title: Novel Soluplus(®)-TPGS mixed micelles for encapsulation of paclitaxel with enhanced in vitro cytotoxicity on breast and ovarian cancer cell lines.
abstract: The aim of this work was to develop mixed micelles based on two biocompatible copolymers of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus(®)) and D-α-tocopheryl polyethylene-glycol 1000 succinate (TPGS), to improve the aqueous solubility and the in vitro anti-tumor activity of paclitaxel (PTX). Pure and mixed nanomicelles were prepared by solvent evaporation method and characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). Solubility of PTX was increased 60,000 and 38,000 times, when it was formulated in pure Soluplus(®) micelles and in mixed micelles (Soluplus(®):TPGS; 4:1 ratio), respectively. The in vitro PTX release profile from micellar systems was characterized employing the dialysis membrane method where all drug-loaded formulations showed a sustained and slow release of PTX. In vitro assays were conducted on human cancer cell lines including ovarian cancer cells SKOV-3, breast cancer cells MCF-7 and triple negative breast cancer cells MDA-MB-231. Cytotoxicity studies showed that mixed micelles exhibited better antitumor activity compared to PTX solution against the three cell lines. Furthermore mixed micelles showed a significant increase on PTX cellular uptake in comparison with pure Soluplus(®) micelles and free drug in all cell lines assayed. More important, blank mixed micelles have shown cytotoxic activity due to the ability of TPGS to induce apoptosis in cancer cells. This effect was associated with the expression levels of cleaved-PARP, an apoptosis-related protein. On the basis of these results, the mixed micelles developed in this study might be a potential nano-drug delivery system for cancer chemotherapy.
authors.affiliation: Departamento de Tecnología Farmacéutica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina; National Science Research Council (CONICET), Buenos Aires, Argentina.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Bernabeu
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina.
authors.forename: Lorena
authors.initials: L
authors.lastname: Gonzalez
authors.affiliation: Departamento de Tecnología Farmacéutica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina; National Science Research Council (CONICET), Buenos Aires, Argentina.
authors.forename: Maximiliano
authors.initials: M
authors.lastname: Cagel
authors.affiliation: Departamento de Tecnología Farmacéutica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina.
authors.forename: Esteban P
authors.initials: EP
authors.lastname: Gergic
authors.affiliation: Departamento de Tecnología Farmacéutica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina; National Science Research Council (CONICET), Buenos Aires, Argentina.
authors.forename: Marcela A
authors.initials: MA
authors.lastname: Moretton
authors.affiliation: Departamento de Tecnología Farmacéutica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina; National Science Research Council (CONICET), Buenos Aires, Argentina. Electronic address: diegochiappetta@yahoo.com.ar.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Chiappetta
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004339:Drug Compounding; D065546:Drug Liberation; D005260:Female; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D011145:Polyvinyls / Q000737:chemistry*; D012995:Solubility; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; D011145:Polyvinyls; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D014810:Vitamin E; D011092:Polyethylene Glycols; D011065:Poly(ADP-ribose) Polymerases; C014225:tocophersolan; D017239:Paclitaxel
keywords: Breast and ovarian cancer cell lines; In vitro anti-tumoral activity; Paclitaxel encapsulation; Soluplus(®)—TPGS mixed micelles