Aptamer–Gemcitabine Conjugates with Enzymatically Cleavable Linker for Targeted Delivery and Intracellular Drug Release in Cancer Cells
Gemcitabine is a chemotherapeutic used clinically to treat a variety of cancers. However, because it lacks tumor cell specificity, gemcitabine may cause off-target cytotoxicity and adversely impact patients. To impart cancer cell specificity to gemcitabine and improve its therapeutic efficacy, we sy...
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| Format: | Article |
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MDPI AG
2022-04-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/5/558 |
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| author | Jianjun Qi Zihua Zeng Zhenghu Chen Cole Nipper Xiaohui Liu Quanyuan Wan Jian Chen Ching-Hsuan Tung Youli Zu |
| author_facet | Jianjun Qi Zihua Zeng Zhenghu Chen Cole Nipper Xiaohui Liu Quanyuan Wan Jian Chen Ching-Hsuan Tung Youli Zu |
| author_sort | Jianjun Qi |
| collection | DOAJ |
| description | Gemcitabine is a chemotherapeutic used clinically to treat a variety of cancers. However, because it lacks tumor cell specificity, gemcitabine may cause off-target cytotoxicity and adversely impact patients. To impart cancer cell specificity to gemcitabine and improve its therapeutic efficacy, we synthesized a unique aptamer–drug conjugate that carries a high gemcitabine payload (three molecules) via a dendrimer structure and enzymatically cleavable linkers for controlled intracellular drug release. First, linker–gemcitabinedendrimer–linker–gemcitabine products were produced, which had significantly lower cytotoxicity than an equimolar amount of free drug. Biochemical analysis revealed that lysosomal cathepsin B protease rapidly cleaved the dendritic linkers and released the conjugated gemcitabine as a free drug. Subsequently, the dendrimer–linker–gemcitabine was coupled with a cell-specific aptamer to form aptamer–gemcitabine conjugates. Functional assays confirmed that, under aptamer guidance, aptamer–gemcitabine conjugates were selectively bound to and then internalized by triple-negative breast cancer cells. Cellular therapy studies indicated that the aptamer–gemcitabine conjugates potentiated cytotoxic activity to targeted cancer cells but did not affect off-target control cells. Our study demonstrates a novel approach to aptamer-mediated targeted drug delivery that combines a high drug payload and an enzymatically controlled drug release switch to achieve higher therapeutic efficacy and fewer off-target effects relative to free-drug chemotherapy. |
| first_indexed | 2024-03-10T03:10:10Z |
| format | Article |
| id | doaj.art-1ba78e0a16fc440f9257bd2436ee8a53 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T03:10:10Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-1ba78e0a16fc440f9257bd2436ee8a532023-11-23T12:34:30ZengMDPI AGPharmaceuticals1424-82472022-04-0115555810.3390/ph15050558Aptamer–Gemcitabine Conjugates with Enzymatically Cleavable Linker for Targeted Delivery and Intracellular Drug Release in Cancer CellsJianjun Qi0Zihua Zeng1Zhenghu Chen2Cole Nipper3Xiaohui Liu4Quanyuan Wan5Jian Chen6Ching-Hsuan Tung7Youli Zu8Department of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USADepartment of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USADepartment of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USADepartment of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USADepartment of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USADepartment of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USADepartment of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USADepartment of Radiology, Molecular Imaging Innovations Institute, Weill Cornell Medicine, New York, NY 10021, USADepartment of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USAGemcitabine is a chemotherapeutic used clinically to treat a variety of cancers. However, because it lacks tumor cell specificity, gemcitabine may cause off-target cytotoxicity and adversely impact patients. To impart cancer cell specificity to gemcitabine and improve its therapeutic efficacy, we synthesized a unique aptamer–drug conjugate that carries a high gemcitabine payload (three molecules) via a dendrimer structure and enzymatically cleavable linkers for controlled intracellular drug release. First, linker–gemcitabinedendrimer–linker–gemcitabine products were produced, which had significantly lower cytotoxicity than an equimolar amount of free drug. Biochemical analysis revealed that lysosomal cathepsin B protease rapidly cleaved the dendritic linkers and released the conjugated gemcitabine as a free drug. Subsequently, the dendrimer–linker–gemcitabine was coupled with a cell-specific aptamer to form aptamer–gemcitabine conjugates. Functional assays confirmed that, under aptamer guidance, aptamer–gemcitabine conjugates were selectively bound to and then internalized by triple-negative breast cancer cells. Cellular therapy studies indicated that the aptamer–gemcitabine conjugates potentiated cytotoxic activity to targeted cancer cells but did not affect off-target control cells. Our study demonstrates a novel approach to aptamer-mediated targeted drug delivery that combines a high drug payload and an enzymatically controlled drug release switch to achieve higher therapeutic efficacy and fewer off-target effects relative to free-drug chemotherapy.https://www.mdpi.com/1424-8247/15/5/558aptamer–drug conjugatesenzymatically cleavable linkercontrolled intracellular drug releasehigh gemcitabine payloadtargeted drug deliverycell-specific chemotherapy |
| spellingShingle | Jianjun Qi Zihua Zeng Zhenghu Chen Cole Nipper Xiaohui Liu Quanyuan Wan Jian Chen Ching-Hsuan Tung Youli Zu Aptamer–Gemcitabine Conjugates with Enzymatically Cleavable Linker for Targeted Delivery and Intracellular Drug Release in Cancer Cells Pharmaceuticals aptamer–drug conjugates enzymatically cleavable linker controlled intracellular drug release high gemcitabine payload targeted drug delivery cell-specific chemotherapy |
| title | Aptamer–Gemcitabine Conjugates with Enzymatically Cleavable Linker for Targeted Delivery and Intracellular Drug Release in Cancer Cells |
| title_full | Aptamer–Gemcitabine Conjugates with Enzymatically Cleavable Linker for Targeted Delivery and Intracellular Drug Release in Cancer Cells |
| title_fullStr | Aptamer–Gemcitabine Conjugates with Enzymatically Cleavable Linker for Targeted Delivery and Intracellular Drug Release in Cancer Cells |
| title_full_unstemmed | Aptamer–Gemcitabine Conjugates with Enzymatically Cleavable Linker for Targeted Delivery and Intracellular Drug Release in Cancer Cells |
| title_short | Aptamer–Gemcitabine Conjugates with Enzymatically Cleavable Linker for Targeted Delivery and Intracellular Drug Release in Cancer Cells |
| title_sort | aptamer gemcitabine conjugates with enzymatically cleavable linker for targeted delivery and intracellular drug release in cancer cells |
| topic | aptamer–drug conjugates enzymatically cleavable linker controlled intracellular drug release high gemcitabine payload targeted drug delivery cell-specific chemotherapy |
| url | https://www.mdpi.com/1424-8247/15/5/558 |
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