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
基本信息
- 批准号:10597075
- 负责人:
- 金额:$ 34.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:4T1Adverse effectsAreaBiocompatible MaterialsBiodistributionBloodBlood Chemical AnalysisBody Weights and MeasuresBreast Cancer ModelBreast Cancer therapyCancer InterventionClinicalClinical TrialsClinical effectivenessCombined Modality TherapyCoupledDiseaseDoseDose LimitingDrug CombinationsDrug Delivery SystemsDrug KineticsEffectivenessEvaluationExhibitsFRAP1 geneFemaleGoalsHemangiosarcomaHistopathologyHourImmunocompetentImmunomodulatorsInbred BALB C MiceInjectionsLactic acidLiquid ChromatographyMAP Kinase GeneMEKsMass Spectrum AnalysisMeasuresMethodsMicellesMicrotubulesModelingMolecular WeightMusNanotechnologyNatureOligonucleotidesOralOrganOrphan DrugsOutcomePI3K/AKTPaclitaxelPathway interactionsPatient SelectionPharmaceutical PreparationsPharmacologyPlasmaProdrugsPropertyPublic HealthResearchRodentSDZ RADSafetySignal TransductionSignal Transduction InhibitorSirolimusSolubilitySprague-Dawley RatsTestingTimeToxic effectchemotherapydruggable targetethylene glycolimmunoregulationimprovedin vivoinhibitormTOR Inhibitormalemalignant breast neoplasmmouse modelnanoformulationnanomedicinenanomicellesnovelratiometricscale upstandard of caretargeted treatmenttriple-negative invasive breast carcinomatumortumor growth
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Glen S. Kwon其他文献
Polymeric micelle nanocarriers in cancer research
- DOI:
10.1007/s11705-016-1582-2 - 发表时间:
2016-08-21 - 期刊:
- 影响因子:4.500
- 作者:
Dae Hwan Shin;Yu Tong Tam;Glen S. Kwon - 通讯作者:
Glen S. Kwon
Polymeric Micelles for Multi-Drug Delivery in Cancer
- DOI:
10.1208/s12249-014-0251-3 - 发表时间:
2014-12-11 - 期刊:
- 影响因子:4.000
- 作者:
Hyunah Cho;Tsz Chung Lai;Keishiro Tomoda;Glen S. Kwon - 通讯作者:
Glen S. Kwon
Soluble Self-Assembled Block Copolymers for Drug Delivery
- DOI:
10.1023/a:1011991617857 - 发表时间:
1999-01-01 - 期刊:
- 影响因子:4.300
- 作者:
Glen S. Kwon;Teruo Okano - 通讯作者:
Teruo Okano
Production of paclitaxel-loaded PEG-emb/em-PLA micelles using PEG for drug loading and freeze-drying
使用聚乙二醇进行药物负载和冷冻干燥来生产紫杉醇负载的聚乙二醇-乳化/包埋-聚乳酸微球
- DOI:
10.1016/j.jconrel.2022.08.032 - 发表时间:
2022-10-01 - 期刊:
- 影响因子:11.500
- 作者:
Morteza Rasoulianboroujeni;Lauren Repp;Hye Jin Lee;Glen S. Kwon - 通讯作者:
Glen S. Kwon
Paclitaxel Prodrugs with Sustained Release and High Solubility in Poly(ethylene glycol)-b-poly(ε-caprolactone) Micelle Nanocarriers: Pharmacokinetic Disposition, Tolerability, and Cytotoxicity
- DOI:
10.1007/s11095-007-9451-9 - 发表时间:
2007-10-03 - 期刊:
- 影响因子:4.300
- 作者:
M. Laird Forrest;Jaime A. Yáñez;Connie M. Remsberg;Yusuke Ohgami;Glen S. Kwon;Neal M. Davies - 通讯作者:
Neal M. Davies
Glen S. Kwon的其他文献
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{{ truncateString('Glen S. Kwon', 18)}}的其他基金
Direct therapeutic intervention of the tumor microenvironment with a potent inhibitor of fibronectin assembly
使用纤连蛋白组装的有效抑制剂对肿瘤微环境进行直接治疗干预
- 批准号:
10409814 - 财政年份:2021
- 资助金额:
$ 34.12万 - 项目类别:
Direct therapeutic intervention of the tumor microenvironment with a potent inhibitor of fibronectin assembly
使用纤连蛋白组装的有效抑制剂对肿瘤微环境进行直接治疗干预
- 批准号:
10199263 - 财政年份:2021
- 资助金额:
$ 34.12万 - 项目类别:
Oligo(lactic acid)n-Prodrug Nanomedicines for Combination Therapy
用于联合治疗的寡(乳酸)n-前药纳米药物
- 批准号:
10371257 - 财政年份:2021
- 资助金额:
$ 34.12万 - 项目类别:
Co-Delivery of Antifungal Agents: Toxicity and Efficacy in Invasive Candidiasis
抗真菌药物的联合给药:侵袭性念珠菌病的毒性和功效
- 批准号:
8497027 - 财政年份:2013
- 资助金额:
$ 34.12万 - 项目类别:
Co-Delivery of Antifungal Agents: Toxicity and Efficacy in Invasive Candidiasis
抗真菌药物的联合给药:侵袭性念珠菌病的毒性和功效
- 批准号:
8605161 - 财政年份:2013
- 资助金额:
$ 34.12万 - 项目类别:
Co-Delivery of Antifungal Agents: Toxicity and Efficacy in Invasive Candidiasis
抗真菌药物的联合给药:侵袭性念珠菌病的毒性和功效
- 批准号:
8786047 - 财政年份:2013
- 资助金额:
$ 34.12万 - 项目类别:
Tri-modal Polymeric Micelles for 'See & Treat' Applications in Surgical Oncology
用于“See”的三峰聚合物胶束
- 批准号:
8298518 - 财政年份:2011
- 资助金额:
$ 34.12万 - 项目类别:
Tri-modal Polymeric Micelles for 'See & Treat' Applications in Surgical Oncology
用于“See”的三峰聚合物胶束
- 批准号:
8175145 - 财政年份:2011
- 资助金额:
$ 34.12万 - 项目类别:
BIOSPECIFIC POLYMER ENZYME CONJUGATES FOR DRUG DELIVERY
用于药物输送的生物特异性聚合物酶缀合物
- 批准号:
6262537 - 财政年份:2001
- 资助金额:
$ 34.12万 - 项目类别:
BIOSPECIFIC POLYMER ENZYME CONJUGATES FOR DRUG DELIVERY
用于药物输送的生物特异性聚合物酶缀合物
- 批准号:
6489389 - 财政年份:2001
- 资助金额:
$ 34.12万 - 项目类别:
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