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

• 批准号: 10411148
• 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
• 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/10411148
• 关键词: ABCB1 gene; Abraxane; Adjuvant; African American; Antibodies; Biodistribution; Blood Circulation; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer cell line; Bypass; Carboplatin; Cells; Cetuximab; 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 group; 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; Race; Recurrence; Regimen; Relapse; Resistance; Rhodamine 123; SN-38; Site; Structure; Surface; Therapeutic; Therapeutic Effect; Time; Toxic effect; Tumor Biology; Ursidae Family; Vertebral column; Visceral metastasis; Woman; Work; Xenograft Model; base; biodegradable polymer; cancer cell; chemotherapeutic agent; chemotherapy; crosslink; cytotoxicity; drug efficacy; drug release kinetics; efficacy study; improved; in vivo; interest; malignant breast neoplasm; molecular targeted therapies; nanoparticle; nanotechnology platform; older women; overexpression; poly(lactide); prevent; programmed cell death ligand 1; 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

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% 癌症与侵袭性肿瘤生物学、预后不良、耐药、内脏转移和 早期疾病复发。TNBC在年轻女性中比在老年女性和非洲人中更常见- 美国和西班牙裔妇女。与非铂类药物相比，铂类药物对TNBC的敏感性更高。 最近，铂类药物在TNBC中的治疗重新引起了人们的兴趣，尤其是 卡铂联合紫杉醇(PTX)。Sacituzumab gov.itecan是由一种抗trop-2抗体组成的 与化疗药物(SN-38)有关，并被FDA批准用于患有 之前至少接受过两次化疗。FDA批准了加速批准 免疫治疗药物阿替唑单抗联合化疗(NAB-紫杉醇)治疗恶性黑色素瘤 TNBC(PD-L1阳性肿瘤)。因此，化疗在非霍奇金淋巴瘤的治疗管理中非常重要。 TNBC甚至在免疫治疗和靶向治疗出现时也是如此。然而，化疗是已知的。 除了反应差、转移、复发和发展外，还会导致致命的周围神经病变 多药耐药。这一应用的目标是开发多功能靶向纳米颗粒 能够为TNBC患者实现更好的结果：(A)有针对性地提供大剂量多种药物 进入癌细胞(与单个免疫靶向药物(例如， 在减少全身毒性的同时最大化治疗效果(偏离目标 毒性)；(B)EGFR受体靶向纳米粒，促进细胞内药物输送和释放，以及 可绕过介导药物分子外流的多药耐药蛋白(P-糖蛋白)；(C) 能够长时间循环而不会被隔离在肝脏中。EGFR被TNBC过度表达，并且 文献中充满了西妥昔单抗通过靶向EFGR进行治疗的例子。我们假设 含卡铂和紫杉醇的可生物降解聚合物纳米技术平台的研究进展 在核心区使用西妥昔单抗(标记在纳米颗粒表面)作为靶向部分将改善TNBC 与大剂量细胞毒药物的重复化疗周期不同，患者的预后不同。我们假设 双重负载的多功能靶向纳米粒在体外将具有活性，并在体内表现出良好的疗效。 小鼠TNBC阳性肿瘤移植模型的建立。目的#1：紫杉醇聚合物染料载体的制备 和卡铂隐形可水解交联西妥昔单抗表面靶向聚乳酸(PLL) 纳米粒子。目的#2：抗EGFR单抗(西妥昔单抗)表面靶向PLL纳米粒的表征 核心中含有卡铂和紫杉醇。目的#3：荷瘤的生物分布和疗效研究 老鼠。这项工作将带来化疗药物、分子靶向治疗的组合力量 以及纳米技术，以克服EGFR阳性的TNBC耐药性，并以最小的毒性提高疗效。