title: Biodistribution and pharmacokinetic analysis of Paclitaxel and ceramide administered in multifunctional polymer-blend nanoparticles in drug resistant breast cancer model.
abstract: In this study, we have investigated the biodistribution and pharmacokinetic analysis of paclitaxel (PTX) and the apoptotic signaling molecule, C6-ceramide (CER), when administered in a multifunctional polymer-blend nanoparticle formulation to female nude mice bearing an orthotopic drug sensitive MCF7 and multidrug resistant MCF7 TR (MDR-1 positive) human breast adenocarcinoma. A polymer-blend nanoparticle system was engineered to incorporate temporally controlled sequential release of the combination drug payload. Hereby, PTX was encapsulated in the pH-responsive rapid releasing polymer, poly(beta-amino ester) (PbAE), while CER was present in the slow releasing polymer, poly(D,L-lactide-co-glycolide) (PLGA) within these blend nanoparticles. When particle formulations were administered intravenously to MCF7 and MCF7 TR tumor bearing mice, higher concentrations of PTX were found in the blood due to longer retention time and an enhanced tumor accumulation relative to administration of free drug. In addition, the PLGA/PbAE blend nanoparticles were effective in enhancing the residence time of both drugs at the tumor site by reducing systemic clearance. Overall, these results are highly encouraging for development of multifunctional polymer-blend nanoparticle formulations that can be used for temporal-controlled administration of two drugs from a single formulation.
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Department of Orthopedic Surgery, Massachusetts General Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Lilian E
authors.initials: LE
authors.lastname: van Vlerken
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Duan
authors.forename: Steven R
authors.initials: SR
authors.lastname: Little
authors.forename: Michael V
authors.initials: MV
authors.lastname: Seiden
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Amiji
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000627:therapeutic use*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011108:Polymers / Q000737:chemistry*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D002518:Ceramides; D011108:Polymers; D017239:Paclitaxel