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:10445055
- 负责人:
- 金额:$ 55.39万
- 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:AbraxaneAddressAlbuminsAllograftingApoptosisApoptoticAutomobile DrivingBRCA1 geneBasic ScienceBenchmarkingBindingBiodistributionBiologicalBiomedical EngineeringBreast Cancer ModelBreast Cancer PatientBreast Cancer therapyCell membraneCellsChemicalsChemistryCholesterolClinicalClinical OncologyConsultationsDevelopmentDoseDoxorubicin Hydrochloride LiposomeDrug Delivery SystemsDrug FormulationsDrug KineticsEndosomesExtrahepaticFDA approvedFaceFormulationGene SilencingGenesGenomeGoalsHepaticHepatocyteHumanImmunocompetentIn SituIn VitroInjectionsInvestigationInvestigational TherapiesLipid BindingLipidsLiverLiver neoplasmsLuciferasesMCL1 geneMalignant NeoplasmsMeasuresMedical OncologistModelingModificationMolecular TargetMusNanotechnologyOligonucleotidesOncogenesOrganPathway interactionsPenetrancePenetrationPermeabilityPharmaceutical PreparationsPharmacologic SubstancePolymersPositioning AttributePre-Clinical ModelPropertyPublishingRNA InterferenceRNA Interference TherapyRNA TransportRenal clearance functionSafetySerumSerum AlbuminSerum ProteinsSiteSmall Interfering RNATechnologyTestingTherapeuticToxic effectToxicologyTransgenic OrganismsTreatment EfficacyTropismTumor TissueUntranslated RNAWorkXenograft procedurec-myc Genescancer clinical trialcancer subtypeschemical synthesischemotherapyclinical translationcookingdesignendosome membraneethylene glycolimprovedin vitro activityin vivoinhibitorinterestintravenous injectionknock-downlead candidatelipid nanoparticlemalignant breast neoplasmmolecular targeted therapiesmutantnanonanocomplexesnanoformsnanoformulationnanomedicinenanotherapeuticnucleaseorthotopic breast cancerpatient derived xenograft modelpre-clinicalresponsescreeningsiRNA deliverysmall moleculesmall molecule inhibitorsuccesstaxanetheoriestherapeutic siRNAtriple-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.
用于输送小分子药物的癌症纳米制剂的靶向性仅为10%,这一点受到限制
在基因组中。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
肿瘤学面临着传递障碍,如核酸酶降解、肾脏快速清除、肿瘤分布不良
组织,细胞膜穿透性差。为了克服这些挑战,大多数RNAi疗法都专注于
合成脂类和复合纳米制剂。不幸的是,虽然这些技术通常实现了非常高的性能
高转移率的肝脏、高透过率的siRNA肿瘤转移率仍然难以捉摸。
该项目的首要目标是开发能够提供有效、安全、
肿瘤穿透性和分子靶向纳米疗法,以对抗目前无法药物治疗的肿瘤驱动因素。这个
该方法建立在我们最近发表的通过PEG45末端修饰siRNA分子的原理证明的基础上
带有二酰基脂的连接物(siRNA-EG45<;L2),它与白蛋白形成原位络合物(Alb-NC)
静脉注射。这种白蛋白“搭便车”siRNA-EG45<;L2增强了siRNA的药代动力学特性,是
非常安全,提供自然的肿瘤趋向性,并提高肿瘤输送水平,肿瘤输送的均质性,
和肿瘤:与传统的体内注射PEI形成的纳米多聚体(PEI-NPs)相比,肝脏递送比率。
在具有挑战性的患者来源的异种移植物中,alb-NCS尤其优于PEI-NPs
(PDX)由于增强的渗透性和滞留(EPR)效应而减少了分娩机会的肿瘤。
这项建议的具体目标是进一步探索和优化针对In的siRNA化学修饰
原位形成有效的白蛋白-纳米粒。我们将以传统的纳米配方为基准对新的候选者进行基准测试
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
Platform将被验证用于沉默癌基因髓系白血病1(Mcl-1)以治疗三阴性
乳腺癌(TNBC)。MCL-1是一个经过审查的靶点,与广泛的癌症相关,支持将其用于
概念验证。此外,TNBC是一种高度侵袭性的临床乳腺癌亚型,几乎没有治疗方法。
选择。TNBC患者目前只能接受化疗,通常不会从分子-
有针对性的治疗。
该项目由我们具有生物工程专业知识的多PI跨学科团队独一无二地访问
细胞内生物给药纳米技术(Duvall)、化学合成(Uddin)、非编码分析
血清成分(Vickers)、Mcl-1途径调制与分析(Cook)和切割上的RNA转运
EDGE临床前模型,包括PDX,用于测试实验疗法(Brantley-Sieders)。我们的基础
科学专业知识将通过咨询英格丽德·梅耶尔博士来补充,英格丽德·梅耶尔博士是一名参与
范德比尔特的乳腺癌临床试验。该小组将使以前无法访问的调查成为可能
开发更有效、更具肿瘤穿透性和分子靶向性的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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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:
10596246 - 财政年份:2021
- 资助金额:
$ 55.39万 - 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:
10737831 - 财政年份:2021
- 资助金额:
$ 55.39万 - 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:
$ 55.39万 - 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:
$ 55.39万 - 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:
$ 55.39万 - 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:
$ 55.39万 - 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:
$ 55.39万 - 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:
$ 55.39万 - 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:
$ 55.39万 - 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:
$ 55.39万 - 项目类别:
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