title: Nanoparticle delivery of chemosensitizers improve chemotherapy efficacy without incurring additional toxicity.
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.
authors.affiliation: 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, Chapel Hill, NC 27599, USA. zawang@med.unc.edu.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Caster
authors.forename: Manish
authors.initials: M
authors.lastname: Sethi
authors.forename: Sonya
authors.initials: S
authors.lastname: Kowalczyk
authors.forename: Edina
authors.initials: E
authors.lastname: Wang
authors.forename: Xi
authors.initials: X
authors.lastname: Tian
authors.forename: Sayed
authors.initials: S
authors.lastname: Nabeel Hyder
authors.forename: Kyle T
authors.initials: KT
authors.lastname: Wagner
authors.forename: Ying-Ao
authors.initials: YA
authors.lastname: Zhang
authors.forename: Chintan
authors.initials: C
authors.lastname: Kapadia
authors.forename: Kin
authors.initials: K
authors.lastname: Man Au
authors.forename: Andrew Z
authors.initials: AZ
authors.lastname: Wang
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D004260:DNA Repair; D004337:Drug Carriers; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D004337:Drug Carriers; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib; D000077191:Wortmannin