title: Triolimus: A Multi-Drug Loaded Polymeric Micelle Containing Paclitaxel, 17-AAG, and Rapamycin as a Novel Radiosensitizer.
abstract: Triolimus is a multi-drug loaded polymeric micelle containing paclitaxel (PTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin (RAP). This study examines the radiosensitizing effect of Triolimus in vitro and in vivo. Radiosensitizing effects of Triolimus on A549 cells are dose dependent and at 2 × 10-9m, Triolimus shows significant radiosensitization even at low radiation doses (2 Gy). By sensitivity enhancement ratio, PTX alone, dual drug combinations, and Triolimus treatment at 2 × 10-9m have radiosensitizing effects with potency as follows: PTX alone (PTX) > PTX and RAP (P/R) > Triolimus (TRIO) > PTX and 17-AAG (P/17) >17-AAG and RAP (17/R). In vivo, fractionated radiation of 15 Gy preceded by infusion of PTX alone, dual drug combinations, or an intermediate dose of Triolimus (Int. TRIO: PTX/17-AAG/RAP at 15/15/7.5 mg kg-1) strongly inhibits A549 tumor growth. Notably, pretreatment with high dose of Triolimus (High TRIO: PTX/17-AAG/RAP at 60/60/30 mg kg-1) before the fractionated radiation leads to tumor control for up to 24 weeks. An enhanced radiosensitizing effect is observed without an increase in acute toxicity compared to PTX alone or radiation alone. These results suggest that further investigations of Triolimus in combination with radiation therapy are merited.
authors.affiliation: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Keishiro
authors.initials: K
authors.lastname: Tomoda
authors.affiliation: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Yu Tong
authors.initials: YT
authors.lastname: Tam
authors.affiliation: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Hyunah
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, 3170 UW Medical Foundation Centennial Building (MFCB), 1685 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Darya
authors.initials: D
authors.lastname: Buehler
authors.affiliation: Mercy Regional Cancer Center, 1000 Mineral Point Ave, Janesville, WI, 53548, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kozak
authors.affiliation: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI, 53705, USA.|Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea.
authors.forename: Glen S
authors.initials: GS
authors.lastname: Kwon
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D055598:Chemical Phenomena; D002999:Clone Cells; D004338:Drug Combinations; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D008823:Micelles; D009336:Necrosis; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation; D011108:Polymers / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D004338:Drug Combinations; D019394:Ki-67 Antigen; D047029:Lactams, Macrocyclic; D008823:Micelles; D011108:Polymers; D011838:Radiation-Sensitizing Agents; C578609:triolimus; C112765:tanespimycin; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D017239:Paclitaxel; D020123:Sirolimus
keywords: chemoradiotherapy; multi-drug delivery; polymeric micelles; radiosensitization