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Nano-delivery of Gemcitabine Derivative as a Therapeutic Strategy in a Desmoplastic KRAS Mutant Pancreatic Cancer.
Das, Manisit; Li, Jun; Bao, Michelle; Huang, Leaf.
Afiliação
  • Das M; 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.
  • Li J; Qualiber Inc., Durham, North Carolina, 27705, USA.
  • Bao M; ZY Therapeutics, Research Triangle Park, North Carolina, 27709, USA.
  • Huang L; 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.
AAPS J ; 22(4): 88, 2020 06 22.
Article em En | MEDLINE | ID: mdl-32572645
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Proteínas Proto-Oncogênicas p21(ras) / Desoxicitidina / Nanopartículas / Antimetabólitos Antineoplásicos Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Proteínas Proto-Oncogênicas p21(ras) / Desoxicitidina / Nanopartículas / Antimetabólitos Antineoplásicos Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article