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Nano-delivery of Gemcitabine Derivative as a Therapeutic Strategy in a Desmoplastic KRAS Mutant Pancreatic Cancer.
- Source :
-
The AAPS journal [AAPS J] 2020 Jun 22; Vol. 22 (4), pp. 88. Date of Electronic Publication: 2020 Jun 22. - Publication Year :
- 2020
-
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.
- Subjects :
- Animals
Antimetabolites, Antineoplastic metabolism
Cell Line, Tumor
Deoxycytidine administration & dosage
Deoxycytidine metabolism
Drug Delivery Systems methods
Humans
Mice
Mice, Inbred C57BL
Mutation genetics
Nanoparticles metabolism
Pancreatic Neoplasms metabolism
Tumor Burden drug effects
Tumor Burden physiology
Gemcitabine
Pancreatic Neoplasms
Antimetabolites, Antineoplastic administration & dosage
Deoxycytidine analogs & derivatives
Nanoparticles administration & dosage
Pancreatic Neoplasms drug therapy
Pancreatic Neoplasms genetics
Proto-Oncogene Proteins p21(ras) genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1550-7416
- Volume :
- 22
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The AAPS journal
- Publication Type :
- Academic Journal
- Accession number :
- 32572645
- Full Text :
- https://doi.org/10.1208/s12248-020-00467-8