The clinical utility of rapamycin (Rapa) is limited by solubility, bioavailability, and side effects. To overcome this, our team recently reported an elastin-like polypeptide (ELP) nanoparticle with high affinity, noncovalent drug binding, and integrin-mediated cellular uptake. Given the scarcity of pharmacology/toxicology studies of ELP-based drug carriers, this article explores safety and efficacy of ELP-Rapa. ELP-Rapa nanoparticles tested negative for hemolysis, did not interfere in plasma coagulation nor in platelet function, and did not activate the complement. Upon incubation with HepG2 cells, ELP-Rapa revealed significant cellular uptake and trafficking to acidic organelles, consistent with lysosomes. Internalized ELP-Rapa nanoparticles increased oxidative stress 4-fold compared to free drug or free ELP controls. However, mice bearing orthotopic hormone receptor positive BT-474 breast tumors, given a high dose (∼10-fold above therapeutic dose) of 1 month administration of ELP-Rapa, did not induce hepatotoxicity. On the other hand, tumor growth and mTOR signaling were suppressed without affecting body weight. Nanoparticles assembled using ELP technology appear to be a safe and efficient strategy for delivering Rapa.

中文翻译：

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乳腺癌弹性蛋白样多肽雷帕霉素制剂的纳米毒理学。

雷帕霉素（Rapa）的临床应用受到溶解度，生物利用度和副作用的限制。为了克服这个问题，我们的团队最近报道了一种具有高亲和力，非共价药物结合和整联蛋白介导的细胞摄取的弹性蛋白样多肽（ELP）纳米颗粒。鉴于基于ELP的药物载体的药理/毒理学研究稀缺，本文探讨了ELP-Rapa的安全性和有效性。ELP-Rapa纳米颗粒的溶血试验结果呈阴性，不干扰血浆凝结或血小板功能，也未激活补体。与HepG2细胞孵育后，ELP-Rapa显示出明显的细胞摄取和转运至酸性细胞器，与溶酶体一致。与游离药物或游离ELP对照相比，内部化的ELP-Rapa纳米颗粒将氧化应激增加了4倍。然而，给予原位激素受体阳性BT-474乳腺肿瘤的小鼠，给予高剂量（比治疗剂量高10倍）的ELP-Rapa 1个月，未引起肝毒性。另一方面，在不影响体重的情况下抑制了肿瘤生长和mTOR信号传导。使用ELP技术组装的纳米颗粒似乎是交付Rapa的安全有效策略。