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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2017-09-01
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| Series: | International Journal of Nanomedicine |
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| Online Access: | https://www.dovepress.com/synthetic-high-density-lipoprotein-nanodisks-for-targeted-withalongoli-peer-reviewed-article-IJN |
| _version_ | 1819021504960004096 |
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| 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 |
| collection | DOAJ |
| 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 |
| first_indexed | 2024-12-21T04:08:10Z |
| format | Article |
| id | doaj.art-3121709d2d9f4162a601725d7783561c |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-12-21T04:08:10Z |
| publishDate | 2017-09-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-3121709d2d9f4162a601725d7783561c2022-12-21T19:16:32ZengDove Medical PressInternational Journal of Nanomedicine1178-20132017-09-01Volume 126581659434603Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinomaKuai RSubramanian CWhite PTTimmermann BNMoon JJCohen MSSchwendeman ARui 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 carcinomashttps://www.dovepress.com/synthetic-high-density-lipoprotein-nanodisks-for-targeted-withalongoli-peer-reviewed-article-IJNSynthetic high-density lipoproteinsscavenger receptor class B1targeted deliverynanodiscswithalongolidesadrenocortical carcinomas |
| spellingShingle | 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 International Journal of Nanomedicine Synthetic high-density lipoproteins scavenger receptor class B1 targeted delivery nanodiscs withalongolides adrenocortical carcinomas |
| title | 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_short | 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 |
| topic | Synthetic high-density lipoproteins scavenger receptor class B1 targeted delivery nanodiscs withalongolides adrenocortical carcinomas |
| url | https://www.dovepress.com/synthetic-high-density-lipoprotein-nanodisks-for-targeted-withalongoli-peer-reviewed-article-IJN |
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