Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer

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

doi:10.3390/pharmaceutics14040713

Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer

Pharmaceutics. 2022 Mar 26;14(4):713. doi: 10.3390/pharmaceutics14040713.

Authors

Vidhi M Shah^{1

2

3}, Craig Dorrell², Adel Al-Fatease^{1

4}, Brittany L Allen-Petersen³, Yeonhee Woo¹, Yuliya Bortnyak¹, Rohi Gheewala⁵, Brett C Sheppard^{2

6

7}, Rosalie C Sears^{2

3

7}, Adam Wg Alani^{1

7

8}

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 South Moody Avenue, Portland, OR 97201, USA.
² Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
³ Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
⁴ Department of Pharmaceutics, College of Pharmacy, King Khalid University, Guraiger, Abha 62529, Saudi Arabia.
⁵ School of Medicine, Oregon Health and Science University, 3181 Southwest Sam Jackson Road, Portland, OR 97239, USA.
⁶ Department of Surgery, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
⁷ Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97120, USA.
⁸ Department of Biomedical Engineering, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA.

Abstract

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.

Keywords: drug delivery; hypoxia-activated prodrug; liposome; organoids; pancreatic cancer.

Abstract

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