MMP responsive polymeric materials for treating acute myocardial infarction
MMP响应性高分子材料治疗急性心肌梗死
基本信息
- 批准号:10734728
- 负责人:
- 金额:$ 59.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:Acute myocardial infarctionAlternative TherapiesAmericanAnimal ModelAntioxidantsBiocompatible MaterialsBiodistributionCathetersCause of DeathDevelopmentDiameterDrug CarriersDrug KineticsEnzyme InductionEnzymesEvaluationExhibitsFlow CytometryFutureGene ExpressionGoalsHeartHeart failureHistologyImmune responseImmunohistochemistryInfarctionInflammationInhibition of Matrix Metalloproteinases PathwayInjectableInjectionsKidneyLeft Ventricular RemodelingLiverMMP2 geneMagnetic Resonance ImagingMatrix Metalloproteinase InhibitorMatrix MetalloproteinasesMethodsModalityMolecular WeightMyocardialMyocardial InfarctionMyocardiumNF-E2-related factor 2Operative Surgical ProceduresPathway interactionsPatientsPeptidesPharmacologic SubstancePhase TransitionPolymersProceduresProcessPropertyProteinsRecoveryRecurrenceRestSafetySiteSpleenStressStructureSystemTestingTherapeuticTranslatingTranslationsVertebral columnWestern Worldaqueousbiomaterial compatibilitycontrolled releasecopolymercost effectivedesignheart functionhemocompatibilityimmunoregulationimprovedinhibitor therapyinnovationminimally invasivenano-stringnanomaterialsnanoparticlenanopatternnanoscalenovelnovel strategiesparticlepatient populationpeptide drugprotein protein interactionrepairedresponsescaffoldsuccesstargeted deliverytherapeutic proteintherapeutic target
项目摘要
Summary
Heart failure (HF) remains the leading cause of death in the U.S., and the rest of the western world.
Approximately 37% of myocardial infarction (MI) patients will die from HF within 1 year, and of those who do
survive, two-thirds do not make a complete recovery. Each year it is estimated that ~550K Americans will have
a new MI, and ~200K will have a recurrent MI, leading to a large body of patients suffering from HF.1 Therefore,
our long-term goal is the development of new, minimally invasive, targeted biomaterial based therapies for the
treatment of acute MI (AMI), thereby limiting the number of patients that progress to HF. Over the past two
decades, there has been significant progress in the development injectable biomaterials that stimulate
endogenous repair on their own or through the controlled release of additional therapeutics. This approach is
attractive since potential therapies could be delivered minimally invasively via catheter, would be off the shelf
and cost-effective, and in the case of therapeutic delivery, would provide targeted delivery limiting systemic off-
target effects that plague traditional pharmaceuticals. However, direct injection of these biomaterials, either
through minimally invasive surgery or percutaneous transendocardial injection, is unlikely to be translated to AMI
patients because of serious safety concerns with the injection procedures, thereby missing the critical therapeutic
window immediately post-MI. Together, the PIs developed enzyme-responsive, injectable nanoparticles (NPs),
capable of responding to matrix metalloproteinases (MMPs) associated with AMI. The particles accumulate
efficiently in infarcted myocardium following systemic administration, by virtue of an enzyme-induced phase
transition from small NP to micron-sized scaffold. While we had initial success with this system and observed
better targeting compared to traditional modalities, this system suffers the same drawback as most nanoparticles,
which have significant off-target accumulation, as they are phagocytosed and transported to the liver following
opsonization. Leveraging our success with the general MMP responsive targeting strategy, we propose that a
new MMP responsive material comprised of a completely aqueous soluble polymer displaying therapeutic
peptides at high densities will have superior biodistribution patterns nanoparticles. Upon systemic administration,
these polymers exhibit exceptionally favorable pharmacokinetics (week-long half-lives) and biodistribution
characterized by kidney clearance combined with very little liver/spleen accumulation. These polymers are
protein like in molecular weight (MW), physicochemical properties and size. They are therapeutic proteomimetic
polymers, designed to accumulate at the site of AMI. Here, we aim to develop new MMP responsive polymeric
systems (termed protein-like polymers, PLPs) and demonstrate proof-of-concept for using these novel
biomaterials for the targeted delivery of therapeutics for AMI.
摘要
心力衰竭(HF)仍然是美国和西方世界其他国家的主要死亡原因。
大约37%的心肌梗塞(MI)患者将在1年内死于心衰,而那些死于心衰的人
幸存下来,三分之二的人没有完全康复。据估计,每年将有约55万美国人
一个新的MI,和~200K将有一个复发的MI,导致大量的患者遭受HF.1因此,
我们的长期目标是开发新的、微创的、有针对性的基于生物材料的治疗方法
治疗急性心肌梗死(AMI),从而限制进展为心力衰竭的患者数量。在过去两年中
几十年来,在开发可注射生物材料方面取得了重大进展,这种材料可以刺激
内源性修复自己或通过控制释放额外的治疗药物。这种方法是
由于潜在的治疗方法可以通过导管以最小的侵入性提供,因此很有吸引力,将是现成的
和成本效益,在治疗性交付的情况下,将提供靶向交付,限制全身非-
针对困扰传统药物的靶向效应。然而,直接注射这些生物材料,或者
通过微创手术或经皮心内膜下注射,不太可能转化为急性心肌梗死
患者由于注射过程中存在严重的安全问题,从而错过了关键的治疗
心肌梗死后立即打开窗口。PIs共同开发了酶反应的可注射纳米颗粒(NPs),
能够对与急性心肌梗死相关的基质金属蛋白酶(MMPs)做出反应。粒子会累积起来
全身性给药后,通过酶诱导时相有效地治疗梗塞心肌
从小NP到微米级支架的过渡。虽然我们在这个系统上取得了初步的成功,并观察到
与传统模式相比,该系统具有更好的靶向性,具有与大多数纳米粒子相同的缺点,
当它们被吞噬并运输到肝脏时,它们有显著的非靶标积累。
奥普索化。利用我们在一般目标管理响应策略方面的成功,我们建议
由完全水溶性聚合物组成的新型基质金属蛋白酶响应性材料具有治疗作用
高密度的多肽将具有更好的生物分布模式纳米粒。在系统管理时,
这些聚合物表现出特别好的药代动力学(长达一周的半衰期)和生物分布。
其特点是肾清,肝/脾积聚极少。这些聚合物是
蛋白质在相对分子质量(MW)、物理化学性质和大小上类似。它们是治疗性的蛋白质组学
聚合物,旨在积聚在急性心肌梗死的部位。在这里,我们的目标是开发新的基质金属蛋白酶响应性聚合物
系统(称为类蛋白质聚合物,PLP),并演示使用这些新技术的概念验证
用于急性心肌梗死治疗药物靶向输送的生物材料。
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Origin of Proteolytic Stability of Peptide-Brush Polymers as Globular Proteomimetics.
- DOI:10.1021/acscentsci.1c01149
- 发表时间:2021-12-22
- 期刊:
- 影响因子:18.2
- 作者:Sun H;Qiao B;Choi W;Hampu N;McCallum NC;Thompson MP;Oktawiec J;Weigand S;Ebrahim OM;de la Cruz MO;Gianneschi NC
- 通讯作者:Gianneschi NC
Innovations in Disease State Responsive Soft Materials for Targeting Extracellular Stimuli Associated with Cancer, Cardiovascular Disease, Diabetes, and Beyond.
- DOI:10.1002/adma.202007504
- 发表时间:2021-11
- 期刊:
- 影响因子:29.4
- 作者:Battistella, Claudia;Liang, Yifei;Gianneschi, Nathan C.
- 通讯作者:Gianneschi, Nathan C.
Hydrogel Formation with Enzyme-Responsive Cyclic Peptides.
- DOI:10.1007/978-1-0716-1689-5_23
- 发表时间:2021-10
- 期刊:
- 影响因子:0
- 作者:A. Carlini;Mary F Cassidy;N. Gianneschi
- 通讯作者:A. Carlini;Mary F Cassidy;N. Gianneschi
Enzyme-Responsive Nanoparticles for Dexamethasone Targeted Delivery to Treat Inflammation in Diabetes.
用于地塞米松靶向递送以治疗糖尿病炎症的酶响应纳米颗粒。
- DOI:10.1002/adhm.202301053
- 发表时间:2023
- 期刊:
- 影响因子:10
- 作者:Schiffmann,Nathan;Liang,Yifei;Nemcovsky,CarlosE;Almogy,Michal;Halperin-Sternfeld,Michal;Gianneschi,NathanC;Adler-Abramovich,Lihi;Rosen,Eyal
- 通讯作者:Rosen,Eyal
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Karen L Christman其他文献
Karen L Christman的其他文献
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{{ truncateString('Karen L Christman', 18)}}的其他基金
Infusible Extracellular Matrix for Treating Myocardial Infarction
可溶性细胞外基质治疗心肌梗塞
- 批准号:
10642880 - 财政年份:2022
- 资助金额:
$ 59.73万 - 项目类别:
Training in Bioengineering Research and Technology Development in Cardiovascular in Cardiopulmonary Health and Disease
心肺健康和疾病领域心血管生物工程研究和技术开发培训
- 批准号:
10614653 - 财政年份:2022
- 资助金额:
$ 59.73万 - 项目类别:
Infusible Extracellular Matrix for Treating Myocardial Infarction
可溶性细胞外基质治疗心肌梗死
- 批准号:
10504948 - 财政年份:2022
- 资助金额:
$ 59.73万 - 项目类别:
New infusible ECM hydrogel for treating acute myocardial infarction
新型可熔ECM水凝胶治疗急性心肌梗死
- 批准号:
9907247 - 财政年份:2020
- 资助金额:
$ 59.73万 - 项目类别:
Injectable Biomaterial for Treating Hypoplastic Left Heart Syndrome
用于治疗左心发育不全综合征的可注射生物材料
- 批准号:
10322051 - 财政年份:2019
- 资助金额:
$ 59.73万 - 项目类别:
MMP Responsive Nanoparticles for Treating Acute Myocardial Infarction
MMP 响应纳米颗粒治疗急性心肌梗死
- 批准号:
9761569 - 财政年份:2017
- 资助金额:
$ 59.73万 - 项目类别:
Extracellular matrix hydrogels for treating ischemia
用于治疗缺血的细胞外基质水凝胶
- 批准号:
9210846 - 财政年份:2016
- 资助金额:
$ 59.73万 - 项目类别:
A 3-D biomimetic human islet to model beta cell function in health and disease
3D 仿生人类胰岛,用于模拟健康和疾病中 β 细胞的功能
- 批准号:
8813754 - 财政年份:2014
- 资助金额:
$ 59.73万 - 项目类别:
A 3-D biomimetic human islet to model beta cell function in health and disease
3D 仿生人类胰岛,用于模拟健康和疾病中 β 细胞的功能
- 批准号:
9169716 - 财政年份:2014
- 资助金额:
$ 59.73万 - 项目类别:
Extracellular matrix hydrogels for treating ischemia
用于治疗缺血的细胞外基质水凝胶
- 批准号:
8657106 - 财政年份:2012
- 资助金额:
$ 59.73万 - 项目类别:
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