensitizers improve chemotherapy efficacy without incurring additional toxicity

Journal article

Open access

Peer reviewed

Nanoparticle delivery of chemosensitizers improve chemotherapy efficacy without incurring additional toxicity

Joseph M Caster, Manish Sethi, Sonya Kowalczyk, Edina Wang, Xi Tian, Sayed Nabeel Hyder, Kyle T Wagner, Ying-Ao Zhang, Chintan Kapadia, Kin Man Au, …

Nanoscale, Vol.7(6), pp.2805-2811

2015

DOI: 10.1039/C4NR07102F

PMCID: PMC4408549

PMID: 25584654

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Abstract

Chemosensitizers can improve the therapeutic index of chemotherapy and overcome treatment resistance. Successful translation of chemosensitizers depends on the development of strategies that can preferentially deliver chemosensitizers to tumors while avoiding normal tissue. We hypothesized that nanoparticle (NP) formulation of chemosensitizers can improve their delivery to tumors which can in turn improve their therapeutic index. To demonstrate the proof of principle of this approach, we engineered NP formulations of two chemosensitizers, the PI3-kindase inhibitor wortmanin (Wtmn) and the PARP inhibitor olaparib. NP Wtmn and NP olaparib were evaluated as chemosensitizers using lung cancer cells and breast cancer cells respectively. We found Wtmn to be an efficient chemosensitizer in all tested lung-cancer cell lines reducing tumor cell growth between 20 and 60% compared to drug alone. NP formulation did not decrease its efficacy in vitro. Olaparib showed less consistent chemosensitization as a free drug or in NP formulation. NP Wtmn was further evaluated as a chemosensitizer using mouse models of lung cancer. We found that NP Wtmn is an effective chemosensitizer and more effective than free Wtmn showing a 32% reduction in tumor growth compared to free Wtmn when given with etoposide. Importantly, NP Wtmn was able to sensitize the multi-drug resistant H69AR cells to etoposide. Additionally, the combination of NP Wtmn and etoposide chemotherapy did not significantly increase toxicity. The present study demonstrates the proof of principle of using NP formulation of chemosensitizing drugs to improve the therapeutic index of chemotherapy.

Details

Title: Subtitle: Nanoparticle delivery of chemosensitizers improve chemotherapy efficacy without incurring additional toxicity
Creators: Joseph M Caster - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill
Manish Sethi - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill
Sonya Kowalczyk - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill
Edina Wang - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill
Xi Tian - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill
Sayed Nabeel Hyder - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill
Kyle T Wagner - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill
Ying-Ao Zhang - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill
Chintan Kapadia - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill
Kin Man Au - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill
Andrew Z Wang - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill
Resource Type: Journal article
Publication Details: Nanoscale, Vol.7(6), pp.2805-2811
DOI: 10.1039/C4NR07102F
PMID: 25584654
PMCID: PMC4408549
NLM abbreviation: Nanoscale
ISSN: 2040-3364
eISSN: 2040-3372
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: R01CA178748-01
Language: English
Date published: 2015
Academic Unit: Radiation Oncology
Record Identifier: 9984047884402771

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