A novel protein-drug conjugate, SSH20, demonstrates significant efficacy in caveolin-1-expressing tumors
In recent years, human serum albumin (HSA) has been characterized as an ideal drug carrier in the cancer arena. Caveolin-1 (Cav-1) has been established as the principal structural protein of caveolae and, thus, critical for caveolae-mediated endocytosis. Cav-1 has been shown to be overexpressed in c...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-09-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770521001108 |
| _version_ | 1818650309490114560 |
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| author | Ryan Robb Jimmy Chun-Tien Kuo Yang Liu Sergio Corrales-Guerrero Tiantian Cui Ahmad Hegazi Gregory Nagy Robert J. Lee Terence M. Williams |
| author_facet | Ryan Robb Jimmy Chun-Tien Kuo Yang Liu Sergio Corrales-Guerrero Tiantian Cui Ahmad Hegazi Gregory Nagy Robert J. Lee Terence M. Williams |
| author_sort | Ryan Robb |
| collection | DOAJ |
| description | In recent years, human serum albumin (HSA) has been characterized as an ideal drug carrier in the cancer arena. Caveolin-1 (Cav-1) has been established as the principal structural protein of caveolae and, thus, critical for caveolae-mediated endocytosis. Cav-1 has been shown to be overexpressed in cancers of the lung and pancreas, among others. We found that Cav-1 expression plays a critical role in both HSA uptake and response to albumin-based chemotherapies. As such, developing a novel albumin-based chemotherapy that is more selective for tumors with high Cav-1 expression or high levels of caveolar-endocytosis could have significant implications in biomarker-directed therapy. Herein, we present the development of a novel and effective HSA-SN-38 conjugate (SSH20). We find that SSH20 uptake decreases significantly by immunofluorescence assays and western blotting after silencing of Cav-1 expression through RNA interference. Decreased drug sensitivity occurs in Cav-1-depleted cells using cytotoxicity assays. Importantly, we find significantly reduced sensitivity to SSH20 in Cav-1-silenced tumors compared to Cav-1-expressing tumors in vivo. Notably, we show that SSH20 is significantly more potent than irinotecan in vitro and in vivo. Together, we have developed a novel HSA-conjugated chemotherapy that is potent, effective, safe, and demonstrates improved efficacy in high Cav-1-expressing tumors. |
| first_indexed | 2024-12-17T01:48:10Z |
| format | Article |
| id | doaj.art-6dbd85d6f99c4202b1a4bb0f11735547 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-17T01:48:10Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-6dbd85d6f99c4202b1a4bb0f117355472022-12-21T22:08:07ZengElsevierMolecular Therapy: Oncolytics2372-77052021-09-0122555564A novel protein-drug conjugate, SSH20, demonstrates significant efficacy in caveolin-1-expressing tumorsRyan Robb0Jimmy Chun-Tien Kuo1Yang Liu2Sergio Corrales-Guerrero3Tiantian Cui4Ahmad Hegazi5Gregory Nagy6Robert J. Lee7Terence M. Williams8University of North Carolina, Chapel Hill, NC, USADivision of Pharmaceutics and Pharmacology, The Ohio State University, 500 W. 12th Ave., Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, The Ohio State University, 500 W. 12th Ave., Columbus, OH 43210, USABiomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USADepartment of Radiation Oncology, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USADivision of Pharmaceutics and Pharmacology, The Ohio State University, 500 W. 12th Ave., Columbus, OH 43210, USABiomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USADivision of Pharmaceutics and Pharmacology, The Ohio State University, 500 W. 12th Ave., Columbus, OH 43210, USA; Corresponding author: Robert J. Lee, PhD, Division of Pharmaceutics and Pharmacology, The Ohio State University, 500 W. 12th Ave., Columbus, OH 43210, USA.Department of Radiation Oncology, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA; Corresponding author: Terence M. Williams, MD, PhD, Department of Radiation Oncology, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.In recent years, human serum albumin (HSA) has been characterized as an ideal drug carrier in the cancer arena. Caveolin-1 (Cav-1) has been established as the principal structural protein of caveolae and, thus, critical for caveolae-mediated endocytosis. Cav-1 has been shown to be overexpressed in cancers of the lung and pancreas, among others. We found that Cav-1 expression plays a critical role in both HSA uptake and response to albumin-based chemotherapies. As such, developing a novel albumin-based chemotherapy that is more selective for tumors with high Cav-1 expression or high levels of caveolar-endocytosis could have significant implications in biomarker-directed therapy. Herein, we present the development of a novel and effective HSA-SN-38 conjugate (SSH20). We find that SSH20 uptake decreases significantly by immunofluorescence assays and western blotting after silencing of Cav-1 expression through RNA interference. Decreased drug sensitivity occurs in Cav-1-depleted cells using cytotoxicity assays. Importantly, we find significantly reduced sensitivity to SSH20 in Cav-1-silenced tumors compared to Cav-1-expressing tumors in vivo. Notably, we show that SSH20 is significantly more potent than irinotecan in vitro and in vivo. Together, we have developed a novel HSA-conjugated chemotherapy that is potent, effective, safe, and demonstrates improved efficacy in high Cav-1-expressing tumors.http://www.sciencedirect.com/science/article/pii/S2372770521001108SSH20lung cancerpancreatic cancercaveolin-1albuminSN-38 |
| spellingShingle | Ryan Robb Jimmy Chun-Tien Kuo Yang Liu Sergio Corrales-Guerrero Tiantian Cui Ahmad Hegazi Gregory Nagy Robert J. Lee Terence M. Williams A novel protein-drug conjugate, SSH20, demonstrates significant efficacy in caveolin-1-expressing tumors Molecular Therapy: Oncolytics SSH20 lung cancer pancreatic cancer caveolin-1 albumin SN-38 |
| title | A novel protein-drug conjugate, SSH20, demonstrates significant efficacy in caveolin-1-expressing tumors |
| title_full | A novel protein-drug conjugate, SSH20, demonstrates significant efficacy in caveolin-1-expressing tumors |
| title_fullStr | A novel protein-drug conjugate, SSH20, demonstrates significant efficacy in caveolin-1-expressing tumors |
| title_full_unstemmed | A novel protein-drug conjugate, SSH20, demonstrates significant efficacy in caveolin-1-expressing tumors |
| title_short | A novel protein-drug conjugate, SSH20, demonstrates significant efficacy in caveolin-1-expressing tumors |
| title_sort | novel protein drug conjugate ssh20 demonstrates significant efficacy in caveolin 1 expressing tumors |
| topic | SSH20 lung cancer pancreatic cancer caveolin-1 albumin SN-38 |
| url | http://www.sciencedirect.com/science/article/pii/S2372770521001108 |
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