Mono-arginine Cholesterol-based Small Lipid Nanoparticles as a Systemic siRNA Delivery Platform for Effective Cancer Therapy.
Mono-arginine Cholesterol-based Small Lipid Nanoparticles as a Systemic siRNA Delivery Platform for Effective Cancer Therapy.
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作者：
Lee J;Saw PE;Gujrati V;Lee Y;Kim H;Kang S;Choi M;Kim JI;Jon S
尽管已经努力开发用于递送RNAi治疗剂的平台载体，但是siRNA的全身性递送在癌症治疗中仅显示出有限的成功。基于阳离子脂质的纳米颗粒已被广泛用于此目的，但由于其阳离子表面，其毒性和全身注射后不期望的肝脏摄取阻碍了进一步的临床转化。本研究描述了由无毒阳离子胆固醇衍生物制成的中性小脂质纳米粒（SLNP）的开发，作为系统性siRNA治疗癌症的合适载体。通过将精氨酸部分经由可裂解的酯键直接连接到胆固醇来合成阳离子胆固醇衍生物，单精氨酸-胆固醇（MA-Chol）。使用MA-Chol和中性辅助脂质二油酰磷脂酰乙醇胺（DOPE）作为主要组分以及与siRNA混合的少量聚乙二醇化磷脂制备siRNA负载的SLNP（siRNA@ SLNP）。所得纳米颗粒直径小于~50 nm，Zeta电位为中性，毒性比典型的基于阳离子胆固醇（DC-Chol）的脂质纳米颗粒低得多。负载有针对驱动蛋白纺锤体蛋白的siRNA的SLNP（siKSP@ SLNP）在各种癌细胞系中表现出高水平的靶基因敲低，如通过KSP mRNA测量和细胞死亡测定所示。此外，全身注射siKSP@ SLNP到携带前列腺肿瘤的小鼠中导致递送的siRNA在肿瘤部位的优先积累和肿瘤生长的显著抑制，具有很小的明显毒性，如体重测量所示。这些结果表明，这些SLNP可以为基于RNAi的癌症治疗提供系统性递送平台。
Although efforts have been made to develop a platform carrier for the delivery of RNAi therapeutics, systemic delivery of siRNA has shown only limited success in cancer therapy. Cationic lipid-based nanoparticles have been widely used for this purpose, but their toxicity and undesired liver uptake after systemic injection owing to their cationic surfaces have hampered further clinical translation. This study describes the development of neutral, small lipid nanoparticles (SLNPs) made of a nontoxic cationic cholesterol derivative, as a suitable carrier of systemic siRNA to treat cancers. The cationic cholesterol derivative, mono arginine-cholesterol (MA-Chol), was synthesized by directly attaching an arginine moiety to cholesterol via a cleavable ester bond. siRNA-loaded SLNPs (siRNA@SLNPs) were prepared using MA-Chol and a neutral helper lipid, dioleoyl phosphatidylethanolamine (DOPE), as major components and a small amount of PEGylated phospholipid mixed with siRNA. The resulting nanoparticles were less than ~50 nm in diameter with neutral zeta potential and much lower toxicity than typical cationic cholesterol (DC-Chol)-based lipid nanoparticles. SLNPs loaded with siRNA against kinesin spindle protein (siKSP@SLNPs) exhibited a high level of target gene knockdown in various cancer cell lines, as shown by measurement of KSP mRNA and cell death assays. Furthermore, systemic injection of siKSP@SLNPs into prostate tumor-bearing mice resulted in preferential accumulation of the delivered siRNA at the tumor site and significant inhibition of tumor growth, with little apparent toxicity, as shown by body weight measurements. These results suggest that these SLNPs may provide a systemic delivery platform for RNAi-based cancer therapy.