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Summary: Several samples of polymeric micelles, formed by amphiphilic derivatives of PHEA, obtained by grafting into polymeric backbone of PEGs and/or hexadecylamine groups (PHEA-PEG-C16 and PHEA-C16) and containing different amount of Tamoxifen, were prepared. All Tamoxifenloaded polymeric micelles showed to increase drug water solubility. TEM studies provided evidence of the formation of supramolecular core/shell architectures containing drug, in the nanoscopic range and with spherical shape. Samples with different amount of encapsulated Tamoxifen were subjected to in vitro cytotoxic studies in order to evaluate the effect of Tamoxifen micellization on cell growth inhibition. All samples of Tamoxifen-loaded polymeric micelles showed a significantly higher antiproliferative activity in comparison with free drug, probably attributable to fluidification of cellular membranes, caused by amphiphilic copolymers, that allows a higher penetration of the drug into tumoral cells. To gain preliminary information about the potential use of prepared micelles as Tamoxifen drug delivery systems, studies evaluating drug release ability of micelle systems in media mimicking biological fluids (buffer solutions at pH 7.4 and
5.5) and in human plasma were carried out. These studies, performed evaluating the amount of Tamoxifen that remains in solution as a function of time, showed that at pH 7.4, as well as in plasma, PHEA-C16 polymeric micelles were able to release lower drug amounts than PHEA-PEG5000-C16 ones, while at pH 5.5, the behavior difference between two kind of micelles was less pronounced.
Tamoxifen-Loaded Polymeric Micelles: Preparation, Physico-Chemical Characterization and In Vitro Evaluation Studies Gennara Cavallaro,* Laura Maniscalco, Mariano Licciardi, Gaetano Giammona Dipartimento di Chimica e Tecnologie Farmaceutiche,Via Archirafi, 32, 90123 Palermo, Italy Fax: 0039-091-6236150; E-mail:
[email protected]
Received: June 22, 2004; Revised: September 13, 2004; Accepted: September 15, 2004; DOI: 10.1002/mabi.200400089 Keywords: amphiphilic copolymers; micelles; poly(aspartamide); polymeric micelles; Tamoxifen
Introduction Among drug delivery systems developed in last years in order to improve the pharmacokinetic and pharmacodynamic profiles of therapeutical agents, the use of polymeric micelles formed by amphiphilic copolymers, as drug carriers seems to be an interesting alternative to classical formulations.[1] The properties of self-assembling molecules have been widely studied.[2–4] High molecular weight surfactants have been demonstrated to be the ideal candidates[5] to form micelles with suitable size, from 10 to 100 nm, with in vitro and in vivo high thermodynamic (low critical micelle concentration, CMC) and kinetic (the actual rate of micelle dissociation below CMC) stability, long circulation in bloodstream[6] and low toxicity.[3,4] For all Macromol. Biosci. 2004, 4, 1028–1038
these reasons, nowadays, polymeric micelles are considered promising carriers for formulation and delivery of water-insoluble anticancer drugs,[7] such as doxorubicin,[8] cisplatin,[9] paclitaxel,[10,11] and methotrexate.[12] The loading of these drugs into polymeric micelles, in fact, improves drug biopharmaceutical properties by increasing drug water solubility, chemical stability, bioavailability and by reducing its toxicity.[8–12] Moreover, the nanoscopic size of these carriers (
