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：
Rebecca Sara Cook
金额：
$ 55.39万
依托单位：
VANDERBILT UNIVERSITY
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：
https://reporter.nih.gov/project-details/10445055
关键词：
Abraxane Address Albumins Allografting Apoptosis Apoptotic Automobile Driving BRCA1 gene Basic Science Benchmarking Binding Biodistribution Biological Biomedical Engineering Breast Cancer Model Breast Cancer Patient Breast Cancer therapy Cell membrane Cells Chemicals Chemistry Cholesterol Clinical Clinical Oncology Consultations Development Dose Doxorubicin Hydrochloride Liposome Drug Delivery Systems Drug Formulations Drug Kinetics Endosomes Extrahepatic FDA approved Face Formulation Gene Silencing Genes Genome Goals Hepatic Hepatocyte Human Immunocompetent In Situ In Vitro Injections Investigation Investigational Therapies Lipid Binding Lipids Liver Liver neoplasms Luciferases MCL1 gene Malignant Neoplasms Measures Medical Oncologist Modeling Modification Molecular Target Mus Nanotechnology Oligonucleotides Oncogenes Organ Pathway interactions Penetrance Penetration Permeability Pharmaceutical Preparations Pharmacologic Substance Polymers Positioning Attribute Pre-Clinical Model Property Publishing RNA Interference RNA Interference Therapy RNA Transport Renal clearance function Safety Serum Serum Albumin Serum Proteins Site Small Interfering RNA Technology Testing Therapeutic Toxic effect Toxicology Transgenic Organisms Treatment Efficacy Tropism Tumor Tissue Untranslated RNA Work Xenograft procedure c-myc Genes cancer clinical trial cancer subtypes chemical synthesis chemotherapy clinical translation cooking design endosome membrane ethylene glycol improved in vitro activity in vivo inhibitor interest intravenous injection knock-down lead candidate lipid nanoparticle malignant breast neoplasm molecular targeted therapies mutant nano nanocomplexes nanoforms nanoformulation nanomedicine nanotherapeutic nuclease orthotopic breast cancer patient derived xenograft model pre-clinical response screening siRNA delivery small molecule small molecule inhibitor success taxane theories therapeutic siRNA triple-negative invasive breast carcinoma tumor tumor xenograft

Abraxane Address Albumins Allografting Apoptosis Apoptotic Automobile Driving BRCA1 gene Basic Science Benchmarking Binding Biodistribution Biological Biomedical Engineering Breast Cancer Model Breast Cancer Patient Breast Cancer therapy Cell membrane Cells Chemicals Chemistry Cholesterol Clinical Clinical Oncology Consultations Development Dose Doxorubicin Hydrochloride Liposome Drug Delivery Systems Drug Formulations Drug Kinetics Endosomes Extrahepatic FDA approved Face Formulation Gene Silencing Genes Genome Goals Hepatic Hepatocyte Human Immunocompetent In Situ In Vitro Injections Investigation Investigational Therapies Lipid Binding Lipids Liver Liver neoplasms Luciferases MCL1 gene Malignant Neoplasms Measures Medical Oncologist Modeling Modification Molecular Target Mus Nanotechnology Oligonucleotides Oncogenes Organ Pathway interactions Penetrance Penetration Permeability Pharmaceutical Preparations Pharmacologic Substance Polymers Positioning Attribute Pre-Clinical Model Property Publishing RNA Interference RNA Interference Therapy RNA Transport Renal clearance function Safety Serum Serum Albumin Serum Proteins Site Small Interfering RNA Technology Testing Therapeutic Toxic effect Toxicology Transgenic Organisms Treatment Efficacy Tropism Tumor Tissue Untranslated RNA Work Xenograft procedure c-myc Genes cancer clinical trial cancer subtypes chemical synthesis chemotherapy clinical translation cooking design endosome membrane ethylene glycol improved in vitro activity in vivo inhibitor interest intravenous injection knock-down lead candidate lipid nanoparticle malignant breast neoplasm molecular targeted therapies mutant nano nanocomplexes nanoforms nanoformulation nanomedicine nanotherapeutic nuclease orthotopic breast cancer patient derived xenograft model pre-clinical response screening siRNA delivery small molecule small molecule inhibitor success taxane theories therapeutic siRNA triple-negative invasive breast carcinoma tumor tumor xenograft

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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.

癌症纳米形成用于递送小分子药物的限制受到靶向〜10％的能力的限制从理论上讲，RNAi分子可以针对任何感兴趣的基因进行设计，但在临床中使用siRNA 肿瘤学面向递送障碍，例如核酸酶降解，快速肾脏清除率，分布较差的肿瘤组织，细胞膜穿透不良。为了克服这些挑战，大多数RNAi疗法都集中在合成脂质和多质子纳米形成。不幸的是，尽管这些技术通常实现高渗透到高渗透siRNA肿瘤递送仍然难以捉摸。该项目的总体目标是开发siRNA化学修饰，以提供潜在的，安全，肿瘤渗透和分子靶向纳米治疗药，以目前不良肿瘤驱动器。方法建立在我们最近发表的原理证明siRNA分子通过PEG45终止修饰的证明带有二酰基脂质（siRNA-EG45 <l2）的接头，该连接器与白蛋白（Alb-nc）形成纳米复合物，以下是静脉注射。这张专辑“ Hitchhiking” sirna-eg45 <l2增强了siRNA药代动力学特性，是非常安全，提供天然肿瘤的向流，并增加肿瘤递送水平，肿瘤递送的同质性，与肿瘤：肝脏递送率与由体内jetpei（PEI-NPS）形成的常规纳米合流相比。 ALB-NC特别优于PEI-NP，用于在挑战患者衍生的异种移植物中积累的PEI-NP （PDX）通过增强的渗透性和保留效应（EPR）效应降低了递送的肿瘤。该提案的具体目标是进一步探索和优化IN的siRNA化学修饰有效ALB-NC的原位形成。我们将基准针对常规纳米形成的新候选人进行基准测试简单（异种移植），免疫能力（同种异体移植）和严格（PDX和赞助）肿瘤模型。这平台将得到验证，以使癌基因髓样细胞白血病1（MCL-1）的沉默以治疗三重阴性乳腺癌（TNBC）。 MCL-1是一个审查的目标，具有广泛癌症的相关性，支持其用于概念证明。此外，TNBC是一种高度侵略性的临床乳腺癌亚型，几乎没有治疗选项。 TNBC患者目前与化学疗法有关，通常不会受益于分子靶向疗法。我们的Multi-Pi跨学科团队可以独特地访问该项目，并具有生物工程专业知识细胞内生物学递送纳米技术（DUVALL），化学合成（UDDIN），非编码分析血清成分（Vickers），MCL-1途径调制和分析（COCK）和切割上的RNA传输用于测试实验疗法（Brantley-Sieders）的边缘临床前模型，包括PDX。我们的基本科学专业知识将通过与参与的医学肿瘤学家Ingrid Mayer博士进行磋商。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对开发更有效，肿瘤渗透和分子靶向的TNBC治疗。