Oligo(lactic acid)n-Prodrug Nanomedicines for Combination Therapy

项目概要/摘要 紫杉醇通常用于治疗TNBC，并且越来越多地与口服信号转导抑制剂联合使用 （STI），如mTOR抑制剂（Afinitor）和MEK抑制剂（Koselugo），旨在针对这种疾病进行靶向治疗。 遗传异质性疾病然而，虽然这些药物组合在TNBC中是活性的，但它们在TNBC中是有效的。 与不良反应相关，限制了临床有效性。我们的目的是研究低聚乳酸 （o（LA）n-）前药、部分药物和部分生物材料以及聚（乙二醇）-嵌段-聚（d，l-乳酸）（PEG-b- PLA）纳米技术用于治疗TNBC，重点是药物组合的同时递送，包括 以协同药物比率递送，称为比率药物给药。我们将通过开发一个 用于o（LA）n-前药和PEG-b-PLA胶束的受控组装的放大方法， 注射用纳米制剂，其特征在于对广泛的化疗和STI的高负荷， 固定的o（LA）n-前药比例和与药物本身相比更慢的释放。接下来，按比例给药 基于紫杉醇、雷帕霉素（RAP）和司美替尼（SEL）的负载（LA）n前药的PEG-b-PLA胶束将被 在TNBC的免疫活性小鼠模型中表征，假设较低的毒性和较高的抗肿瘤活性， 活性优于紫杉醇、口服EVE和口服SEL。从机理上讲，我们假设o（LA）n-前药将延长， 与紫杉醇、口服EVE和口服SEL相比，协同药物比例的肿瘤暴露量升高和重叠。 此外，o（LA）n-前药组合可以是有效的免疫调节剂，其可以用于TNBC。 鉴于PEG-b-PLA胶束在安全性、溶解性和注射放大方面满足严格要求，而PEG-b-PLA胶束在注射和放大方面满足严格要求。 b-PLA是容易获得的GMP级的不同分子量的，用于调节体内胶束稳定性， o（LA）n-前药具有很强的潜力来改善基于PTX和紫杉醇的药物组合的有效性。 性传播感染，旨在推进TNBC疗法。

Project Summary/Abstract Taxol is commonly used to treat TNBC and increasingly in combination with oral signal transduction inhibitors (STIs), such as mTOR inhibitor (Afinitor) and MEK inhibitor (Koselugo), aiming for targeted therapies for this genetically heterogeneous disease. However, while these drug combinations are active in TNBC, they are associated with adverse effects, limiting clinical effectiveness. Our objective is to investigate oligo(lactic acid) (o(LA)n-) prodrugs, part drug and part biomaterial, and poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b- PLA) nanotechnology for the treatment of TNBC, focusing on concurrent delivery of drug combinations, including delivery at synergistic drug ratios, termed ratiometric drug dosing. We will achieve this goal by developing a scale-up approach for the controlled assembly of o(LA)n-prodrugs and PEG-b-PLA micelles that produces novel nano-formulations for injection, characterized by high loading for a wide repertoire of chemotherapy and STIs, fixed o(LA)n-prodrug ratios and slower release in comparison to drugs themselves. Next, ratiometric dosing of o(LA)n-prodrug-loaded PEG-b-PLA micelles based on PTX, rapamycin (RAP) and selumetinib (SEL) will be characterized in immunocompetent mouse models of TNBC, hypothesizing lower toxicity and higher antitumor activity than Taxol, oral EVE and oral SEL. Mechanistically, we hypothesize that o(LA)n-prodrugs will prolong, elevate and overlap tumor exposure for synergistic drug ratios in comparison to Taxol, oral EVE and oral SEL. Further, o(LA)n-prodrug combinations may be potent immuno-modulators, which may be exploited for TNBC. Given that PEG-b-PLA micelles satisfy strict requirements in safety, solubility and scale-up for injection and PEG- b-PLA is readily available GMP-grade at varied molecular weights for adjustment of micelle stability in vivo, o(LA)n-prodrugs have strong potential to improve the effectiveness of drug combinations based on PTX and STIs, aimed at advancing TNBC therapies.