In vitro anticancer activity of docetaxel-loaded micelles based on poly(ethylene oxide)-poly(epsilon-caprolactone) block copolymers: Do nanocarrier properties have a role?

• Published in: Journal of controlled release Vol. 148; no. 2; pp. 255 - 263
• Main Authors: Ostacolo, Luisanna, Marra, Monica, Ungaro, Francesca, Zappavigna, Silvia, Maglio, Giovanni, Quaglia, Fabiana, Abbruzzese, Alberto, Caraglia, Michele
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.12.2010; Elsevier
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biological Transport; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Pharmaceutical; Cytotoxicity; Delayed-Action Preparations; Docetaxel; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Drug Stability; Female; General pharmacology; Humans; Inhibitory Concentration 50; Kinetics; Male; Medical sciences; Micelles; Nanoparticles; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Poly(ethylene oxide)-poly(epsilon-caprolactone); Polyesters - chemistry; Polyesters - metabolism; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Solubility; Stability; Taxoids - chemistry; Taxoids - metabolism; Taxoids - pharmacology; Poly(ethylene oxide)-poly(epsilon-caprolactone); Cytotoxicity; Stability; Micelles; Docetaxel; Antineoplastic agent; Lactone copolymer; Pharmaceutical technology; Micelle; In vitro; Biological activity; Ethylene oxide polymer; Caprolactone copolymer; Cyclic ether polymer; Taxane derivatives; Antimitotic; Physicochemical properties; Block copolymer; Nanotechnology
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2010.08.006

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. Biodegradable micelles delivering an anticancer drug and made of poly(ethylene oxide)/poly(epsilon-caprolactone) block copolymers with different architectures share similar technological features while showing very different cytotoxicity. [Display omitted]