title: In vitro anticancer activity of docetaxel-loaded micelles based on poly(ethylene oxide)-poly(epsilon-caprolactone) block copolymers: Do nanocarrier properties have a role?
abstract: In this paper we have investigated the behavior of core-shell poly(ethylene oxide)-poly(epsilon-caprolactone) (PEO-PCL) micelles derived from copolymers with linear triblock (TR) and 4-arm star-diblock (ST) architectures for the delivery of docetaxel (DTX). DTX was loaded inside micelles (DTX-TR(m) and DTX-ST(m)) with high efficiency and released slowly for more than two weeks. DTX-loaded micelles based on both copolymers had very similar properties in terms of mean size, zeta potential, loading ability and release rate in buffered saline. However, the stability of DTX-ST(m) was very poor in aqueous media with proteins resulting in a strong and progressive aggregation. We studied the effect of increasing concentrations of free DTX or DTX-loaded micelles on growth inhibition of human breast MCF-7 and MDA-MB468 and prostate PC3 and DU145 adenocarcinoma cell lines. DTX-loaded TR micelles induced cell growth inhibition similarly to free DTX whereas DTX-ST(m) showed lower cytotoxicity. On the other hand, by normalizing IC(50) values for the actual amount of DTX released from micelles in the medium, DTX-loaded ST micelles became more active than free DTX in all cell lines tested. Both free DTX and DTX-loaded TR micelles displayed a significantly lower cytotoxic activity in G(2)/M phase synchronized cells, whereas cytotoxicity of DTX-loaded ST micelles did not change. Cytotoxicity was related to micelle stability, uptake and release rate in cell culture media. Our results suggest that for a correct interpretation of cytotoxicity of nanocarriers, the evaluation of their behavior in biologically relevant conditions is of utmost importance to select proper systems for further in vivo testing.
authors.affiliation: Department of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, Via D. Montesano 49, 80131, Naples, Italy.
authors.forename: Luisanna
authors.initials: L
authors.lastname: Ostacolo
authors.forename: Monica
authors.initials: M
authors.lastname: Marra
authors.forename: Francesca
authors.initials: F
authors.lastname: Ungaro
authors.forename: Silvia
authors.initials: S
authors.lastname: Zappavigna
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maglio
authors.forename: Fabiana
authors.initials: F
authors.lastname: Quaglia
authors.forename: Alberto
authors.initials: A
authors.lastname: Abbruzzese
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008297:Male; D008823:Micelles; D053758:Nanoparticles; D011091:Polyesters / Q000737:chemistry* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012995:Solubility; D043823:Taxoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; D043823:Taxoids; C458722:polyethylene oxide-polycaprolactone copolymer; D000077143:Docetaxel