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

用于联合治疗的寡聚（乳酸）n-前药纳米药物

• 批准号: 10597075
• 负责人: Glen S. Kwon
• 金额: $ 34.12万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597075
• 关键词: 4T1; Adverse effects; Area; Biocompatible Materials; Biodistribution; Blood; Blood Chemical Analysis; Body Weights and Measures; Breast Cancer Model; Breast Cancer therapy; Cancer Intervention; Clinical; Clinical Trials; Clinical effectiveness; Combined Modality Therapy; Coupled; Disease; Dose; Dose Limiting; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Effectiveness; Evaluation; Exhibits; FRAP1 gene; Female; Goals; Hemangiosarcoma; Histopathology; Hour; Immunocompetent; Immunomodulators; Inbred BALB C Mice; Injections; Lactic acid; Liquid Chromatography; MAP Kinase Gene; MEKs; Mass Spectrum Analysis; Measures; Methods; Micelles; Microtubules; Modeling; Molecular Weight; Mus; Nanotechnology; Nature; Oligonucleotides; Oral; Organ; Orphan Drugs; Outcome; PI3K/AKT; Paclitaxel; Pathway interactions; Patient Selection; Pharmaceutical Preparations; Pharmacology; Plasma; Prodrugs; Property; Public Health; Research; Rodent; SDZ RAD; Safety; Signal Transduction; Signal Transduction Inhibitor; Sirolimus; Solubility; Sprague-Dawley Rats; Testing; Time; Toxic effect; chemotherapy; druggable target; ethylene glycol; immunoregulation; improved; in vivo; inhibitor; mTOR Inhibitor; male; malignant breast neoplasm; mouse model; nanoformulation; nanomedicine; nanomicelles; novel; ratiometric; scale up; standard of care; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor growth

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.

项目概要/摘要 紫杉醇通常用于治疗三阴性乳腺癌，并且越来越多地与口服信号转导抑制剂联合使用 （STI），例如 mTOR 抑制剂（Afinitor™）和 MEK 抑制剂（Koselugo™），旨在针对该疾病进行靶向治疗 遗传异质性疾病。然而，虽然这些药物组合在 TNBC 中有效，但它们 与不良反应相关，限制了临床效果。我们的目标是研究低聚（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，重点是同时递送药物组合，包括 以协同药物比例递送，称为比例药物剂量。我们将通过开发一个 o(LA)n-前药和 PEG-b-PLA 胶束的受控组装放大方法，可产生新型 注射用纳米制剂，其特点是高载量，适用于多种化疗和性传播感染， 与药物本身相比，固定的 o(LA)n-前药比例和更慢的释放。接下来，按比例给药 基于 PTX、雷帕霉素 (RAP) 和司美替尼 (SEL) 的 o(LA)n-前药负载 PEG-b-PLA 胶束将被 在 TNBC 免疫活性小鼠模型中进行表征，假设毒性较低，抗肿瘤能力较高 活性优于Taxol、口服EVE和口服SEL。从机制上讲，我们假设 o(LA)n-前药会延长， 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-前药组合可能是有效的免疫调节剂，可用于 TNBC。 鉴于 PEG-b-PLA 胶束满足注射用和 PEG-b-PLA 在安全性、溶解度和放大方面的严格要求 b-PLA 是现成的 GMP 级，具有不同的分子量，可调节体内胶束的稳定性， o(LA)n-前药具有提高基于 PTX 和 PTX 的药物组合的有效性的巨大潜力 STI，旨在推进 TNBC 疗法。