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.

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、预后差、耐药性、内脏转移和 早期疾病复发。TNBC在年轻女性中比老年女性更常见，在非洲， 美国和西班牙裔女性。铂类药物在TNBC中显示出比非TNBC更高的敏感性。 TNBC患者，最近对TNBC中的铂治疗重新产生了兴趣，特别是 卡铂与紫杉醇（PTX）的组合。Sacituzumab govitecan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。 至少接受过两次化疗。FDA批准了一项加速批准， 免疫治疗药物atezolizumab与化疗（nab-紫杉醇）组合用于治疗 TNBC（PD-L1阳性肿瘤）。因此，化疗是重要的治疗管理， TNBC甚至在免疫疗法和靶向疗法的出现。然而，化疗是已知的 除了反应差、转移、复发和发展外， 多药耐药该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）靶向递送大剂量的多种药物 进入癌细胞（与单一免疫靶向药物（例如， sacituzumab govitecan-hziy）），以使治疗效果最大化，同时降低全身毒性（脱靶 毒性）;（B）促进细胞内药物递送和释放的EGFR受体靶向纳米颗粒， 其可以绕过介导药物分子外排的多药耐药蛋白（p-糖蛋白）;（c） 能够长时间循环而不会被隔离到肝脏中。EGFR被TNBC过表达， 文献中充满了西妥昔单抗通过靶向EFGR用于治疗的例子。我们假设 含卡铂和紫杉醇的生物可降解聚合物纳米技术平台的开发 在核心中加入西妥昔单抗并使用西妥昔单抗（在纳米颗粒表面上标记）作为靶向部分将改善TNBC 患者的结果，不像重复化疗周期与高剂量的细胞毒性药物。我们假设 双负载的多功能靶向纳米颗粒将在体外具有活性并显示出体内功效， TNBC阳性肿瘤的小鼠异种移植模型。目的#1：制备聚合物染料负载的紫杉醇 和负载卡铂的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 mAb（西妥昔单抗）表面靶向PLL纳米颗粒的表征 在核心中含有卡铂和紫杉醇。目标3：荷瘤患者的生物分布和疗效研究 小鼠这项工作将带来联合化疗药物的力量，分子靶向治疗， 和纳米技术来克服EGFR阳性TNBC耐药性并以最小的毒性提高疗效。