In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
基本信息
- 批准号:10596246
- 负责人:
- 金额:$ 11.76万
- 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:2021-07-05 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AlbuminsAllograftingApoptoticAutomobile DrivingBasic ScienceBenchmarkingBindingBiologicalBiomedical EngineeringBreast Cancer PatientCell membraneChemicalsClinicalClinical OncologyConsultationsDevelopmentDrug Delivery SystemsDrug KineticsFaceGenesGenomeGoalsImmunocompetentIn SituInvestigationInvestigational TherapiesLipidsLiverLiver neoplasmsMCL1 geneMalignant NeoplasmsMedical OncologistModelingModificationMolecular TargetNanotechnologyOncogenesPathway interactionsPenetrancePenetrationPermeabilityPharmaceutical PreparationsPre-Clinical ModelPropertyPublishingRNA InterferenceRNA Interference TherapyRNA TransportRenal clearance functionSerumSmall Interfering RNATechnologyTestingTherapeuticTropismTumor TissueUntranslated RNAXenograft procedurecancer clinical trialcancer subtypeschemical synthesischemotherapycookingdesignin vivointerestintravenous injectionmalignant breast neoplasmmolecular targeted therapiesnanonanocomplexesnanoformsnanoformulationnanotherapeuticnucleasepatient derived xenograft modelsmall moleculetheoriestriple-negative invasive breast carcinomatumortumor xenograft
项目摘要
Cancer nano-formulations for delivery of small molecule drugs are limited by the ability to target only ~10%
of the genome. RNAi molecules can, in theory, be designed against any gene of interest, but siRNA use in clinical
oncology faces delivery barriers such as nuclease degradation, rapid renal clearance, poor distribution into tumor
tissues, and poor cell membrane penetration. To overcome these challenges, most RNAi therapies focus on
synthetic lipo- and poly-plex nano-formulations. Unfortunately, while these technologies typically achieve very
high delivery into the liver, high-penetrance siRNA tumor delivery remains elusive.
The overarching goal of this project is to develop siRNA chemical modifications that provide potent, safe,
tumor-penetrating, and molecularly targeted nano-therapeutics against currently undruggable tumor drivers. The
approach builds upon our recently published proof of principle siRNA molecules end-modified through a PEG45
linker with a diacyl lipid (siRNA-EG45<L2), which forms a nano-complex with albumin (alb-NC) in situ following
intravenous injection. This albumin “hitchhiking” siRNA-EG45<L2 enhances siRNA pharmacokinetic properties, is
very safe, provides natural tumor tropism, and increases tumor delivery level, homogeneity of tumor delivery,
and tumor:liver delivery ratio compared to conventional nano-polyplexes formed with in vivo-jetPEI (PEI-NPs).
The alb-NCs especially outperformed PEI-NPs for accumulating within challenging patient derived xenograft
(PDX) tumors that have reduced access to delivery by the enhanced permeability and retention (EPR) effect.
The specific goal of this proposal is to further explore and optimize siRNA chemical modifications for in
situ formation of effective alb-NCs. We will benchmark new candidates against conventional nano-formulations
in simple (xenograft), immune-competent (allograft) and rigorous (PDX and spontaneous) tumor models. This
platform will be validated for silencing of the oncogene myeloid cell leukemia 1 (Mcl-1) to treat triple negative
breast cancer (TNBC). Mcl-1 is a vetted target with relevance in a broad range of cancers, supporting its use for
proof-of-concept. Furthermore, TNBC is a highly aggressive clinical breast cancer subtype with few treatment
options. TNBC patients are currently relegated to chemotherapies, and do not typically benefit from molecularly-
targeted therapies.
This project is uniquely accessible by our multi-PI interdisciplinary team with bioengineering expertise in
intracellular biologic drug delivery nanotechnologies (Duvall), chemical synthesis (Uddin), analysis of noncoding
RNA transport on serum components (Vickers), Mcl-1 pathway modulation and analysis (Cook), and cutting
edge preclinical models, including PDX, for testing experimental therapies (Brantley-Sieders). Our basic
science expertise will be supplemented by consultation with Dr. Ingrid Mayer, a medical oncologist involved in
breast cancer clinical trials at Vanderbilt. This group will enable previously inaccessible investigations toward
development of more effective, tumor-penetrating, and molecularly-targeted TNBC therapeutics.
用于递送小分子药物的癌症纳米制剂受限于仅靶向~10%的能力。
的基因组。理论上,RNAi分子可以针对任何感兴趣的基因进行设计,但siRNA在临床上的应用
肿瘤学面临递送障碍,例如核酸酶降解、快速肾清除、肿瘤中的不良分布
组织和差的细胞膜渗透。为了克服这些挑战,大多数RNAi疗法专注于
合成的脂质复合物和聚合复合物纳米制剂。不幸的是,虽然这些技术通常实现非常
高递送到肝脏中,高转移率siRNA肿瘤递送仍然是难以捉摸的。
该项目的总体目标是开发siRNA化学修饰,提供有效,安全,
肿瘤穿透性和分子靶向纳米治疗剂,以对抗目前无法治疗的肿瘤驱动因素。的
该方法建立在我们最近发表的通过PEG 45末端修饰的siRNA分子的原理证明上
连接子与二酰基脂质(siRNA-EG 45 <L2),其与白蛋白(alb-NC)原位形成纳米复合物,
静脉注射这种白蛋白“搭便车”siRNA-EG 45 <L2增强siRNA药代动力学性质,
非常安全,提供了天然的肿瘤向性,增加了肿瘤的递送水平,肿瘤递送的均匀性,
和与用体内喷射PEI(PEI-NP)形成的常规纳米复合物相比的肿瘤:肝脏递送比。
alb-NC在挑战性患者来源的异种移植物内的积累方面尤其优于PEI-NP
(PDX)通过增强的渗透性和滞留(EPR)效应减少了递送途径的肿瘤。
该提案的具体目标是进一步探索和优化siRNA化学修饰,
原位形成有效的alb-NC。我们将以传统的纳米配方为基准,
在简单(异种移植)、免疫活性(同种异体移植)和严格(PDX和自发)肿瘤模型中。这
该平台将被验证用于沉默癌基因骨髓细胞白血病1(Mcl-1),以治疗三阴性
乳腺癌(TNBC)。Mcl-1是一种经过审查的靶点,与广泛的癌症相关,支持其用于治疗癌症。
概念验证此外,TNBC是一种高度侵袭性的临床乳腺癌亚型,几乎没有治疗
选项. TNBC患者目前被降级为化疗,并且通常不受益于分子-
靶向治疗。
这个项目是唯一的访问我们的多PI跨学科团队与生物工程专业知识,
细胞内生物药物递送纳米技术(杜瓦尔),化学合成(乌丁),非编码分析
血清组分上的RNA转运(Vickers)、Mcl-1途径调节和分析(Cook)以及切割
边缘临床前模型,包括PDX,用于测试实验疗法(Brantley-Sieders)。我们的基本
科学专业知识将通过与Ingrid Mayer博士的咨询得到补充,Ingrid Mayer博士是一位参与
范德比尔特的乳腺癌临床试验。该小组将使以前无法进行的调查能够进行,
开发更有效的、肿瘤穿透的和分子靶向的TNBC治疗剂。
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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Rebecca Sara Cook其他文献
Rebecca Sara Cook的其他文献
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{{ truncateString('Rebecca Sara Cook', 18)}}的其他基金
In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
- 批准号:
10737831 - 财政年份:2021
- 资助金额:
$ 11.76万 - 项目类别:
In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
- 批准号:
10445055 - 财政年份:2021
- 资助金额:
$ 11.76万 - 项目类别:
In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
- 批准号:
10661771 - 财政年份:2021
- 资助金额:
$ 11.76万 - 项目类别:
McI-1 Inhibitors for the treatment of Breast Cancer
用于治疗乳腺癌的 MCI-1 抑制剂
- 批准号:
8764759 - 财政年份:2014
- 资助金额:
$ 11.76万 - 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
- 批准号:
8196980 - 财政年份:2009
- 资助金额:
$ 11.76万 - 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
- 批准号:
8591383 - 财政年份:2009
- 资助金额:
$ 11.76万 - 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
- 批准号:
7768523 - 财政年份:2009
- 资助金额:
$ 11.76万 - 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
- 批准号:
7998156 - 财政年份:2009
- 资助金额:
$ 11.76万 - 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
- 批准号:
8390510 - 财政年份:2009
- 资助金额:
$ 11.76万 - 项目类别:
McI-1 Inhibitors for the treatment of Breast Cancer
用于治疗乳腺癌的 MCI-1 抑制剂
- 批准号:
8593797 - 财政年份:2003
- 资助金额:
$ 11.76万 - 项目类别:
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