Engineering Biomaterials to Modulate the Bone Marrow Microenvironment in Multiple Myeloma
工程生物材料调节多发性骨髓瘤的骨髓微环境
基本信息
- 批准号:10744373
- 负责人:
- 金额:$ 4.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-09 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAdhesionsAntineoplastic AgentsAntitumor ResponseArchitectureBig DataBindingBiocompatible MaterialsBioinformaticsBiomedical EngineeringBlood CirculationBone MarrowBortezomibCancer BiologyCell AdhesionCell CommunicationCellsCessation of lifeChemistryClinicClinicalComplexCustomCyclophilin ADevelopmentDiseaseDrug Delivery SystemsDrug resistanceE-SelectinEncapsulatedEndothelial CellsEndotheliumEngineeringFormulationFundingGene SilencingGenetic TranscriptionGoalsHematologic NeoplasmsHistologyHomingHybridsIn VitroKnowledgeLaboratoriesLaboratory ResearchLibrariesLigandsLipidsMalignant Bone Marrow NeoplasmMalignant NeoplasmsMechanicsMembraneMentorsMessenger RNAMethodsMicrofluidicsMigration AssayModalityModelingMultiple MyelomaMusNanotechnologyNeoplasm MetastasisNucleic AcidsPatientsPennsylvaniaPhasePlasma CellsPolyethylene GlycolsPolymersPostdoctoral FellowPropertyProteasome InhibitorRNA Interference TherapyRNA SequencesRNA deliveryResearchResearch Project GrantsResistanceResistance developmentSmall Interfering RNASpecificitySurfaceTechnologyTestingTherapeuticTissue EngineeringTrainingTranslatingTumor BiologyTumor BurdenUnited StatesUnited States National Institutes of HealthUniversitiesWorkXenograft Modeladhesion receptoraptamercancer drug resistancecancer therapyclinical translationdesigndosageeffective therapyhigh dimensionalityimprovedin vitro Assayin vivoinnovationmigrationnanoparticlenew therapeutic targetnovelnucleic acid deliverypost-doctoral trainingpre-doctoralprogramsscreeningskillssmall moleculetargeted deliverytherapeutic RNAtherapeutic nanoparticlestherapeutic targetthree-dimensional modelingtranscriptome sequencingtumortumor microenvironmenttumor progressiontumor-immune system interactionsvirtualwhole body imaging
项目摘要
PROJECT SUMMARY
Multiple myeloma (MM) accounts for ~23% of all hematologic malignancies with a 2.1% of cancer-related deaths
in the United States in 2022. Despite tremendous efforts to develop effective therapies, MM remains largely
incurable, and virtually all patients develop resistance to current therapies. Thus, there is an urgent clinical need
for innovative and improved MM therapeutics. It has been demonstrated that bone marrow endothelium is critical
to MM cell homing, progression, survival, and drug resistance. Specifically, cyclophilin A and E-selectin, a
homing factor and adhesion receptor, respectively, expressed by bone marrow endothelial cells, are critical to
MM survival. Thus, inhibition of cyclophilin A and E-selectin provides a potential therapeutic strategy to abolish
MM dissemination and resistance. However, direct- and specific-inhibition of cyclophilin A and E-selectin by
small molecules has been elusive. Thus, cyclophilin A and E-selectin are promising candidates for combination
RNA interference (RNAi) therapy, which inhibits traditionally undruggable targets by directly reducing their
messenger RNA (mRNA) expression. The challenge of utilizing small-interfering RNA (siRNA) is the need for
safe and effective delivery methods, as siRNA degrades in the bloodstream and does not readily cross
membranes. During my predoctoral studies, I have engineered a library of polymer-lipid hybrid biomaterials, that
in combination with polyethylene glycol (PEG)-lipid conjugates and siRNA, assembled into nanoparticles (NPs)
via microfluidic mixing. Through high-throughput in vivo screening, I identified a NP formulation with potent gene
silencing in bone marrow endothelial cells in vivo. This formulation was used to encapsulate cyclophilin A siRNA,
and showed inhibition of MM progression in vivo, and sensitized MM cells to the proteasome inhibitor bortezomib,
a current therapeutic modality to treat MM. During the F99 phase, I will improve our NP design by incorporating
bone marrow endothelial-targeting ligands on the NP’s surface to enhance their specificity to bone marrow
endothelium, minimizing off-target effects. I will use our targeted NP to co-encapsulate cyclophilin A and E-
selectin siRNA sequences, and evaluate their inhibition in vitro through adhesion and transendothelial migration
assays, to determine the invasive abilities of MM cells. Further, I will test our co-delivery siRNA nanotechnology
through a survival study in a validated mouse xenograft model of MM and quantify its effects either alone or in
combination with bortezomib. This technology is expected to provide with a broadly enabling platform to target
other bone marrow-homing cancers. For the K00 phase, I will identify a renowned cancer biology laboratory to
study cell-cell interactions in the bone marrow immune microenvironment utilizing high-dimensional single-cell
approaches and tissue-engineered models, with the aim to determine mechanisms that drive cancer progression
and drug resistance. Completion of this project will successfully prepare me to launch an NIH-funded research
laboratory that focuses on drug delivery targeting the tumor microenvironment as means of cancer therapy.
项目总结
多发性骨髓瘤(MM)约占所有血液系统恶性肿瘤的23%,占癌症相关死亡的2.1%
2022年在美国。尽管为开发有效的治疗方法付出了巨大的努力,MM在很大程度上仍然
无法治愈,而且几乎所有的患者都对目前的治疗产生了抵抗力。因此,临床上存在着迫切的需求。
用于创新和改进的多发性骨髓瘤疗法。已有研究表明,骨髓内皮细胞是至关重要的。
多发性骨髓瘤细胞归巢、进展、存活和耐药性。具体地说,亲环素A和E-选择素
归巢因子和黏附受体分别由骨髓内皮细胞表达,对
Mm存活期。因此,抑制亲环素A和E-选择素提供了一种潜在的治疗策略来废除
MM的传播和抵抗。然而,亲环素A和E-选择素的直接和特异性抑制
小分子一直难以捉摸。因此,亲环素A和E-选择素是很有前途的组合候选者
RNA干扰(RNAi)疗法,通过直接减少传统上不可药物的靶点
信使核糖核酸(MRNA)的表达。利用小干扰RNA(SiRNA)的挑战是需要
安全有效的给药方法,因为siRNA在血液中降解,不容易通过
膜。在我的博士前研究期间,我设计了一个聚合物-脂质杂化生物材料库,
与聚乙二醇脂结物和siRNA结合,组装成纳米颗粒(NPs)
通过微流控混合。通过体内高通量筛选,我确定了一种具有有效基因的NP配方
体内骨髓内皮细胞沉默。该制剂用于包裹亲环素A siRNA,
并在体内表现出抑制MM进展的作用,并使MM细胞对蛋白酶体抑制剂Bortezomib增敏,
目前治疗多发性骨髓瘤的一种治疗方法。在F99阶段,我将改进我们的NP设计,包括
NP表面的骨髓内皮靶向配体增强其对骨髓的特异性
内皮,最大限度地减少偏离目标的影响。我将使用我们的靶向NP共包裹亲环素A和E-
选择素siRNA序列,并通过黏附和跨内皮细胞迁移评价其体外抑制作用
测定MM细胞的侵袭能力。此外,我将测试我们共同交付的siRNA纳米技术
通过在经过验证的MM小鼠异种移植模型中进行存活研究,并量化其单独或
与波特佐米联合使用。这项技术有望为目标用户提供一个广泛的支持平台
其他与骨髓有关的癌症。对于K00阶段,我将找到一家著名的癌症生物实验室来
用高维单细胞研究骨髓免疫微环境中的细胞-细胞相互作用
方法和组织工程模型,目的是确定推动癌症进展的机制
以及抗药性。这个项目的完成将成功地为我启动NIH资助的研究做好准备
专注于针对肿瘤微环境的药物输送作为癌症治疗手段的实验室。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Christian Gabriel FIGUEROA-ESPADA其他文献
Christian Gabriel FIGUEROA-ESPADA的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y004841/1 - 财政年份:2024
- 资助金额:
$ 4.92万 - 项目类别:
Research Grant
Defining a role for non-canonical mTORC1 activity at focal adhesions
定义非典型 mTORC1 活性在粘着斑中的作用
- 批准号:
BB/Y001427/1 - 财政年份:2024
- 资助金额:
$ 4.92万 - 项目类别:
Research Grant
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y005414/1 - 财政年份:2024
- 资助金额:
$ 4.92万 - 项目类别:
Research Grant
Development of a single-use, ready-to-use, sterile, dual chamber, dual syringe sprayable hydrogel to prevent postsurgical cardiac adhesions.
开发一次性、即用型、无菌、双室、双注射器可喷雾水凝胶,以防止术后心脏粘连。
- 批准号:
10669829 - 财政年份:2023
- 资助金额:
$ 4.92万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10587090 - 财政年份:2023
- 资助金额:
$ 4.92万 - 项目类别:
Improving Maternal Outcomes of Cesarean Delivery with the Prevention of Postoperative Adhesions
通过预防术后粘连改善剖宫产的产妇结局
- 批准号:
10821599 - 财政年份:2023
- 资助金额:
$ 4.92万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10841832 - 财政年份:2023
- 资助金额:
$ 4.92万 - 项目类别:
Prevention of Intraabdominal Adhesions via Release of Novel Anti-Inflammatory from Surface Eroding Polymer Solid Barrier
通过从表面侵蚀聚合物固体屏障中释放新型抗炎剂来预防腹内粘连
- 批准号:
10532480 - 财政年份:2022
- 资助金额:
$ 4.92万 - 项目类别:
I-Corps: A Sprayable Tissue-Binding Hydrogel to Prevent Postsurgical Cardiac Adhesions
I-Corps:一种可喷雾的组织结合水凝胶,可防止术后心脏粘连
- 批准号:
10741261 - 财政年份:2022
- 资助金额:
$ 4.92万 - 项目类别:
Sprayable Polymer Blends for Prevention of Site Specific Surgical Adhesions
用于预防特定部位手术粘连的可喷涂聚合物共混物
- 批准号:
10674894 - 财政年份:2022
- 资助金额:
$ 4.92万 - 项目类别: