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: 10553132
• 负责人: KIT S LAM
• 金额: $ 56.02万
• 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/10553132
• 关键词: 4T1; Abscopal effect; Biodistribution; Blood Tests; Body Weight decreased; Breast Cancer Model; Breast Cancer cell line; Cell Death; Cells; Colorectal Cancer; Derivation procedure; Development; Dimerization; Disease remission; Dose; Epidermal Growth Factor Receptor; Esters; Future; Galectin 1; Hispanic; Homing; Human; Imiquimod; Immune; Immune response; Immunocompetent; Immunologic Adjuvants; Immunologic Stimulation; Immunotherapeutic agent; Implant; In Situ; Integrin alpha4beta1; Integrins; Ligand Binding; Ligands; Light; Lighting; Macrophage; 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; Nanodelivery; Pathway interactions; Patient-derived xenograft models of breast cancer; Patients; Peptides; Permeability; Pertuzumab; Phototherapy; Porphyrins; Positron-Emission Tomography; Proliferating; 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; cancer type; chelation; chemotherapy; design; esterase; hormone therapy; imaging modality; imaging system; immune stimulatory agent; improved; in vivo monitoring; inhibitor; innovation; intravital imaging; 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(HER2)在超过20%的乳腺癌中过表达，并且 胃癌、结直肠癌、卵巢癌和膀胱癌的发病率较低。在HER2+中 肿瘤，HER2大量过度表达和结构性二聚体，导致无情 下游增殖和生存通路的激活与恶性表型。因为 抗HER2单抗HER2、曲妥珠单抗和派妥珠单抗的高表达 作为单一疗法对这些肿瘤是无效的。它们需要与其他药物结合使用 HER2-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改进 一种新型HER2介导的、基于多肽的无毒可转化纳米制剂已被证明 作为HER2+乳腺癌异种移植模型的单一疗法，具有很高的疗效。这种受体- 介导性可变形纳米疗法是由一种具有独特结构域的多肽组成的，这种多肽允许自身 在水条件下组装形成胶束并在肿瘤部位转化为纳米纤维， 在那里遇到了HER2。由此产生的纳米纤维网络有效地抑制了HER2 二聚化和下游信号导致肿瘤细胞死亡增加和完全缓解 异种移植模型中的HER2+肿瘤。 我们最近报道了一种ICG衍生化纳米平台的开发，它可以提供有效的 免疫刺激剂咪喹莫特在4T1同基因乳腺癌模型中的肿瘤部位，我们 能够证明在肿瘤的局部光照(800 Nm)时，光活性胶束 纳米平台能够诱导强烈的系统性抗肿瘤免疫反应，特别是在给予 与抗PD1抗体联合使用。除了强大的非局域效应外，这种纳米光免疫- 治疗方案能够激发对未来肿瘤植入的强大免疫记忆。 对于这个R01-IRCN提案，我们将应用上述两个方案的一些有希望的特性 纳米平台，生成一种新型的HER2靶向可转化肿瘤靶向纳米平台(TCTN) 不仅可以直接抑制HER2二聚化和导致肿瘤细胞死亡的信号转导，而且可以 还能大大增强全身抗肿瘤免疫反应。为了实现这一点，我们将模块化地 掺入可变形纳米平台HER2结合配体，捕获T细胞和巨噬细胞 药物(例如LLP2A靶标激活免疫细胞的α4β1整合素)、Galectin-1抑制剂(例如LLS30)和 免疫刺激剂(如瑞奎莫德)。 具体目标： 目的1.设计、合成和表征新型可转化的HER2靶向TCTN 纳米平台。 目的2.使用光学和磁共振成像方法来确定TCTN构建物的生物分布 在异种移植、PDX和同基因肿瘤模型中。使用新的内部开发的EyePod Inlive 实时纵向评估肿瘤内分布和原位的成像系统 TCTN的转化、细胞免疫反应和视网膜下肿瘤植入物的肿瘤反应。 目的3.评价TCTN对HER2+PDX乳腺癌和胃癌模型的治疗效果。 目的4.评价TCTN对免疫活性小鼠同基因小鼠的免疫治疗效果 HuHER2-L2-Luc+小鼠乳腺癌模型的建立 在MMTV.f.HuHER2转基因小鼠中进行原位检测。