Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma
Year: 2017
Type: article
Abstract: : Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and has a 5-year survival rate of <35%. ACC cells require cholesterol for steroid hormone production, and this requirement is met via expression on the cell surface of a high level of SRB1, responsible for the uptake of high-density lipoproteins (HDLs), which carry and transport cholesterol in vivo. Here, we describe how this natural lipid carrier function of SRB1 can be utilized to improve the tumor-targeted delivery of a novel natural product derivative – withalongolide A 4,19,27-triacetate (WGA-TA) – which has shown potent antitumor efficacy, but poor aqueous solubility. Our strategy was to use synthetic HDL (sHDL) nanodisks, which are effective in tumor-targeted delivery due to their smallness, long circulation half-life, documented safety, and ability to bind to SRB1. In this study, we prepared sHDL nanodisks using an optimized phospholipid composition combined with ApoA 1 mimetic peptide (22A), which has previously been tested in clinical trials, to load WGA-TA. Following optimization, WGA-TA nanodisks showed drug encapsulation efficiency of 78%, a narrow particle size distribution (9.81±0.41 nm), discoid shape, and sustained drug release in phosphate buffered saline. WGA-TA-sHDL nanodisks exhibited higher cytotoxicity in the ACC cell line H295R half maximal inhibitory concentration ([IC 50 ] 0.26±0.045 µM) than free WGA-TA (IC 50 0.492±0.115 µM, P <0.05). Fluorescent dye-loaded sHDL nanodisks efficiently accumulated in H295R adrenal carcinoma xenografts 24 hours following dosing. Moreover, daily intraperitoneal administration of 7 mg/kg WGA-TA-loaded sHDL nanodisks significantly inhibited tumor growth during 21-day administration to H295R xenograft-bearing mice compared to placebo ( P <0.01). Collectively, these results suggest that WGA-TA-loaded nanodisks may represent a novel and beneficial therapeutic strategy for the treatment of ACC. Keywords: synthetic high-density lipoproteins, scavenger receptor class B 1 , targeted delivery, nanodisks, withalongolides, adrenocortical carcinomas
DOI: 10.2147/ijn.s140591
Authors: Rui Kuai, Chitra Subramanian, Peter T White, Barbara Timmermann, James J Moon, Mark Cohen, Anna Schwendeman
Institutions: University of Michigan, University of Kansas
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $2,836
Funders: American Heart Association, National Institutes of Health, University of Michigan Comprehensive Cancer Center, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering
Awards: HDL-Loaded Nanoparticles for Glioma Therapeutics, Biomaterials for treatment of head and neck cancer, The use of synthetic high density lipoproteins as carriers to regulate PCSK9 for LDL management, Elicitation of mucosal immune responses against HIV, G3549828030, Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors, Tuning Biomaterials-immune cell interactions for treatment of glioblastoma multiforme, Engineering Nanomaterials to Prime Immunity, University of Michigan Surgical Oncology Research Training Program
OpenAlex ID: W2751971954