Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) presents as an unmet clinical challenge for drug delivery due to its unique hypoxic biology. Vinblastine-N-Oxide (CPD100) is a hypoxia-activated prodrug (HAP) that selectively converts to its parent compound, vinblastine, a potent cytotoxic agent, under oxygen...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/4/713 |
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| author | Vidhi M. Shah Craig Dorrell Adel Al-Fatease Brittany L. Allen-Petersen Yeonhee Woo Yuliya Bortnyak Rohi Gheewala Brett C. Sheppard Rosalie C. Sears Adam WG. Alani |
| author_facet | Vidhi M. Shah Craig Dorrell Adel Al-Fatease Brittany L. Allen-Petersen Yeonhee Woo Yuliya Bortnyak Rohi Gheewala Brett C. Sheppard Rosalie C. Sears Adam WG. Alani |
| author_sort | Vidhi M. Shah |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) presents as an unmet clinical challenge for drug delivery due to its unique hypoxic biology. Vinblastine-N-Oxide (CPD100) is a hypoxia-activated prodrug (HAP) that selectively converts to its parent compound, vinblastine, a potent cytotoxic agent, under oxygen gradient. The study evaluates the efficacy of microfluidics formulated liposomal CPD100 (CPD100Li) in PDAC. CPD100Li were formulated with a size of 95 nm and a polydispersity index of 0.2. CPD100Li was stable for a period of 18 months when freeze-dried at a concentration of 3.55 mg/mL. CPD100 and CPD100Li confirmed selective activation at low oxygen levels in pancreatic cancer cell lines. Moreover, in 3D spheroids, CPD100Li displayed higher penetration and disruption compared to CPD100. In patient-derived 3D organoids, CPD100Li exhibited higher cell inhibition in the organoids that displayed higher expression of hypoxia-inducible factor 1 alpha (HIF1A) compared to CPD100. In the orthotopic model, the combination of CPD100Li with gemcitabine (GEM) (standard of care for PDAC) showed higher efficacy than CPD100Li alone for a period of 90 days. In summary, the evaluation of CPD100Li in multiple cellular models provides a strong foundation for its clinical application in PDAC. |
| first_indexed | 2024-03-09T10:30:08Z |
| format | Article |
| id | doaj.art-683dea412c074d39add29de2c831bed1 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T10:30:08Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-683dea412c074d39add29de2c831bed12023-12-01T21:18:26ZengMDPI AGPharmaceutics1999-49232022-03-0114471310.3390/pharmaceutics14040713Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic CancerVidhi M. Shah0Craig Dorrell1Adel Al-Fatease2Brittany L. Allen-Petersen3Yeonhee Woo4Yuliya Bortnyak5Rohi Gheewala6Brett C. Sheppard7Rosalie C. Sears8Adam WG. Alani9Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 South Moody Avenue, Portland, OR 97201, USABrenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USADepartment of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 South Moody Avenue, Portland, OR 97201, USADepartment of Molecular and Medical Genetics, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USADepartment of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 South Moody Avenue, Portland, OR 97201, USADepartment of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 South Moody Avenue, Portland, OR 97201, USASchool of Medicine, Oregon Health and Science University, 3181 Southwest Sam Jackson Road, Portland, OR 97239, USABrenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USABrenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USADepartment of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 South Moody Avenue, Portland, OR 97201, USAPancreatic ductal adenocarcinoma (PDAC) presents as an unmet clinical challenge for drug delivery due to its unique hypoxic biology. Vinblastine-N-Oxide (CPD100) is a hypoxia-activated prodrug (HAP) that selectively converts to its parent compound, vinblastine, a potent cytotoxic agent, under oxygen gradient. The study evaluates the efficacy of microfluidics formulated liposomal CPD100 (CPD100Li) in PDAC. CPD100Li were formulated with a size of 95 nm and a polydispersity index of 0.2. CPD100Li was stable for a period of 18 months when freeze-dried at a concentration of 3.55 mg/mL. CPD100 and CPD100Li confirmed selective activation at low oxygen levels in pancreatic cancer cell lines. Moreover, in 3D spheroids, CPD100Li displayed higher penetration and disruption compared to CPD100. In patient-derived 3D organoids, CPD100Li exhibited higher cell inhibition in the organoids that displayed higher expression of hypoxia-inducible factor 1 alpha (HIF1A) compared to CPD100. In the orthotopic model, the combination of CPD100Li with gemcitabine (GEM) (standard of care for PDAC) showed higher efficacy than CPD100Li alone for a period of 90 days. In summary, the evaluation of CPD100Li in multiple cellular models provides a strong foundation for its clinical application in PDAC.https://www.mdpi.com/1999-4923/14/4/713hypoxia-activated prodrugliposomedrug deliveryorganoidspancreatic cancer |
| spellingShingle | Vidhi M. Shah Craig Dorrell Adel Al-Fatease Brittany L. Allen-Petersen Yeonhee Woo Yuliya Bortnyak Rohi Gheewala Brett C. Sheppard Rosalie C. Sears Adam WG. Alani Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer Pharmaceutics hypoxia-activated prodrug liposome drug delivery organoids pancreatic cancer |
| title | Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer |
| title_full | Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer |
| title_fullStr | Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer |
| title_full_unstemmed | Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer |
| title_short | Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer |
| title_sort | microfluidics formulated liposomes of hypoxia activated prodrug for treatment of pancreatic cancer |
| topic | hypoxia-activated prodrug liposome drug delivery organoids pancreatic cancer |
| url | https://www.mdpi.com/1999-4923/14/4/713 |
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