Multifunctional Nanotechnology Platform for Triple Negative Breast Cancer Treatment

用于三阴性乳腺癌治疗的多功能纳米技术平台

基本信息

批准号：
10672232
负责人：
EMMANUEL O AKALA
金额：
$ 15.45万
依托单位：
HOWARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672232
关键词：
ABCB1 gene Abraxane Acceleration Adjuvant African American Antibodies Biodistribution Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Bypass Carboplatin Cells Cetuximab Circulation Clinic Clinical Research Combination Drug Therapy Confocal Microscopy Coupled Cytotoxic agent Data Reporting Development Disease Dose Drug Combinations Drug Delivery Systems Drug Efflux Drug Kinetics Dyes ERBB2 gene Epidermal Growth Factor Receptor Ethnic Population Event FDA approved Female Fluorescent Dyes Goals Grant Hispanic Immunotherapy Implant In Vitro In complete remission Label Link Literature Liver MDA MB 231 Mediating Medical Molecular Monoclonal Antibodies Morphology Multi-Drug Resistance Mus Nanotechnology Neoadjuvant Therapy Neoplasm Metastasis Nude Mice Numbness Outcome Paclitaxel Pain Particle Size Pathologic Patient-Focused Outcomes Patients Peripheral Nervous System Diseases Persons Pharmaceutical Preparations Phase Platinum Polymers Prior Chemotherapy Prognosis Proteins Recurrent disease Regimen Relapse Resistance Rhodamine 123 SN-38 Site Structure Surface Therapeutic Therapeutic Effect Time Toxic effect Tumor Biology Vertebral column Visceral metastasis Woman Work Xenograft Model antibody conjugate biodegradable polymer cancer cell chemotherapeutic agent chemotherapy crosslink cytotoxicity drug efficacy drug release kinetics efficacy evaluation efficacy study fabrication improved in vivo interest malignant breast neoplasm molecular targeted therapies nanoparticle nanopolymer nanotechnology platform older women overexpression poly(lactide)prevent programmed cell death ligand 1 racial population receptor response standard of care subcutaneous systemic toxicity targeted agent targeted delivery targeted treatment taxane triple-negative invasive breast carcinoma tumor young woman zeta potential

项目摘要

Project Summary: Triple-negative breast cancer (TNBC) accounts for approximately 15% of invasive breast cancers and is associated with aggressive tumor biology, poor prognosis, resistance, visceral metastases and earlier disease recurrence. TNBC is more common in younger women than in older women and in African- American and Hispanic women. Platinum-based drugs showed higher sensitivity in TNBC compared to non- TNBC patients and recently there has been a renewed interest for platinum therapy in TNBC, especially combination of carboplatin with paclitaxel (PTX). Sacituzumab govitecan is made up of an anti–Trop-2 antibody linked to the chemotherapy drug (SN-38) and was cleared by the FDA for TNBC patients who have undergone at least two prior chemotherapies. The FDA granted an accelerated approval for the immunotherapy drug atezolizumab in combination with chemotherapy (nab-paclitaxel) for the treatment of TNBC (for tumors positive for PD-L1). Thus chemotherapy is important in the therapeutic management of TNBC even in the advent of immunotherapy and targeted therapy. However, chemotherapies are known to cause fatal peripheral neuropathy in addition to poor response, metastasis, relapse and development of multidrug resistance. The goal of this application is the development of multifunctional targeted nanoparticles capable of achieving better outcomes for TNBC patients: (a) targeted delivery of large doses of multiple drugs into cancer cells (per a single biorecognition event compared to a single immunotargeted drug (e.g. sacituzumab govitecan-hziy)) to maximize therapeutic effects while reducing systemic toxicity (off target toxicity); (b) EGFR-receptor targeted nanoparticles that promote intracellular drug delivery and release and which can bypass multidrug resistant protein (p-glycoprotein) which mediates efflux of drug molecules; (c) capable of long circulation without being sequestered into the liver. EGFR is overexpressed by TNBC and literature is replete with examples of the use of cetuximab in therapy by targeting EFGR. We hypothesize that the development of biodegradable polymeric nanotechnology platform containing carboplatin and paclitaxel in the core and using cetuximab (tagged on nanoparticle surface) as a targeting moiety will improve TNBC patients’ outcomes, unlike repeated chemotherapy cycles with high doses of cytotoxic drugs. We hypothesize that the dual-loaded multifunctional targeted nanoparticles will be active in vitro and show in vivo efficacy in mouse xenograft models of TNBC positive tumors. Aim #1: Fabrication of polymeric dye-loaded and-paclitaxel and carboplatin-loaded stealth hydrolysable crosslinked cetuximab surface-targeted polylactide (PLL) nanoparticles. Aim #2: Characterization of anti-EGFR mAb (cetuximab) surface-targeted-PLL-nanoparticles containing carboplatin and paclitaxel in the core. Aim #3: Biodistribution and efficacy studies in tumor-bearing mice. This work will bring to bear the combined power of chemotherapeutic agents, molecular targeted therapy and nanotechnology to overcome EGFR positive TNBC resistance and improve efficacy with minimal toxicity.

项目摘要：三阴性乳腺癌 (TNBC) 约占浸润性乳腺癌的 15% 癌症，并与侵袭性肿瘤生物学、不良预后、耐药性、内脏转移和较早的疾病复发在年轻女性中比在老年女性和非洲女性中更常见。与非铂类药物相比，美国和西班牙裔女性对 TNBC 的敏感性更高。 TNBC 患者最近对 TNBC 铂类治疗重新产生了兴趣，尤其是 Sacituzumab govitecan 是卡铂与紫杉醇 (PTX) 的组合，由抗 Trop-2 抗体组成。与化疗药物 (SN-38) 相关，并已被 FDA 批准用于患有 TNBC 的患者之前至少接受过两次化疗，FDA 加速批准了该药物。免疫治疗药物 atezolizumab 与化疗（白蛋白结合型紫杉醇）联合治疗 TNBC（对于 PD-L1 阳性的肿瘤）因此化疗在治疗管理中很重要。 TNBC即使在免疫治疗和靶向治疗出现的情况下，化疗也是众所周知的。除了反应不良、转移、复发和发展外，还会引起致命的周围神经病变该应用的目标是开发多功能靶向纳米颗粒。能够为 TNBC 患者取得更好的结果：(a) 大剂量多种药物的靶向输送进入癌细胞（与单一免疫靶向药物（例如，每一次生物识别事件相比） sacituzumab govitecan-hziy)) 最大限度地提高治疗效果，同时降低全身毒性（脱靶） (b) EGFR 受体靶向纳米颗粒，促进细胞内药物递送和释放，它可以绕过介导药物分子流出的多药耐药蛋白（p-糖蛋白）（c）能够长时间循环而不被隔离到肝脏中 EGFR 被 TNBC 过表达，并且文献中充满了使用西妥昔单抗靶向 EFGR 进行治疗的例子。含卡铂和紫杉醇的可生物降解聚合物纳米技术平台的开发在核心中并使用西妥昔单抗（标记在纳米颗粒表面）作为靶向部分将改善 TNBC 与使用高剂量细胞毒性药物的重复化疗周期不同。双负载多功能靶向纳米颗粒将在体外具有活性，并在体内显示出功效 TNBC 阳性肿瘤的小鼠异种移植模型。目标#1：制备负载聚合物染料的紫杉醇。和载有卡铂的隐形可水解交联西妥昔单抗表面靶向聚丙交酯 (PLL) 目标#2：抗 EGFR mAb（西妥昔单抗）表面靶向 PLL 纳米颗粒的表征。核心含有卡铂和紫杉醇，目标#3：荷瘤体内的生物分布和功效研究。这项工作将发挥化疗药物、分子靶向治疗的综合作用。和纳米技术克服 EGFR 阳性 TNBC 耐药性并以最小的毒性提高疗效。