Trilayer micelles for combination delivery of rapamycin and siRNA targeting Y-box binding protein-1 (siYB-1)

• Published in: Biomaterials Vol. 34; no. 28; pp. 6882 - 6892
• Main Authors: Zeng, San, Xiong, May P
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.09.2013
• Subjects: Advanced Basic Science; Animals; Combination therapy; Dentistry; Drug Carriers - chemistry; Humans; Male; Mice; Mice, Nude; Micelles; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - therapy; Rapamycin; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; siRNA; Sirolimus - administration & dosage; Sirolimus - therapeutic use; Y-Box-Binding Protein 1 - genetics; YB-1; siRNA; Rapamycin; Animals; YB-1; Combination therapy; Micelles
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2013.05.010

Abstract A three layer (trilayer) polymeric micelle system based on the self-association of the triblock polymer poly(ethylene glycol)-b-poly{N-[N-(2-aminoethyl)-2-aminoethyl] aspartamide}-b-poly(ɛ-caprolactone) (PEG-b-PAsp(DET)-b-PCL) has been synthesized and investigated for combination delivery of rapamycin (RAP) and siRNA targeting Y-box binding protein-1 (siYB-1). The trilayer micelle is composed of (a) a hydrophilic poly(ethylene glycol) (PEG) block constituting the outer layer to improve pharmacokinetics, (b) an intermediate compartment composed of the cationic poly{2-[(2-aminoethyl)amino] ethyl aspartamide} (PAsp(DET)) segment for interacting with siYB-1, and (c) an inner hydrophobic poly(ɛ-caprolactone) (PCL) compartment for encapsulation of RAP. A major advantage of this system is biocompatibility since PEG and PCL are both approved by the FDA, and PAsp(DET) is a non-toxic pH responsive cationic poly(amino acid)-based polymer. In this study, it has been shown that PCL can encapsulate RAP with high loading efficiencies, and PAsp(DET) can successfully interact with siRNA for efficient transfection/knockdown with negligible cytotoxicity. The enhanced therapeutic efficacy of RAP/siYB-1 micelles was demonstrated in cell cultures and in a PC3 xenograft nude mouse model of human prostate cancer. Herein, we demonstrate that trilayer micelles are a promising approach to improve the simultaneous delivery of combination siRNA/drug therapies.