title: Improving DNA double-strand repair inhibitor KU55933 therapeutic index in cancer radiotherapy using nanoparticle drug delivery.
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.
authors.affiliation: 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, USA. zawang@med.unc.edu.
authors.forename: Xi
authors.initials: X
authors.lastname: Tian
authors.forename: Haydee
authors.initials: H
authors.lastname: Lara
authors.forename: Kyle T
authors.initials: KT
authors.lastname: Wagner
authors.forename: Srinivas
authors.initials: S
authors.lastname: Saripalli
authors.forename: Syed Nabeel
authors.initials: SN
authors.lastname: Hyder
authors.forename: Michael
authors.initials: M
authors.lastname: Foote
authors.forename: Manish
authors.initials: M
authors.lastname: Sethi
authors.forename: Edina
authors.initials: E
authors.lastname: Wang
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Caster
authors.forename: Longzhen
authors.initials: L
authors.lastname: Zhang
authors.forename: Andrew Z
authors.initials: AZ
authors.lastname: Wang
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D053903:DNA Breaks, Double-Stranded; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000627:therapeutic use*; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry; D011753:Pyrones / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D011878:Radiotherapy / Q000379:methods
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D004337:Drug Carriers; D008055:Lipids; D009025:Morpholines; D011108:Polymers; D011753:Pyrones; D011838:Radiation-Sensitizing Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid