Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma

Rui Kuai,1,2,* Chitra Subramanian,3,* Peter T White,3,* Barbara N Timmermann,4 James J Moon,1,2,5 Mark S Cohen,3,6 Anna Schwendeman1,2 1Department of Pharmaceutical Sciences, College of Pharmacy, 2Biointerfaces Institute, University of Michigan, 3Department of Surgery, University of Michigan, Ann A...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Kuai R, Subramanian C, White PT, Timmermann BN, Moon JJ, Cohen MS, Schwendeman A
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	Synthetic high-density lipoproteins scavenger receptor class B1 targeted delivery nanodiscs withalongolides adrenocortical carcinomas Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/3121709d2d9f4162a601725d7783561c
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:3121709d2d9f4162a601725d7783561c
record_format	dspace
spelling	oai:doaj.org-article:3121709d2d9f4162a601725d7783561c2021-12-02T03:11:04ZSynthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma1178-2013https://doaj.org/article/3121709d2d9f4162a601725d7783561c2017-09-01T00:00:00Zhttps://www.dovepress.com/synthetic-high-density-lipoprotein-nanodisks-for-targeted-withalongoli-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Rui Kuai,1,2,* Chitra Subramanian,3,* Peter T White,3,* Barbara N Timmermann,4 James J Moon,1,2,5 Mark S Cohen,3,6 Anna Schwendeman1,2 1Department of Pharmaceutical Sciences, College of Pharmacy, 2Biointerfaces Institute, University of Michigan, 3Department of Surgery, University of Michigan, Ann Arbor, MI, 4Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, 5Department of Biomedical Engineering, 6Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA *These authors contributed equally to this work 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 ApoA1 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 ([IC50] 0.26±0.045 µM) than free WGA-TA (IC50 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 B1, targeted delivery, nanodisks, withalongolides, adrenocortical carcinomasKuai RSubramanian CWhite PTTimmermann BNMoon JJCohen MSSchwendeman ADove Medical PressarticleSynthetic high-density lipoproteinsscavenger receptor class B1targeted deliverynanodiscswithalongolidesadrenocortical carcinomasMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 6581-6594 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Synthetic high-density lipoproteins scavenger receptor class B1 targeted delivery nanodiscs withalongolides adrenocortical carcinomas Medicine (General) R5-920
spellingShingle	Synthetic high-density lipoproteins scavenger receptor class B1 targeted delivery nanodiscs withalongolides adrenocortical carcinomas Medicine (General) R5-920 Kuai R Subramanian C White PT Timmermann BN Moon JJ Cohen MS Schwendeman A Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma
description	Rui Kuai,1,2,* Chitra Subramanian,3,* Peter T White,3,* Barbara N Timmermann,4 James J Moon,1,2,5 Mark S Cohen,3,6 Anna Schwendeman1,2 1Department of Pharmaceutical Sciences, College of Pharmacy, 2Biointerfaces Institute, University of Michigan, 3Department of Surgery, University of Michigan, Ann Arbor, MI, 4Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, 5Department of Biomedical Engineering, 6Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA *These authors contributed equally to this work 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 ApoA1 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 ([IC50] 0.26±0.045 µM) than free WGA-TA (IC50 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 B1, targeted delivery, nanodisks, withalongolides, adrenocortical carcinomas
format	article
author	Kuai R Subramanian C White PT Timmermann BN Moon JJ Cohen MS Schwendeman A
author_facet	Kuai R Subramanian C White PT Timmermann BN Moon JJ Cohen MS Schwendeman A
author_sort	Kuai R
title	Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma
title_short	Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma
title_full	Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma
title_fullStr	Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma
title_full_unstemmed	Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma
title_sort	synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/3121709d2d9f4162a601725d7783561c
work_keys_str_mv	AT kuair synthetichighdensitylipoproteinnanodisksfortargetedwithalongolidedeliverytoadrenocorticalcarcinoma AT subramanianc synthetichighdensitylipoproteinnanodisksfortargetedwithalongolidedeliverytoadrenocorticalcarcinoma AT whitept synthetichighdensitylipoproteinnanodisksfortargetedwithalongolidedeliverytoadrenocorticalcarcinoma AT timmermannbn synthetichighdensitylipoproteinnanodisksfortargetedwithalongolidedeliverytoadrenocorticalcarcinoma AT moonjj synthetichighdensitylipoproteinnanodisksfortargetedwithalongolidedeliverytoadrenocorticalcarcinoma AT cohenms synthetichighdensitylipoproteinnanodisksfortargetedwithalongolidedeliverytoadrenocorticalcarcinoma AT schwendemana synthetichighdensitylipoproteinnanodisksfortargetedwithalongolidedeliverytoadrenocorticalcarcinoma
_version_	1718401908877557760

Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma

Ejemplares similares