Abstract：
Advanced hepatocellular carcinoma (HCC) is one of the most challenging cancers because of its heterogeneous and aggressive nature, precluding the use of curative treatments. Sorafenib (SOR) is the first approved molecular targeting agent against the mitogen-activated protein kinase (MAPK) pathway for the noncurative therapy of advanced HCC; yet, any clinically meaningful benefits from the treatment remain modest, and are accompanied by significant side effects. Here, we hypothesized that using a nanomedicine platform to co-deliver SOR with another molecular targeting drug, metformin (MET), could tackle these issues. A micelle self-assembled with amphiphilic polypeptide methoxy poly(ethylene glycol)-block-poly(L-phenylalanine-co-l-glutamic acid) (mPEG-b-P(LP-co-LG)) (PM) was therefore designed for combinational delivery of two molecular targeted drugs, SOR and MET, to hepatomas. Compared with free drugs, the proposed, dual drug-loaded micelle (PM/SOR+MET) enhanced the drugs\' half-life in the bloodstream and drug accumulation at the tumor site, thereby inhibiting tumor growth effectively in the preclinical subcutaneous, orthotopic and patient-derived xenograft hepatoma models without causing significant systemic and organ toxicity. Collectively, these findings demonstrate an effective dual-targeting nanomedicine strategy for treating advanced HCC, which may have a translational potential for cancer therapeutics. STATEMENT OF SIGNIFICANCE: Treatment of advanced hepatocellular carcinoma (HCC) remains a formidable challenge due to its aggressive nature and the limitations inherent to current therapies. Despite advancements in molecular targeted therapies, such as Sorafenib (SOR), their modest clinical benefits coupled with significant adverse effects underscore the urgent need for more efficacious and less toxic treatment modalities. Our research presents a new nanomedicine platform that synergistically combines SOR with metformin within a specialized diblock polypeptide micelle, aiming to enhance therapeutic efficacy while reducing systemic toxicity. This innovative approach not only exhibits marked antitumor efficacy across multiple HCC models but also significantly reduces the toxicity associated with current treatments. Our dual-molecular targeting approach unveils a promising nanomedicine strategy for the molecular treatment of advanced HCC, potentially offering more effective and safer treatment alternatives with significant translational potential.
摘要：
晚期肝细胞癌（HCC）是最具挑战性的癌症之一，因为其异质性和侵袭性，排除使用治愈性治疗。索拉非尼（SOR）是第一个批准的分子靶向剂，用于晚期肝癌的非治愈性治疗，从治疗中获得的任何有临床意义的益处仍然是适度的，并伴有明显的副作用。这里,我们假设使用纳米医学平台与另一种分子靶向药物共同递送SOR，二甲双胍（MET），可以解决这些问题。因此，设计了一种由两亲性多肽甲氧基聚（乙二醇）-嵌段-聚（L-苯丙氨酸-co-L-谷氨酸）（mPEG-b-P（LP-co-LG））（PM）自组装的胶束，用于两种分子靶向药物的组合递送，SOR和MET,肝癌。与免费药物相比，提议的,双重载药胶束（PM/SOR+MET）增强了药物在血液中的半衰期和药物在肿瘤部位的积累，从而在临床前皮下有效抑制肿瘤生长，原位和患者来源的异种移植肝癌模型，不会引起明显的全身和器官毒性。总的来说，这些发现证明了治疗晚期HCC的有效双靶向纳米药物策略，可能具有癌症治疗的翻译潜力。重要性声明：晚期肝细胞癌（HCC）的治疗仍然是一个巨大的挑战，由于其侵袭性和现有疗法固有的局限性。尽管分子靶向治疗取得了进展，例如索拉非尼(SOR)，其适度的临床获益加上显著的不良反应,强调迫切需要更有效,毒性更小的治疗方式.我们的研究提出了一种新型的纳米医学平台，该平台将SOR与二甲双胍协同地结合在一个专门的二嵌段多肽胶束中，旨在提高治疗效果，同时减少全身毒性。这种创新的方法不仅在多个HCC模型中表现出明显的抗肿瘤功效，而且还显着降低了与当前治疗相关的毒性。我们的双分子靶向方法揭示了一种有前途的纳米医学策略，用于晚期HCC的分子治疗，可能提供更有效和更安全的治疗替代方案，具有显著的转化潜力。
