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

项目摘要/摘要 紫杉醇通常用于治疗肿瘤，并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(阿菲尼托)和肌醇释放酶抑制剂(Koselugo)，旨在针对这一问题进行靶向治疗 遗传异质性疾病。然而，尽管这些药物组合在TNBC中很活跃，但它们 与不良反应相关，限制了临床疗效。我们的目标是研究低聚乳酸 (O(LA)n-)前体药，部分药物和部分生物材料，以及聚乙二醇嵌段聚(d，L-乳酸)(聚乙二醇b-乳酸) 解放军)治疗TNBC的纳米技术，重点是同时提供药物组合，包括 以协同给药比例给药，称为比率给药。我们将通过制定一项 控制组装o(LA)N-前体药和聚乙二醇b-聚乳酸胶束的放大方法 注射用纳米制剂，其特征是高负载量，用于广泛的化疗和性传播感染， 修复了o(LA)n-前体药物的比例，与药物本身相比释放速度较慢。下一步，比率计量法 基于PTX、雷帕霉素(RAP)和赛鲁米替尼(SEL)的O(LA)N-前药载药聚乙二醇b-聚乳酸胶束将被 以具有免疫活性的TNBC小鼠模型为特征，假设毒性较低，抗肿瘤能力较强 活性高于紫杉醇、口服前夜和口服SEL。从机制上讲，我们假设o(LA)n-前体药将延长， 与紫杉醇、口服EVE和口服SEL相比，提高和重叠肿瘤暴露的协同药物比率。 此外，o(LA)n-前体药物组合可能是一种有效的免疫调节剂，可用于治疗TNBC。 鉴于聚乙二醇b-聚乳酸胶束在注射和聚乙二醇酯的安全性、溶解性和放大方面满足严格的要求。 B-聚乳酸是易于获得的不同分子量的GMP级，用于调节体内胶束的稳定性， O(LA)N-前体药具有很强的潜力来提高基于PTX和 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.