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.

项目摘要/摘要 紫杉醇通常用于治疗TNBC，并越来越多地与口服信号转导抑制剂结合使用 （STIS），例如MTOR抑制剂（AFINitor）和MEK抑制剂（Koselugo），旨在为此靶向疗法 遗传异质性疾病。但是，尽管这些药物组合在TNBC中活跃，但它们是 与不良反应相关，限制临床有效性。我们的目标是研究寡核酸（乳酸） （o（la）n-）前药，部分药物和部分生物材料和聚（乙二醇） - 玻璃聚糖（d，l-乳酸）（PEG-B-- PLA）用于治疗TNBC的纳米技术，重点是同时提供药物组合，包括 以协同药物比率递送，称为比率药物剂量。我们将通过开发一个 O（la）N-果酱和PEG-B-PLA胶束的受控组装的扩展方法，产生新型 注射纳米形成，其特征在于化学疗法和性传播疾病的广泛曲目， 与药物本身相比，固定的O（LA）N-产量比和较慢的释放。接下来，比率剂量的 O（la）基于PTX，Rapamycin（RAP）和Selumetinib（SEL）的N-加载的PEG-B-PLA胶束将是 在TNBC的免疫能力小鼠模型中表征，假设较低的毒性和较高的抗毒液 活动比紫杉醇，口头和口服。从机械上讲，我们假设o（la）n-prodrugs将延长， 与紫杉醇，口服前夕和口服相比，协同药物比率的升高和重叠肿瘤暴露。 此外，o（la）n-grodrug组合可能是有效的免疫调节剂，可以探索TNBC。 鉴于PEG-B-Pla胶束满足了对注射和PEG-的安全性，溶解度和扩大规模的严格要求 B-Pla在不同的分子量下容易获得GMP级，以调节体内胶束稳定性， o（la）n-产物具有强大的潜力，可以提高基于PTX和的药物组合的有效性 ETI，旨在推进TNBC疗法。