title: Trilayer micelles for combination delivery of rapamycin and siRNA targeting Y-box binding protein-1 (siYB-1).
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(ε-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(ε-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.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705-2222, USA.
authors.forename: San
authors.initials: S
authors.lastname: Zeng
authors.forename: May P
authors.initials: MP
authors.lastname: Xiong
mesh_terms: D000818:Animals; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D051840:Y-Box-Binding Protein 1 / Q000235:genetics*
chemical_list: D004337:Drug Carriers; D008823:Micelles; D034741:RNA, Small Interfering; D051840:Y-Box-Binding Protein 1; D020123:Sirolimus