HER2-targeting transformable nanotherapeutic platform against HER2+ cancers

针对 HER2 癌症的可转化纳米治疗平台

基本信息

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
项目类别：
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

项目摘要

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.

抽象的人类表皮生长因子受体2（HER2）在20％以上的乳腺癌中过表达，并且胃癌，有色癌，卵巢癌和膀胱癌的程度较低。在Her2+中肿瘤，HER2大量过表达和组成二的二聚体，导致不懈下游增殖和存活途径和恶性表型的激活。因为 HER2，Trastuzumab和Pertuzumab的高表达水平，两种抗HER2单克隆抗体无效作为对这些肿瘤的单一疗法。它们需要与其他 HER2靶向疗法，化学疗法或荷尔蒙治疗。在这里，我们将优化并进一步改进已证明的一种新型HER2介导的，基于肽和无毒的纳米代理作为对HER2+乳腺癌异种移植模型的单一疗法的高效效率。这个接收器 - 可介导的可转化纳米疗法已完成具有独特域的肽，允许自我在水性条件下形成胶束并转化为肿瘤部位的纳米纤维的组装，遇到Her2的地方。由此产生的纳米纤维网络有效地抑制了HER2 二聚化和下游信号传导导致肿瘤细胞死亡增加并完全缓解 HER2+肿瘤中的元素模型。我们最近报道了ICG衍生的纳米板的开发，该纳米板可以提供有效 4T1合成性乳腺癌模型中肿瘤部位的免疫刺激性咪喹莫德模型，我们是可以证明，在肿瘤的局部光照明（800nm）下，光活性胶束纳米植物能够引起强大的全身性抗肿瘤免疫响应，尤其是在给出时与抗PD1抗体结合使用。除了潜在的脱节作用外，这种纳米 - 光免疫 - 治疗方案能够对未来的肿瘤入侵产生强有力的免疫记忆。对于此R01-cirn提案，我们将应用上述两个的承诺功能纳米植物，生成一种新型的HER2靶向转化癌靶向纳米植物（TCTN）不仅可以直接抑制HER2二聚化和信号导致肿瘤细胞死亡，而且可以还大大增加了系统性的抗肿瘤免疫响应。为了实现这一目标，我们将模块化纳入可转换的纳米板型HER2结合配体，T细胞和巨噬细胞捕获药物（例如LLP2A靶标激活免疫细胞的α4β1整合素），lectectin-1抑制剂（例如LLS30）和免疫刺激剂（例如regiquimod）。具体目的：目的1。设计，合成和表征可转换的新型Her2靶向TCTN 纳米板。目标2。使用光学和MR成像方法来确定TCTN构建体的生物分布在Xenographic，PDX和同步肿瘤模型中。使用小说内开发的眼睛弹药成像系统以实时纵向评估肿瘤内分布和原位 TCTN，细胞免疫响应和视网膜下肿瘤植入物的肿瘤反应的转化。目标3。评估HER2+ PDX乳腺癌和胃癌模型中TCTN的治疗效率。目的4。评估TCTN免疫能力鼠类同性素的免疫治疗效率 Huher2-L2-Luc+鼠乳腺癌细胞系的乳腺癌模型植入了在MMTV.F.HUHER2转基因小鼠中截骨。