CpG-ODN Coated Hollow Gold Nanoshells for Photothermal Therapy

用于光热治疗的 CpG-ODN 涂层空心金纳米壳

• 批准号: 8641332
• 负责人: Aaron E. Foster
• 金额: $ 33.26万
• 依托单位: BELLICUM PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641332
• 关键词: Antigens; Biodistribution; Cancer Model; Cancer Vaccine Related Development; Cancer Vaccines; Carcinoma in Situ; Cell physiology; Cells; Clinical; Colon Carcinoma; Contralateral; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Dendritic cell activation; Disease; Dissection; Disseminated Malignant Neoplasm; Distant; Dose; Generations; Gold; Growth; Heating; Immune; Immune Cell Activation; Immune response; Immunosuppression; Immunotherapy; In Situ; In Vitro; Infiltration; Inflammatory; Injection of therapeutic agent; Intravenous; Knowledge; Lasers; Light; Lighting; Location; Lung; Lung Neoplasms; Mediating; Metastatic Lesion; Methods; Modeling; Mus; Myelogenous; Nanotechnology; Neoplasm Metastasis; Oligonucleotides; Primary Neoplasm; Problem Solving; Production; Radiation; Resistance; Reticuloendothelial System; Role; Simulate; Site; Source; Suppressor-Effector T-Lymphocytes; Surface; T cell response; T-Cell Proliferation; T-Lymphocyte; TLR9 gene; Techniques; Technology; Therapeutic; Therapeutic Agents; Thermal Ablation Therapy; arginase; base; bioluminescence imaging; cancer therapy; chemokine; chemotherapy; clinical application; cytokine; effective therapy; human NOS2A protein; immune activation; immunoregulation; in vivo; killings; lymph nodes; macrophage; melanoma; minimally invasive; nanocarrier; nanoparticle; nanoshell; novel; novel strategies; public health relevance; response; subcutaneous; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Gold nanoparticle (GNP)-mediated photothermal cancer therapy (PTT) treats primary tumors using a laser source to heat GNPs tuned to strongly absorb light in the NIR spectral region. While the technology is highly promising, clinical application of the technique is limited by the need for a priori knowledge of tumor location to determine the site of laser application. While the immune response to GNP-enabled PTT has not been carefully examined, it is known that thermal ablation induces production of pro-inflammatory cytokines and chemokines that can activate innate immune cells including myeloid-derived suppressor cells (MDSCs), which suppress antitumor T cells and facilitate tumor survival and proliferation. Furthermore, activation of immune cells may promote growth of metastatic lesions after GNP-enabled PTT. These challenges exist for all ablative thermal therapies. A GNP-enabled PTT strategy that favored generation of tumor-specific T cells while minimizing the immune suppressive effects of MDSCs could significantly enhance efficacy both for primary and distant metastatic lesions. Unlike other ablative therapies, therapy employing GNPs offers the potential for co- delivery of therapeutic agents that target MDSCs and other cellular constituents of the reticuloendothelial system, including antigen presenting dendritic cells (DCs). Recent studies have found that immunostimulatory CpG oligonucleotides (ODN) can promote tumor regression by reducing the immune suppressive activity of MDSCs and activating lymph node resident DCs to increase stimulation of tumor-specific T cells. Based on these studies, we hypothesize that GNPs conjugated to CpG ODN will enable NIR-activated PTT on accessible tumors while decreasing the effects of immune suppressive MDSCs and boosting DC function. In this project, we first investigate the role of MDSCs in promoting metastatic tumor growth and suppressing tumor-specific T cells following GNP-enabled PTT. We will then evaluate if GNPs coated with CpG ODN can reverse the effects of MDSCs in vivo following PTT. Finally, we will evaluate whether CpG ODN coated GNPs can be used in combination with PTT to destroy accessible tumors while stimulating lymph node resident DCs, providing an in situ cancer vaccine. Using nanocarriers to deliver CpG offers a number of potential advantages including reduced degradation during delivery and ability to adjust biodistribution through physicochemical feature selection. Moreover, preliminary data indicates increased effects of CpG ODN in vitro using GNP delivered CpG ODN as opposed to the equivalent dose of ODN alone. The potential impact of GNP-CpG on MDSCs is particularly important in light of preliminary data suggesting GNP-enabled PTT alone can promote growth of metastatic lesions in some cases. To further develop the clinical potential of PTT, this project will investigate why and when growth of metastatic lesions may occur after PTT, whether this effect can be reversed, and how GNP-enabled PTT based therapeutic approaches might be developed that enable effective treatment not only of primary tumors but secondary tumors and metastatic lesions as well.

描述(申请人提供)：金纳米颗粒(GNP)介导的光热癌症疗法(PTT)使用激光光源加热GNP，使其在近红外光谱区域强烈吸收光。虽然这项技术前景看好，但由于需要事先了解肿瘤的位置来确定激光应用的位置，该技术的临床应用受到限制。虽然对GNP激活的PTT的免疫应答尚未被仔细研究，但已知热消融可诱导产生促炎细胞因子和趋化因子，这些细胞因子和趋化因子可以激活包括髓系来源的抑制细胞(MDSCs)在内的天然免疫细胞，从而抑制抗肿瘤T细胞，促进肿瘤的存活和增殖。此外，免疫细胞的激活可能促进了GNP激活的PTT后转移灶的生长。这些挑战对于所有的消融性热疗都存在。GNP激活的PTT策略有利于肿瘤特异性T细胞的产生，同时将MDSCs的免疫抑制作用降至最低，可以显著提高对原发和远处转移灶的疗效。与其他消融疗法不同，使用GNPs的治疗提供了联合输送治疗剂的潜力，这些治疗剂针对MDSCs和网状内皮系统的其他细胞成分，包括抗原提呈树突状细胞(DC)。最近的研究发现，免疫刺激性CpG寡核苷酸(ODN)可以通过降低MDSCs的免疫抑制活性，激活淋巴驻留的DC来增加对肿瘤特异性T细胞的刺激，从而促进肿瘤的消退。基于这些研究，我们假设与CpG ODN结合的GNPs将在可及性肿瘤上实现近红外激活的PTT，同时减少免疫抑制MDSCs的作用并增强DC功能。在这个项目中，我们首先研究了MDSCs在GNP激活的PTT后促进肿瘤转移生长和抑制肿瘤特异性T细胞中的作用。然后，我们将评估包被CpG ODN的GNPs是否可以逆转PTT后体内MDSCs的作用。最后，我们将评估CpG ODN包裹的GNPs是否可以与PTT联合使用，在刺激淋巴驻留的DC的同时破坏可接近的肿瘤，提供一种原位肿瘤疫苗。使用纳米载体递送CpG具有许多潜在的优点，包括减少递送过程中的降解，以及能够通过物理化学特征选择来调节生物分布。此外，初步数据表明，与同等剂量的单独使用相比，使用GNP递送的CpG ODN在体外增强了CpG ODN的效果。GNP-CpG对MDSCs的潜在影响尤其重要，因为初步数据表明，在某些情况下，GNP-CpG单独启用PTT可以促进转移灶的生长。为了进一步开发PTT的临床潜力，该项目将调查PTT后转移灶生长的原因和时间，这种影响是否可以逆转，以及如何开发基于GNP的PTT治疗方法，使其不仅能够有效治疗原发肿瘤，而且能够有效治疗继发性肿瘤和转移病变。