期刊
JOURNAL OF CONTROLLED RELEASE
卷 331, 期 -, 页码 335-349出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2021.01.021
关键词
Sorafenib-resistant hepatocellular carcinoma; Midkine; Gene therapy; Stroma barrier; Ultra-small lipid nanoparticles; Microfluidic device
资金
- Japan International Cooperation Agency (JICA)
- Egyptian Ministry of High Education (MOHE)-Cultural Affairs and Missions Sector
- Special Education and Research Expenses from the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-Japan
The usLNPs, composed of a novel pH-sensitive lipid, phospholipids, and a targeting peptide, demonstrated enhanced tumor accumulation, selectivity, and in vivo gene silencing. This combination therapy synergistically eradicated HCC in mice at a low dose of SOR and showed promising potential for clinical applications.
Hepatocellular carcinoma (HCC) is a fatal disease with limited therapeutic choices. The stroma-rich tumor microenvironment hinders the in vivo delivery of most nanomedicines. Ultra-small lipid nanoparticles (usLNPs) were designed for the selective co-delivery of the cytotoxic drug, sorafenib (SOR), and siRNA against the Midkine gene (MK-siRNA) to HCC in mice. The usLNPs composed of a novel pH-sensitive lipid, a diversity of phospholipids and a highly-selective targeting peptide. A microfluidic device, iLiNP, was used and a variety of factors were controlled to tune particle size aiming at maximizing tumor penetration efficiency. Optimizing the composition and physico-chemical properties of the usLNPs resulted in an enhanced tumor accumulation, selectivity and in vivo gene silencing. The optimized usLNPs exerted potent gene silencing in the tumor (median effective dose, ED50 similar to 0.1 mg/Kg) with limited effect on the healthy liver. The novel combination synergistically-eradicated HCC in mice (similar to 85%) at a surprisingly-low dose of SOR (2.5 mg/Kg) which could not be achieved via individual monotherapy. Toxicity studies revealed the biosafety of the usLNPs upon either acute or chronic treatment. Furthermore, the SOR-resistant HCC established in mice was eradicated by 70% using this approach. We conclude that our strategy is promising for potential clinical applications in HCC treatment.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据