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Plasmonic nanoparticle-mediated immunotherapy to treat metastatic cancer

等离子纳米粒子介导的免疫疗法治疗转移性癌症

基本信息

批准号：
10326341
负责人：
Tuan Vo-Dinh
金额：
$ 52.84万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10326341
关键词：
Ablation Acute Age-Years American Animals Biodistribution Biological Biophotonics Bladder Bladder Tissue Cancer Model Cancer Patient Cause of Death Cessation of life Chronic Clinical Clinical Trials Combined Modality Therapy Complementary therapies Cystoscopy Disseminated Malignant Neoplasm Distant Effectiveness Electromagnetic Energy Electromagnetic Fields Esters FDA approved Failure Fluorescence Formulation Fractionation Future Generations Geometry Goals Gold Heat shock proteins Human Image Immune checkpoint inhibitor Immune response Immunize Immunocompetent Immunohistochemistry Immunophenotyping Immunotherapy Impairment Individual Inductively Coupled Plasma Mass Spectrometry Injections Intravenous KDR gene Lasers Length Lesion Leukocytes Life Ligand Binding Ligands Light Malignant Neoplasms Malignant neoplasm of urinary bladder Maps Mediating Methods Modality Morbidity - disease rate Mus Nanotechnology Neoplasm Metastasis Operative Surgical Procedures Optics PD-1/PD-L1 Patients Penetration Permeability Photons Phototherapy Positron-Emission Tomography Process Property Quality of life Radical Cystectomy Recurrence Regimen Reporter Research Research Proposals Sulfhydryl Compounds Surface T-Cell Receptor Technology Testing Therapeutic Time Toxic effect Transgenic Organisms Treatment Cost Treatment Efficacy Treatment Protocols Tumor Burden Vaccines Woman Work absorption anti-PD-1 anti-cancer anti-tumor immune response base bioaccumulation biomaterial compatibility cancer cell cancer imaging cancer recurrence chemotherapy clinical translation cytokine dosimetry effectiveness evaluation efficacy evaluation immune activation immune checkpoint immune checkpoint blockade immune resistance immunogenic improved in vivo individualized medicine innovation men mortality mouse model multimodality nanoGold nanoparticle nanoplasmonic nanotherapy new technology next generation novel novel drug class novel therapeutics phantom model photothermal therapy plasmonics prevent programmed cell death ligand 1 programmed cell death protein 1 real time monitoring resistance mechanism response synergism therapeutically effective translational goal treatment optimization tumor tumor ablation

项目摘要

Bladder cancer (BC) is the 4th most common cancer in men and the 11th most common in women. BC has the highest lifetime per-patient treatment cost of all cancers, mainly because of its high recurrence rate. Also, regular invasive cystoscopy and the subsequent surgical treatment of recurrences impair patient quality of life and cause significant morbidity. Therefore, there is a clear clinical need for novel technologies to effectively treat BC, ultimately reducing tumor recurrences, treatment costs, number of radical cystectomies, and mortality. A promising therapeutic platform for cancer is offered by gold nanoparticles (GNP). Taking advantage of gold’s high biocompatibility, GNP can be injected intravenously and accumulate preferentially in cancer cells due to the enhanced permeability and retention effect. Among GNP platforms, gold nanostars (GNS) have great therapeutic potential due to the unique star-shaped geometry that dramatically enhances light absorption and effective conversion into heat due to the plasmonic effect. This photothermal process can be exploited to specifically ablate tumors and, importantly, to amplify the anti-tumor immune response following the highly immunogenic thermal death of cancer cells. Relatedly, many cancers exploit immune checkpoints – such as the interaction between programmed cell death 1 (PD-1) and its ligand (PD-L1) – to evade the anti- cancer immune response. Recent immunotherapies disabling this immune resistance mechanism have shown encouraging clinical results, are FDA approved in BC, but do not offer a permanent cure for most patients. We thus propose to develop the GNS technology for use in SYnergistic iMmuno PHOtothermal NanotherapY (SYMPHONY), a novel therapy that integrates nanotechnology, biophotonics, and immunotherapy. The central hypothesis of this proposal is that combining GNS-mediated photothermal nanotherapy with PD-1/PD-L1 immune checkpoint blockade will result in dramatic therapeutic synergism to treat cancer metastasis. The rationale for this hypothesis is that photothermal therapy not only reduces tumor burden by direct heat-based ablation, but also causes intense immune responses that can be amplified with PD-1/PD-L1 immune checkpoint blockade. The specific aims are: (1) Fabricate and modulate optical properties of next-generation plasmonics GNS to maximize photothermal therapy of deep tumors;; (2) Coat and functionalize GNS to safely improve in vivo BC targeting;; and (3) Evaluate effectiveness of SYMPHONY therapy for treating BC in murine models. The results of our research proposal intends to prove that nanoparticle therapy and immunotherapy can be synergistically combined to produce an antitumor systemic response far superior to either single therapy alone. We will also prove that SYMPHONY triggers an extremely potent systemic response that cures both primary and distant lesions, producing a ‘vaccine’ effect to prevent future BC recurrences. The proposed work will set the stage for SYMPHONY’s rapid future clinical translation to improve life quality and reduce mortality of BC patients.

膀胱癌 (BC) 是男性中第 4 位最常见的癌症，女性中第 11 位最常见的癌症。公元前在所有癌症中，每位患者的生命周期治疗成本最高，主要是因为其复发率高。此外，定期的侵入性膀胱镜检查和随后的复发手术治疗也会损害患者的质量生命并导致显着的发病率。因此，临床上显然需要新技术有效治疗乳腺癌，最终减少肿瘤复发、治疗费用、根治性膀胱切除术的数量，和死亡率。金纳米粒子 (GNP) 提供了一个有前景的癌症治疗平台。服用利用金的高生物相容性，GNP可以静脉注射并优先在体内蓄积由于增强的渗透性和滞留作用而对癌细胞产生影响。在 GNP 平台中，金纳米星 (GNS) 具有巨大的治疗潜力，因为其独特的星形几何形状可显着增强由于等离子体效应，光吸收并有效转化为热量。这种光热过程可以可用于专门消融肿瘤，并且重要的是，可增强随后的抗肿瘤免疫反应癌细胞的高度免疫原性热死亡。与此相关的是，许多癌症都会利用免疫检查点—— 例如程序性细胞死亡 1 (PD-1) 与其配体 (PD-L1) 之间的相互作用 – 以逃避抗- 癌症免疫反应。最近的免疫疗法已表明可以禁用这种免疫抵抗机制令人鼓舞的临床结果，已在 BC 省获得 FDA 批准，但不能为大多数患者提供永久治愈。因此，我们建议开发 GNS 技术用于协同免疫光热 NanotherapY（SYMPHONY）是一种集成了纳米技术、生物光子学和免疫疗法。该提案的中心假设是结合 GNS 介导的光热纳米疗法与 PD-1/PD-L1 免疫检查点阻断将产生显着的治疗协同作用治疗癌症转移。该假设的基本原理是光热疗法不仅可以减少肿瘤直接基于热的消融造成的负担，但也会引起强烈的免疫反应，这种反应可以通过以下方法放大： PD-1/PD-L1 免疫检查点阻断。具体目标是：(1) 制造和调制光学特性下一代等离子体 GNS，以最大限度地提高深部肿瘤的光热疗法；；(2) 涂层和使 GNS 功能化，以安全地改善体内 BC 靶向；；以及 (3) 评估 SYMPHONY 的有效性在小鼠模型中治疗 BC 的疗法。我们的研究计划的结果旨在证明纳米颗粒疗法和免疫疗法可以协同组合以产生全身性抗肿瘤反应远远优于单独的单一疗法。我们还将证明 SYMPHONY 会引发极端的后果有效的全身反应，可治愈原发性病变和远处病变，产生“疫苗”效应以预防 BC 未来的复发。拟议的工作将为 SYMPHONY 未来快速临床转化奠定基础提高 BC 患者的生活质量并降低死亡率。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Accurate in vivo tumor detection using plasmonic-enhanced shifted-excitation Raman difference spectroscopy (SERDS).

DOI：
10.7150/thno.53101
发表时间：
2021
期刊：
Theranostics
影响因子：
12.4
作者：
Strobbia P;Cupil-Garcia V;Crawford BM;Fales AM;Pfefer TJ;Liu Y;Maiwald M;Sumpf B;Vo-Dinh T
通讯作者：
Vo-Dinh T

Intravital optical imaging for immune cell tracking after photoimmunotherapy with plasmonic gold nanostars.