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 W.G. Alani

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number713
JournalPharmaceutics
Volume14
Issue number4
DOIs
StatePublished - Apr 2022
Externally publishedYes

Keywords

  • drug delivery
  • hypoxia-activated prodrug
  • liposome
  • organoids
  • pancreatic cancer

ASJC Scopus subject areas

  • Pharmaceutical Science

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