SiRNA-Loaded Hydroxyapatite Nanoparticles for KRAS Gene Silencing in Anti-Pancreatic Cancer Therapy.

Dandan Luo,Quan Zhang,Ruibo Zhao,M Zubair Iqbal,Jabeen Farheen,Xiaochun Xu,Xiangdong Kong,Qingwei Zhao,Peiliang Zhang

doi:10.3390/pharmaceutics13091428

Dandan Luo, Quan Zhang + Show 7 more

Open Access

https://doi.org/10.3390/pharmaceutics13091428

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Abstract

Pancreatic carcinoma (PC) is greatly induced by the KRAS gene mutation, but effective targeted delivery for gene therapy has not existed. Small interfering ribonucleic acid (siRNA) serves as an advanced therapeutic modality and holds great promise for cancer treatment. However, the development of a non-toxic and high-efficiency carrier system to accurately deliver siRNA into cells for siRNA-targeted gene silencing is still a prodigious challenge. Herein, polyethylenimine (PEI)-modified hydroxyapatite (HAp) nanoparticles (HAp-PEI) were fabricated. The siRNA of the KRAS gene (siKras) was loaded onto the surface of HAp-PEI via electrostatic interaction between siRNA and PEI to design the functionalized HAp-PEI nanoparticle (HAp-PEI/siKras). The HAp-PEI/siKras was internalized into the human PC cells PANC-1 to achieve the maximum transfection efficiency for active tumor targeting. HAp-PEI/siKras effectively knocked down the expression of the KRAS gene and downregulated the expression of the Kras protein in vitro. Furthermore, the treatment with HAp-PEI/siKras resulted in greater anti-PC cells’ (PANC-1, BXPC-3, and CFPAC-1) efficacy in vitro. Additionally, the HAp-PEI exhibited no obvious in vitro cytotoxicity in normal pancreatic HPDE6-C7 cells. These findings provided a promising alternative for the therapeutic route of siRNA-targeted gene engineering for anti-pancreatic cancer therapy.

Highlights

Pancreatic carcinoma (PC) is the most severe type of human melanoma that caused secondary neural microenvironment and has the highest mortality among all diagnosed tumors [1,2,3]
Structural characterizations were observed by transmission electron microscope (TEM) (Figure 1a) and field emission scanning electron microscope (FE-SEM)
We have developed a biocompatible HAp-PEI nanoparticle as an efficient carrier to deliver KRAS-Small interfering ribonucleic acid (siRNA) for anti-pancreatic cancer therapy by a simple and effective electrostatic interaction strategy

Summary

Introduction

Pancreatic carcinoma (PC) is the most severe type of human melanoma that caused secondary neural microenvironment and has the highest mortality among all diagnosed tumors [1,2,3]. The available treatments such as chemotherapy combined with radiotherapy can only enhance 5.0–70 months, and a 5-year survival rate is about 4% in PC patients [4,5,6]. Several factors are involved in PC induction and progression, and among them KRAS proto-oncogene activation mutation is the most crucial in diagnosed patients [10]. Almost 95% of cases of PC have point mutation at G12, G13, and Q61 codons in the KRAS activation domain as a result of the mutant Kras protein generation, which

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