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

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能力仅约 10% 理论上，RNAi 分子可以针对任何感兴趣的基因进行设计，但 siRNA 用于临床。肿瘤学面临递送障碍，例如核酸酶降解、肾脏快速清除、肿瘤分布不良为了克服这些挑战，大多数 RNAi 疗法都集中在不幸的是，虽然这些技术通常实现的效果非常差。虽然高外显率 siRNA 能够高递送至肝脏，但高外显率 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，提供有效、安全、针对目前无法成药的肿瘤驱动因素的肿瘤穿透性分子靶向纳米疗法。该方法建立在我们最近发表的通过 PEG45 末端修饰的 siRNA 分子原理证明的基础上与二酰基脂质 (siRNA-EG45<L2) 连接，在原位与白蛋白 (alb-NC) 形成纳米复合物这种白蛋白“搭便车”siRNA-EG45<L2 增强了 siRNA 的药代动力学特性。非常安全，提供天然的肿瘤趋向性，并提高肿瘤递送水平、肿瘤递送的均匀性，与使用 in vivo-jetPEI (PEI-NPs) 形成的传统纳米复合物相比，肿瘤：肝脏递送比。在具有挑战性的患者来源的异种移植物中积累方面，alb-NC 的表现尤其优于 PEI-NP (PDX) 肿瘤通过增强渗透性和保留 (EPR) 效应而减少了递送途径。该提案的具体目标是进一步探索和优化 siRNA 化学修饰，以用于我们将根据传统纳米制剂对新候选物进行基准测试。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。该平台将通过沉默癌基因骨髓细胞白血病 1 (Mcl-1) 来治疗三阴性进行验证乳腺癌 (TNBC) 是一个经过审查的靶点，与多种癌症相关，支持其用于治疗。此外，TNBC 是一种高度侵袭性的临床乳腺癌亚型，治疗方法很少。 TNBC 患者目前与化疗相关，通常不会从分子治疗中受益。靶向治疗。我们的多 PI 跨学科团队具有独特的生物工程专业知识，可以轻松访问该项目细胞内生物药物递送纳米技术（Duvall）、化学合成（Uddin）、非编码分析血清成分上的 RNA 转运 (Vickers)、Mcl-1 通路调节和分析 (Cook) 以及切割用于测试实验疗法的边缘临床前模型，包括 PDX（Brantley-Sieders）。科学专业知识将通过咨询英格丽德·梅耶尔博士（Dr. Ingrid Mayer）来补充，她是一位参与以下研究的肿瘤内科医生该小组将在范德比尔特开展乳腺癌临床试验，从而实现以前无法进行的研究。开发更有效、具有肿瘤穿透性和分子靶向的 TNBC 疗法。