Nanoformulation of Apolipoprotein E3-Tagged Liposomal Nanoparticles for the co-Delivery of KRAS-siRNA and Gemcitabine fo
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RESEARCH PAPER
Nanoformulation of Apolipoprotein E3-Tagged Liposomal Nanoparticles for the co-Delivery of KRAS-siRNA and Gemcitabine for Pancreatic Cancer Treatment Fengyong Wang 1 & Zhen Zhang 1 Received: 1 May 2020 / Accepted: 7 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose 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. Methods In this study, we successfully synthesized apolipoprotein E3-based liposomes for the co-delivery of gemcitabine (GEM) and a small interfering RNA targeting KRAS (KRASsiRNA) to improve the efficacy of pancreatic cancer treatment. Results 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 KRASdependent 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. Conclusion 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.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11095-020-02949-y) contains supplementary material, which is available to authorized users. * Zhen Zhang [email protected] 1
Department of General Surgery, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
KEYWORDS KRAS . Pancreatic cancer . E3-based liposomes . Gemcitabine . RNA interference
ABBREVIATIONS A3-SGLP ApoE3 EPR GEM SGLP
ApoE3-conjugated SGLP Apolipoprotein E3 Enhanced permeation and retention effect Gemcitabine siRNA/GEM-loaded liposome
INTRODUCTION Pancreatic cancer is one of the most aggressive and lethal malignant cancers and is the fourth leading cause of cancerrelated deaths (1). The 5-year survival rate of pancreatic cancer is 8%, with an average mortality rate of 40,000 people per year in the United States alone. However, 50% of patients are already in the metastatic stage at the time of diagnosis, and survival does not exceed more than 6 months in most cases (2,3). Despite the efforts from clinical research teams over the last decade, pancreatic cancer treatment remains hampered by drug resistance, the systemic side effects of chemotherapeutic drugs, and tumor relapse (4). The standard treatment of care for pancreatic cancer is gemcitabine (GEM); ho
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