Galactose-decorated liver tumor-specific nanoliposomes incorporating selective BRD4-targeted PROTAC for hepatocellular carcinoma therapy

被引:42
作者
Saraswat, Aishwarya [1 ]
Vemana, Hari Priya [1 ]
Dukhande, Vikas V. [1 ]
Patel, Ketan [1 ]
机构
[1] St Johns Univ, Coll Pharm & Hlth Sci, Queens, NY 11439 USA
关键词
ARV-825; BRD4; PROTAC; Galactosylated nanoliposomes; Active drug delivery; Hepatocellular carcinoma; C-MYC; IN-VITRO; PEGYLATED LIPOSOMES; GENE DELIVERY; DRUG; CELLS; INHIBITION; GROWTH; PROLIFERATION; DEGRADATION;
D O I
10.1016/j.heliyon.2021.e08702
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
This research deals with the development of asialoglycoprotein receptors (ASGPR) directed nanoliposomes incorporating a novel BRD4 (Bromodomain-containing protein 4) protein-targeted PROTAC (Proteolysis Targeting Chimera), ARV-825 (ARV) (GALARV), and to investigate the anticancer efficacy of GALARV for specific delivery in hepatocellular carcinoma. GALARV were prepared using the modified hydration method and characterized for their physicochemical properties as well as anticancer activity using 2D and 3D cell culture models. ARV and GALARV (93.83 +/- 10.05 nm) showed significant in vitro cytotoxicity and apoptosis in hepatocellular carcinoma cells. GALARV also demonstrated a substantially higher intracellular concentration of ARV compared to non-targeted nanoliposomes (similar to 3 fold) and ARV alone (similar to 4.5 fold), showed good physical stability and negligible hemolysis. Immunoblotting results depicted substantial downregulation of target BRD4 protein, oncogenic c-Myc, apoptotic Bcl-2, and survivin proteins. Notably, GALARV treatment resulted in significant apoptosis and subsequent inhibition of the cell viability of 3D tumor spheroids of hepatocellular carcinoma. These results suggest that GALARV is a novel actively targeted PROTAC-based nanotherapeutic approach for hepatocellular carcinoma.
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页数:11
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