Sorafenib (SOR) is a multi-kinase inhibitor that was approved as the first-line systematic treatment agent of hepatocellular carcinoma (HCC). However, the anti-cancerous effect of SOR is dramatically impaired by the drug resistance, insufficient accumulation at tumor tissues, and limited tumor inner penetration. To combat the above issues, the PLA-based nanoparticles were first fabricated and co-loaded with SOR and plantamajoside (PMS), natural herbal medicines that possess excellent anti-cancerous effect on many types of drug resistant cancers. Then, the polypeptide CT, which is tumor-homing and cell membrane penetrable, was further decorated on the dual-agents loaded nanoparticles (CTNP-PMS/SOR) to enhance tumor accumulation of drugs. Importantly, the CT peptide is a conjugate derived from the covalent conjugation of CVNHPAFAC peptide, a tumor-homing peptide, on the fourth lysine of TAT, namely cell membrane penetrating peptide, through a pH-sensitive hydrazone bond. By this way, the cell penetrating ability of TAT was dramatically sealed under the normal condition and immediately recovered once the nanoparticles reached tumor sites. Both in vivo and in vitro experiments demonstrated that the anti-cancerous effect of SOR on malignant HCC was significantly enhanced after co-loaded with PMS. Mechanisms studies revealed that the PMS is capable of reprograming the tumor hypoxic microenvironment, which represents the main cause of drug-resistance of tumor cells. Besides, functionalization of the NP-PMS/SOR with CT peptides signally improved the accumulation of drugs at tumor sites and penetration of agents into tumor cells, which in turn resulted in stronger capacity of tumor growth inhibition.

中文翻译：

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多功能纳米粒子可通过重新编程肿瘤缺氧的微环境，对抗植物肝素和索拉非尼的共同递送，从而对抗肝细胞癌的耐药性。

索拉非尼（SOR）是一种多激酶抑制剂，已被批准作为肝细胞癌（HCC）的一线系统治疗剂。但是，SOR的抗癌作用被耐药性，在肿瘤组织中的积累不足以及有限的肿瘤内部穿透力大大削弱。为了解决上述问题，首先制造了基于PLA的纳米颗粒，并将其与SOR和Plantamajoside（PMS）（一种对多种类型的耐药性癌症具有出色的抗癌作用的天然草药）共同装载。然后，将具有肿瘤归巢性且可穿透细胞膜的多肽CT进一步修饰在载有双药的纳米颗粒（CTNP-PMS / SOR）上，以增强药物的肿瘤蓄积性。重要的是，CT肽是衍生自CVNHPAFAC肽共价结合的结合物，通过pH敏感的fourth键，在TAT的第四赖氨酸上的一种肿瘤归巢肽，即细胞膜穿透肽。通过这种方式，TAT的细胞穿透能力在正常条件下被显着密封，并且一旦纳米粒子到达肿瘤部位就立即恢复。体内和体外实验均表明，与PMS共同加载后，SOR对恶性HCC的抗癌作用显着增强。机制研究表明，PMS能够重编程肿瘤低氧微环境，这代表了肿瘤细胞耐药的主要原因。此外，使用CT肽对NP-PMS / SOR进行功能化可显着改善药物在肿瘤部位的蓄积以及药物在肿瘤细胞中的渗透，