Berunda Polypeptides Carrying Rapalogues Inhibit Tumor mTORC1 Better than Oral Everolimus.,Biomacromolecules

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Berunda Polypeptides Carrying Rapalogues Inhibit Tumor mTORC1 Better than Oral Everolimus.
Biomacromolecules ( IF 5.5 ) Pub Date : 2020-06-02 , DOI: 10.1021/acs.biomac.0c00375
Santosh Peddi ₁ , John Andrew MacKay _{1,

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Affiliation

Rapalogues are a unique class of drugs with both cytostatic and immunosuppressive properties. Two founding members, rapamycin (Rapa) and its chemical derivative everolimus (Eve), are extremely potent, but their clinical use presents multiple challenges. Being water-insoluble, administration is restricted to the oral route, which results in a low bioavailability of <10%. Human studies of rapalogues are reported to yield a high blood to plasma ratio and poor correlation between blood concentration and dose. Moreover, treatment results in dose-limiting toxicities such as stomatitis and pneumonitis, which often leads to discontinuation of therapy. We previously reported an elastin-like polypeptide decorated with two-headed FKBP rapalogue-binding domains. Called “FAF”, this biomacromolecular drug-carrier solubilizes, retargets, and releases rapalogues within disease sites. FAF-rapalogue formulations are free of cosolvents or surfactants, which promotes their parenteral administration. In this study, subcutaneously given FAF-Rapa significantly suppressed tumor growth in a mouse model of hormone receptor positive (HR+) breast cancer, compared to an oral formulation of Eve (Affinitor). Additionally, mTOR, the pharmacological target of rapalogues, was inhibited to a greater extent in tumors of FAF-Rapa and FAF-Eve groups compared to mice that received oral Eve. No signaling suppression was detected in the liver and spleen, which were evaluated to represent off-target organs exposed to the circulating formulation.

中文翻译：

携带 Rapalogues 的 Berunda 多肽比口服依维莫司更好地抑制肿瘤 mTORC1。

Rapalogues 是一类独特的药物，具有细胞抑制和免疫抑制特性。两个创始成员雷帕霉素 (Rapa) 及其化学衍生物依维莫司 (Eve) 非常有效，但它们的临床使用面临多重挑战。由于不溶于水，给药仅限于口服途径，导致生物利用度较低，为 <10%。据报道，rapalogues 的人体研究显示其血液与血浆的比率较高，并且血液浓度和剂量之间的相关性较差。此外，治疗会导致剂量限制性毒性，例如口腔炎和肺炎，这通常会导致治疗停止。我们之前报道了一种装饰有双头 FKBP rapalogue 结合域的弹性蛋白样多肽。这种生物大分子药物载体被称为“FAF”，可在疾病部位溶解、重新靶向和释放雷帕拉同源物。 FAF-rapalogue 制剂不含助溶剂或表面活性剂，这有利于其胃肠外给药。在这项研究中，与 Eve (Affinitor) 口服制剂相比，皮下注射 FAF-Rapa 显着抑制激素受体阳性 (HR+) 乳腺癌小鼠模型中的肿瘤生长。此外，与接受口服 Eve 的小鼠相比，FAF-Rapa 和 FAF-Eve 组的肿瘤中，rapalogues 的药理学靶点 mTOR 受到更大程度的抑制。在肝脏和脾脏中没有检测到信号抑制，经评估这些肝脏和脾脏代表暴露于循环制剂的脱靶器官。

更新日期：2020-08-10

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