title: Paclitaxel in tyrosine-derived nanospheres as a potential anti-cancer agent: in vivo evaluation of toxicity and efficacy in comparison with paclitaxel in Cremophor.
abstract: Paclitaxel (PTX) has gained widespread clinical use yet its administration is associated with significant toxicity. In the present study, the toxicity and anti-tumor efficacy of tyrosine-derived nanospheres (NSP) for the delivery of PTX was compared to a clinical formulation of PTX in PBS-diluted Cremophor® EL (PTX-CrEL-D). Maximum tolerated dose was determined using a concentration series of PTX in NSP and CrEL-D, with toxicity assessed by measuring changes in body weight. Healthy mice administered PTX-NSP continued to gain weight normally while treatment with PTX-CrEL-D resulted in significant weight loss that failed to recover following treatment. Even at the dose of 50mg/kg, PTX-NSP showed better tolerance than 25mg/kg of PTX-CrEL-D. Xenograft studies of breast cancer revealed that the anti-tumor efficacy of PTX-NSP was equal to that of PTX-CrEL-D in tumors originating from both MDA-MB-435 and ZR-75-1 cancer lines. Larger volume of distribution and longer half-life were measured for PTX-NSP administration compared to those reported in the literature for a CrEL formulation. This trend suggests the potential for improved therapeutic index of PTX when administered via NSP. The findings reported here confirm that the NSP formulation is an efficient method for PTX administration with significant increase in maximum tolerated dose, offering possible clinical implications in the treatment of breast tumors.
authors.affiliation: New Jersey Center for Biomaterials, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ 08854, United States.
authors.forename: Larisa
authors.initials: L
authors.lastname: Sheihet
authors.forename: Olga B
authors.initials: OB
authors.lastname: Garbuzenko
authors.forename: Jared
authors.initials: J
authors.lastname: Bushman
authors.forename: Murugesan K
authors.initials: MK
authors.lastname: Gounder
authors.forename: Tamara
authors.initials: T
authors.lastname: Minko
authors.forename: Joachim
authors.initials: J
authors.lastname: Kohn
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D054118:Nanospheres / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D014677:Pharmaceutical Vehicles / Q000737:chemistry*; D014443:Tyrosine / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D014677:Pharmaceutical Vehicles; D014443:Tyrosine; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol