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
• 负责人: Rebecca Sara Cook
• 金额: $ 11.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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/10596246
• 关键词: Albumins; Allografting; Apoptotic; Automobile Driving; Basic Science; Benchmarking; Binding; Biological; Biomedical Engineering; Breast Cancer Patient; Cell membrane; Chemicals; Clinical; Clinical Oncology; Consultations; Development; Drug Delivery Systems; Drug Kinetics; Face; Genes; Genome; Goals; Immunocompetent; In Situ; Investigation; Investigational Therapies; Lipids; Liver; Liver neoplasms; MCL1 gene; Malignant Neoplasms; Medical Oncologist; Modeling; Modification; Molecular Target; Nanotechnology; Oncogenes; Pathway interactions; Penetrance; Penetration; Permeability; Pharmaceutical Preparations; Pre-Clinical Model; Property; Publishing; RNA Interference; RNA Interference Therapy; RNA Transport; Renal clearance function; Serum; Small Interfering RNA; Technology; Testing; Therapeutic; Tropism; Tumor Tissue; Untranslated RNA; Xenograft procedure; cancer clinical trial; cancer subtypes; chemical synthesis; chemotherapy; cooking; design; in vivo; interest; intravenous injection; malignant breast neoplasm; molecular targeted therapies; nano; nanocomplexes; nanoforms; nanoformulation; nanotherapeutic; nuclease; patient derived xenograft model; small molecule; theories; triple-negative invasive breast carcinoma; tumor; tumor xenograft

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能靶向约10%