HER2-targeting transformable nanotherapeutic platform against HER2+ cancers

针对 HER2 癌症的可转化纳米治疗平台

• 批准号: 10524157
• 负责人: KIT S LAM
• 金额: $ 11.35万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-11 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524157
• 关键词: 4T1; Abscopal effect; Biodistribution; Blood Tests; Body Weight decreased; Breast Cancer Model; Breast Cancer cell line; Cell Death; Cell Proliferation; Cells; Colorectal Cancer; Development; Dimerization; Disease remission; Dose; Epidermal Growth Factor Receptor; Future; Galectin 1; Hispanic; Homing; Human; Imiquimod; Immune; Immune response; Immunization; Immunocompetent; Immunologic Adjuvants; Immunotherapeutic agent; Implant; In Situ; Integrin alpha4beta1; Integrins; Ligand Binding; Ligands; Light; Lighting; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of urinary bladder; Mediating; Memory; Micelles; Modeling; Monoclonal Antibodies; Mouse Mammary Tumor Virus; Mus; Nano delivery; Pathway interactions; Patient-derived xenograft models of breast cancer; Patients; Peptides; Permeability; Pertuzumab; Phototherapy; Porphyrins; Positron-Emission Tomography; Regimen; Reporting; Signal Transduction; Site; T-Lymphocyte; Therapeutic Studies; Time; Transgenic Mice; Trastuzumab; Treatment Efficacy; Xenograft Model; Xenograft procedure; anti-PD1 antibodies; anti-cancer; anti-tumor immune response; aqueous; base; cancer type; chelation; chemotherapy; design; dimer; esterase; hormone therapy; imaging modality; imaging system; improved; in vivo monitoring; inhibitor; innovation; intravital imaging; macrophage; malignant breast neoplasm; malignant phenotype; malignant stomach neoplasm; nano; nanofibrillar; nanotechnology platform; nanotherapeutic; nanotherapy; neoplastic cell; novel; optical imaging; overexpression; patient derived xenograft model; receptor; resiquimod; response; self assembly; side effect; targeted treatment; translational potential; tumor

Abstract Human epidermal growth factor receptor 2 (HER2) is overexpressed in over 20% breast cancers, and to a lesser degree in gastric cancers, colorectal cancer, ovarian cancers and bladder cancers. In HER2+ tumors, HER2s are massively overexpressed and constitutively dimerized, leading to unrelenting activation of down-stream proliferation and survival pathways and malignant phenotype. Because of the high expression level of HER2, trastuzumab and pertuzumab, the two anti-HER2 monoclonal antibodies are ineffective as monotherapy against these tumors. They need to be given in combinations with other HER2-targeted therapy, chemotherapy or hormonal therapy. Here we will optimize and further improve a novel HER2-mediated, peptide-based, and non-toxic transformable nano-agent that has been proven to be highly efficacious as a monotherapy against HER2+ breast cancer xenograft models. This receptor- mediated transformable nanotherapy is comprised of a peptide with unique domains that allow self- assembly forming micelles under aqueous conditions and transformation into nanofibrils at the tumor site, where HER2 is encountered. The resulting nanofibrillar network effectively suppresses HER2 dimerization, and downstream signaling leading to increased tumor cell death and complete remission of the HER2+ tumors in xenograft models. We recently reported the development of an ICG-derivatized nanoplatform that can deliver potent immuno-stimulant imiquimod to the tumor sites in a 4T1 syngeneic breast cancer model, and we were able to demonstrate that upon local light illumination (800nm) of the tumor, the photo-active micellar nanoplatform was able to elicit a strong systemic anti-tumor immune response, particularly when given in conjunction with anti-PD1 antibody. In addition to potent abscopal effects, this nano-photo-immuno- therapeutic regimen was able to elicit strong immuno-memory against future tumor implants. For this R01-IRCN proposal, we will apply some of the promising features of the two above mentioned nanoplatforms, to generate a novel HER2-targeting transformable cancer targeting nanoplatform (TCTN) that not only can directly suppress HER2 dimerization and signaling leading to tumor cell death, but can also greatly augment systemic anti-tumor immune response. To achieve this, we will modularly incorporate to the transformable nanoplatform HER2 binding ligands, T-cell and macrophage capturing agents (e.g. LLP2A targets activated α4β1 integrin of immune cells), galectin-1 inhibitor (e.g. LLS30) and immunostimulant (e.g. resiquimod). Specific Aims: Aim 1. To design, synthesize, & characterize the novel transformable HER2-targeting TCTN nanoplatform. Aim 2. To use optical and MR imaging methods to determine the biodistribution of the TCTN constructs in xenograft, PDX and syngeneic tumor models. To use the novel in-house developed EyePod intravital imaging system to longitudinally evaluate, in real time, the intra-tumoral distribution and in situ transformation of TCTN, cellular immune response, and tumor response of sub-retinal tumor implant. Aim 3. To evaluate the therapeutic efficacy of TCTN in HER2+ PDX models of breast and gastric cancers. Aim 4. To evaluate the immunotherapeutic efficacy of TCTN in an immunocompetent murine syngeneic breast cancer model comprised of HuHER2-L2-Luc+ murine breast cancer cell lines implanted orthotopically in MMTV.f.HuHER2 transgenic mice.

摘要 人表皮生长因子受体2（HER 2）在超过20%的乳腺癌中过表达， 在胃癌、结肠直肠癌、卵巢癌和膀胱癌中的程度较小。在her 2 + 在肿瘤中，HER 2大量过表达并组成性二聚化，导致持续的 下游增殖和存活途径的激活以及恶性表型。因为 HER 2、曲妥珠单抗和帕妥珠单抗这两种抗HER 2单克隆抗体的高表达水平 作为单一疗法对这些肿瘤无效。它们需要与其他药物结合使用 HER 2靶向治疗、化疗或激素治疗。在这里我们将进行优化和进一步完善 一种新的HER 2介导的、基于肽的、无毒的可转化纳米制剂，已被证明 作为针对HER 2+乳腺癌异种移植模型的单一疗法是高度有效的。这个受体- 介导的可转化纳米疗法由具有独特结构域的肽组成， 在水性条件下组装形成胶束并在肿瘤部位转化为纳米原纤维， HER 2在哪里被发现所得纳米原纤网络有效抑制HER 2 二聚化和下游信号传导导致增加的肿瘤细胞死亡和完全缓解。 异种移植模型中的HER 2+肿瘤。 我们最近报道了一种ICG衍生的纳米平台的开发， 在4 T1同基因乳腺癌模型中，我们将免疫刺激剂咪喹莫特用于肿瘤部位， 能够证明在肿瘤的局部光照（800 nm）下，光活性胶束 纳米平台能够引发强烈的全身性抗肿瘤免疫应答，特别是当给予 与抗PD 1抗体联合使用。除了强大的远位效应，这种纳米光免疫， 治疗方案能够引发针对未来肿瘤植入物的强免疫记忆。 对于此R 01-IRCN提案，我们将应用上述两个提案中的一些有前途的功能 纳米平台，以产生新的HER 2靶向可转化的癌症靶向纳米平台（TCTN） 它不仅可以直接抑制HER 2二聚化和导致肿瘤细胞死亡的信号传导， 也大大增强了全身抗肿瘤免疫应答。为了实现这一目标，我们将模块化地 将HER 2结合配体、T细胞和巨噬细胞捕获结合配体、T细胞和巨噬细胞结合配体、T细胞结合配体和巨噬细胞结合配体结合。 药剂（例如LLP 2A靶向免疫细胞的活化的α4β1整联蛋白）、半乳糖凝集素-1抑制剂（例如LLS 30）和 免疫刺激剂（例如瑞喹莫特）。 具体目标： 目标1.设计、合成和表征新型可转化的HER 2靶向TCTN 纳米平台。 目标2.使用光学和MR成像方法确定TCTN结构的生物分布 在异种移植物、PDX和同基因肿瘤模型中。使用内部开发的新型EyePod活体 成像系统，以真实的时间纵向评估肿瘤内分布和原位 TCTN的转化、细胞免疫应答和视网膜下肿瘤植入物的肿瘤应答。 目标3.评价TCTN对乳腺癌和胃癌HER 2 + PDX模型的治疗效果。 目标4。为了评价TCTN在免疫活性小鼠同基因小鼠中的免疫效力， 乳腺癌模型包括植入的HuHER 2-L2-Luc+鼠乳腺癌细胞系 在MMTV.f.HuHER2转基因小鼠中原位。