Nanoformulation of Apolipoprotein E3-Tagged Liposomal Nanoparticles for the co-Delivery of KRAS-siRNA and Gemcitabine for Pancreatic Cancer Treatment.

Pharmaceutical Research
Fengyong Wang, Zhen Zhang

Abstract

KRAS is the most frequently mutated gene in human cancers, and ~ 90% of pancreatic cancers exhibit KRAS mutations. Despite the well-known role of KRAS in malignancies, directly inhibiting KRAS is challenging. In this study, we successfully synthesized apolipoprotein E3-based liposomes for the co-delivery of gemcitabine (GEM) and a small interfering RNA targeting KRAS (KRAS-siRNA) to improve the efficacy of pancreatic cancer treatment. Apolipoprotein E3 self-assembly on the liposome surface led to a substantial increase in its internalization in PANC1 human pancreatic cancer cells. KRAS-siRNA led to downregulated KRAS protein expression and KRAS-dependent carcinogenic pathways, resulting in the inhibition of cell proliferation, cell cycle arrest, increased apoptosis, and suppression of tumor progression. The combination of KRAS-siRNA and GEM induced a synergistic improvement in cell apoptosis and significantly lower cell viability compared with single-agent therapy. The low IC50 value of A3-SGLP might be attributed to potentiation of the anticancer effect of GEM by siRNA-mediated silencing of KRAS mutations, thereby inducing synergistic effects on cancer cells. A3-SGLP led to a marked decrease in the overall tumor burden and did...Continue Reading

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Methods Mentioned

BETA
GTPases
electrophoresis
dynamic light scattering
transmission electron microscopy
FACS
Assay
xenograft
transmission
flow cytometry

Software Mentioned

GraphPad prism
Cell Quest
- V10
FlowJo

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