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Nano-delivery of Gemcitabine Derivative as a Therapeutic Strategy in a Desmoplastic KRAS Mutant Pancreatic Cancer

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Abstract

Pancreatic ductal adenocarcinoma remains one of the challenging malignancies to treat, and chemotherapy is the primary treatment strategy available to most patients. Gemcitabine, one of the oldest chemotherapeutic drugs approved for pancreatic cancer, has limited efficacy, due to low drug distribution to the tumor and chemoresistance following therapy. In this study, we delivered gemcitabine monophosphate using lipid calcium phosphate nanoparticles, to desmoplastic pancreatic tumors. Monophosphorylation is a critical, rate-limiting step following cellular uptake of gemcitabine and precursor of the pharmacologically active gemcitabine triphosphate. Our drug delivery strategy enabled us to achieve robust tumor regression with a low parenteral dose in a clinically relevant, KRAS mutant, syngeneic orthotopic allograft, lentivirus-transfected KPC cell line-derived model of pancreatic cancer. Treatment with gemcitabine monophosphate significantly increased apoptosis of cancer cells, enabled reduction in the proportion of immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells, and did not increase expression of cancer stem cell markers. Overall, we could trigger a strong antitumor response in a treatment refractory PDAC model, while bypassing critical hallmarks of gemcitabine chemoresistance.

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Funding

The work was supported by National Institute of Health (NIH) grant CA198999, from National Cancer Institute (NCI).

Author information

Author notes

  1. Jun Li

    Present address: ZY Therapeutics, Research Triangle Park, North Carolina, 27709, USA

  2. Michelle Bao

    Present address: Stanford University, Stanford, California, USA

Authors and Affiliations

  1. Division of Pharmacoengineering and Molecular Pharmaceutics, and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA

    Manisit Das, Michelle Bao & Leaf Huang

  2. Qualiber Inc., Durham, North Carolina, 27705, USA

    Jun Li

  3. North Carolina School of Science and Mathematics, Durham, North Carolina, 27705, USA

    Michelle Bao

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  1. Manisit Das
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Corresponding author

Correspondence to Leaf Huang.

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Conflict of Interest

L.H. is a consultant for PDS Biotechnology, Samyang Biopharmaceutical, Stemirna, and Beijing Inno Medicine.

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All animal experiments were conducted in compliance with regulations of the University of North Carolina at Chapel Hill Institutional Animal Care and Use Committee (IACUC).

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Das, M., Li, J., Bao, M. et al. Nano-delivery of Gemcitabine Derivative as a Therapeutic Strategy in a Desmoplastic KRAS Mutant Pancreatic Cancer. AAPS J 22, 88 (2020). https://doi.org/10.1208/s12248-020-00467-8

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