Journal article
Improving DNA double-strand repair inhibitor KU55933 therapeutic index in cancer radiotherapy using nanoparticle drug delivery
Nanoscale, Vol.7(47), pp.20211-20219
01/01/2015
DOI: 10.1039/c5nr05869d
PMCID: PMC4664156
PMID: 26575637
Abstract
Radiotherapy is a key component of cancer treatment. Because of its importance, there has been high interest in developing agents and strategies to further improve the therapeutic index of radiotherapy. DNA double-strand repair inhibitors (DSBRIs) are among the most promising agents to improve radiotherapy. However, their clinical translation has been limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this limitation. In this study, we aim to demonstrate the proof of principle by developing and evaluating nanoparticle (NP) formulations of KU55933, a DSBRI. We engineered a NP formulation of KU55933 using nanoprecipitation method with different lipid polymer nanoparticle formulation. NP KU55933 using PLGA formulation has the best loading efficacy as well as prolonged drug release profile. We demonstrated that NP KU55933 is a potent radiosensitizer in vitro using clonogenic assay and is more effective as a radiosensitizer than free KU55933 in vivo using mouse xenograft models of non-small cell lung cancer (NSCLC). Western blots and immunofluorescence showed NP KU55933 exhibited more prolonged inhibition of DNA repair pathway. In addition, NP KU55933 leads to lower skin toxicity than KU55933. Our study supports further investigations using NP to deliver DSBRIs to improve cancer radiotherapy treatment.
Details
- Title: Subtitle
- Improving DNA double-strand repair inhibitor KU55933 therapeutic index in cancer radiotherapy using nanoparticle drug delivery
- Creators
- Xi Tian - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAHaydee Lara - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill,Chapel Hill,USAKyle T. Wagner - University of North Carolina at Chapel HillSrinivas Saripalli - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill,Chapel Hill,USASyed Nabeel Hyder - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill,Chapel Hill,USAMichael Foote - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill,Chapel Hill,USAManish Sethi - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill,Chapel Hill,USAEdina Wang - Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill,Chapel Hill,USAJoseph M. Caster - University of North Carolina at Chapel HillLongzhen Zhang - Xuzhou Medical CollegeAndrew Z. Wang - University of North Carolina at Chapel Hill
- Resource Type
- Journal article
- Publication Details
- Nanoscale, Vol.7(47), pp.20211-20219
- DOI
- 10.1039/c5nr05869d
- PMID
- 26575637
- PMCID
- PMC4664156
- NLM abbreviation
- Nanoscale
- ISSN
- 2040-3364
- eISSN
- 2040-3372
- Publisher
- Royal Soc Chemistry
- Number of pages
- 9
- Grant note
- R01CA178748-01 / National Institutes of Health/National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) K12CA120780 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) University Cancer Research Fund from University of North Carolina 1-U54-CA151652-01 / National Institutes of Health Center for Nanotechnology Excellence Grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 5-K12-CA120780-01-05 / Career Development Award
- Language
- English
- Date published
- 01/01/2015
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984312988402771
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