Key Laboratory of Hebei Province for Innovative Drug Research and Evaluation, School of Pharmaceutical Sciences, Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
J Nanobiotechnology. 2022 Apr 2;20(1):177. doi: 10.1186/s12951-022-01383-z.
Small interfering RNA (siRNA) is utilized as a potent agent for cancer therapy through regulating the expression of genes associated with tumors. While the widely application of siRNAs in cancer treatment is severely limited by their insufficient biological stability and its poor ability to penetrate cell membranes. Targeted delivery systems hold great promise to selectively deliver loaded drug to tumor site and reduce toxic side effect. However, the elevated tumor interstitial fluid pressure and efficient cytoplasmic release are still two significant obstacles to siRNA delivery. Co-delivery of chemotherapeutic drugs and siRNA represents a potential strategy which may achieve synergistic anticancer effect. Herein, we designed and synthesized a dual pH-responsive peptide (DPRP), which includes three units, a cell-penetrating domain (polyarginine), a polyanionic shielding domain (ehG), and an imine linkage between them. Based on the DPRP surface modification, we developed a pH-responsive liposomal system for co-delivering polo-like kinase-1 (PLK-1) specific siRNA and anticancer agent docetaxel (DTX), D-Lsi/DTX, to synergistically exhibit anti-tumor effect.
In contrast to the results at the physiological pH (7.4), D-Lsi/DTX lead to the enhanced penetration into tumor spheroid, the facilitated cellular uptake, the promoted escape from endosomes/lysosomes, the improved distribution into cytoplasm, and the increased cellular apoptosis under mildly acidic condition (pH 6.5). Moreover, both in vitro and in vivo study indicated that D-Lsi/DTX had a therapeutic advantage over other control liposomes. We provided clear evidence that liposomal system co-delivering siPLK-1 and DTX could significantly downregulate expression of PLK-1 and inhibit tumor growth without detectable toxic side effect, compared with siPLK-1-loaded liposomes, DTX-loaded liposomes, and the combinatorial administration.
These results demonstrate great potential of the combined chemo/gene therapy based on the multistage pH-responsive codelivery liposomal platform for synergistic tumor treatment.
小干扰 RNA（siRNA）可通过调节与肿瘤相关的基因表达，作为一种有效的癌症治疗药物。然而，siRNA 在癌症治疗中的广泛应用受到其生物稳定性不足和跨细胞膜能力差的严重限制。靶向递送系统有望选择性地将负载药物递送到肿瘤部位，并减少毒性副作用。然而，提高肿瘤间质液压力和有效细胞质释放仍然是 siRNA 递送达的两个重大障碍。化疗药物和 siRNA 的共递呈代表了一种可能实现协同抗癌作用的潜在策略。在这里，我们设计并合成了一种双 pH 响应性肽（DPRP），它包含三个单元，一个细胞穿透结构域（多聚精氨酸），一个多阴离子屏蔽结构域（ehG），和它们之间的亚胺键。基于 DPRP 表面修饰，我们开发了一种 pH 响应性脂质体系统，用于共递呈有丝分裂激酶-1（PLK-1）特异性 siRNA 和抗癌药物多西他赛（DTX），即 D-Lsi/DTX，以协同发挥抗肿瘤作用。
与生理 pH（7.4）下的结果相比，D-Lsi/DTX 在酸性条件下（pH 6.5）增强了对肿瘤球体的穿透能力，促进了细胞摄取，促进了从内体/溶酶体中的逃逸，改善了分布到细胞质中，并增加了细胞凋亡。此外，体内外研究均表明，与其他对照脂质体相比，D-Lsi/DTX 具有治疗优势。我们提供了明确的证据，表明与 siPLK-1 负载的脂质体、DTX 负载的脂质体和联合给药相比，共递呈 siPLK-1 和 DTX 的脂质体系统可以显著下调 PLK-1 的表达并抑制肿瘤生长，而没有可检测的毒性副作用。
这些结果表明，基于多阶段 pH 响应共递药脂质体平台的联合化疗/基因治疗具有很大的潜力，可用于协同肿瘤治疗。
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