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

• Published in: Pharmaceutical research Vol. 37; no. 12; p. 247
• Main Authors: Wang, Fengyong, Zhang, Zhen
• Format: Journal Article
• Language: English
• Published: United States 01.12.2020
• Subjects: Animals; Antimetabolites, Antineoplastic - chemistry; Antimetabolites, Antineoplastic - metabolism; Antimetabolites, Antineoplastic - pharmacology; Apolipoprotein E3 - chemistry; Apolipoprotein E3 - metabolism; Apoptosis - drug effects; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Combined Modality Therapy; Deoxycytidine - analogs & derivatives; Deoxycytidine - chemistry; Deoxycytidine - metabolism; Deoxycytidine - pharmacology; Drug Compounding; Gene Transfer Techniques; Humans; Lipids - chemistry; Liposomes; Male; Mice, Inbred BALB C; Mice, Nude; Mutation; Nanoparticles; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Receptors, LDL - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RNAi Therapeutics; Xenograft Model Antitumor Assays; KRAS; RNA interference; Gemcitabine; E3-based liposomes; Pancreatic cancer
• ISSN: 1573-904X
• DOI: 10.1007/s11095-020-02949-y

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 IC 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 not show any signs of toxicity. Therefore, the combination of KRAS-siRNA and GEM holds great potential for the treatment of pancreatic cancer.