期刊
INTERNATIONAL JOURNAL OF PHARMACEUTICS
卷 529, 期 1-2, 页码 178-192出版社
ELSEVIER
DOI: 10.1016/j.ijpharm.2017.06.077
关键词
Letrozole; Celecoxib; Protamine nanocapsules; Multi-compartmental nanocarriers; PEGylated phospholipid-drug complex; Hyaluronate targeting
Despite several reports have revealed the beneficial effect of co-administration of COX-2 inhibitors with aromatase inhibitors in managing postmenopausal breast cancer; no nanocarriers for such combined delivery have been developed till now. Therefore, protamine nanocapsules (PMN-NCs) have been developed to co-deliver letrozole (LTZ) that inhibits aromatase-mediated estrogen biosynthesis and celecoxib (CXB) that synergistically inhibits aromatase expression. Inspired by the CD44-mediated tumor targeting ability of hyaluronate (HA), we developed HA-coated PMN-NCs (HA-NCs) via electrostatic layer-by-layer assembly. Moreover, multi-compartmental PEGylated phospholipid-CXB complex bilayer enveloping PMN-NCs (PEG-NCs) were designed for conferring biphasic CXB release from the phospholipid corona and oily core as well as enabling passive-targeting. The NCs demonstrated excellent stability, prolonged circulation and could be scaled up with the aid of spray-drying technology. Hemolysis, serum stability and cytotoxicity studies confirmed the superiority of combined LTZ-CXB nano-delivery. Mechanistically, the NCs especially HA-NCs and PEG-NCs demonstrated precious antitumor effects in vivo revealed as reduction in the tumor volume and aromatase level, increased apoptosis, as well as inhibition of VEGF, NF-kappa B and TNF-alpha augmented by histopathological and immunohistochemical studies. Overall, our approach provided for the first time a potential strategy for targeted LTZ-CXB combined therapy of hormone-dependent breast cancer via singular nanocapsule delivery system. (C) 2017 Elsevier B.V. All rights reserved.
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