Disease-homing light delivery by engineering bioluminescent immune cells for whole body precision photomedicine

通过工程生物发光免疫细胞进行疾病引导光传输，用于全身精准光医学

基本信息

批准号：
10578425
负责人：
Bryan Quilty Spring
金额：
$ 23.64万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-03 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578425
关键词：
3-Dimensional Abdomen Adoption Antibodies Antigens Apoptotic Area Biological Markers Bioluminescence Calibration Cancer Model Carcinoma Carcinomatosis Cell Culture Techniques Cell Death Cell Line Cell Therapy Cells Cetuximab Chemicals Chemoresistance Chemotaxis Clinic Clinical Trials Coculture Techniques Collaborations Combined Modality Therapy Complex Creativeness Cytoplasm Deposition Development Diffuse Disease Disease model Disseminated Malignant Neoplasm Dose Dose Limiting Drug Delivery Systems Drug resistance pathway Engineering Ensure Enzymes Esophagus Exhibits Fiber Optics Flow Cytometry Fluorescence Microscopy Funding Future Generations Genetic Engineering Goals Homing Human Immune Immune system Immunologic Surveillance In Vitro Infusion procedures Injections Kidney Lasers Lesion Light Liver Macrophage Malignant Neoplasms Mediating Methods Modeling Monitor Monte Carlo Method Mus Nature Neoplasm Metastasis Outcome Output PUVA Photochemotherapy Pathway interactions Patients Penetration Peritoneal Pharmaceutical Preparations Pharmacologic Substance Phenotype Photons Photosensitizing Agents Phototherapy Production Property Prostate Proteins Protocols documentation Research Semiconductors Shock Singlet Oxygen Site Skin Source Superficial Lesion T cell therapy T-Lymphocyte Technology Testing Therapeutic Therapeutic Index Tissues Toxic effect Translations Treatment Efficacy Tumor-infiltrating immune cells Universities Verteporfin Xenograft Model Xenograft procedure bioluminescence imaging cancer cell cancer type cellular engineering chemotherapy clinical translation clinically relevant combat comorbidity cost effective cytotoxic delivery vehicle design dosimetry efficacy study experimental study genetically modified cells high reward high risk in vivo innovation intraperitoneal intravenous injection irradiation mouse model nano nanoparticle nanoparticle delivery novel novel therapeutics optical fiber photoactivation photoimmunotherapy photonics programs recruit refractory cancer safety study side effect simulation subcutaneous synergism tumor tumor specificity

项目摘要

PROJECT SUMMARY Photodynamic therapy (PDT) offers unique mechanisms of cell death and is used to treat many cancers in the clinic. The principal of phototherapy is that photoactive chemicals delivered to the disease site convert incident photonic energy into local chemical toxicity, avoiding a systemic shock. PDT is agnostic to classical drug- resistance pathways and does not cause critical co-morbidities, making it attractive as a monotherapy or as a component of multi-modal therapy. However, a major criticism of PDT is the need for an external light source, which limits the application of PDT to superficial lesions or those accessible by fiber optics. To overcome this, a paradigm shift in the mechanism of light delivery for PDT has recently emerged: bioluminescence (BL) mediated PDT (BL-PDT), wherein BL enzymes activate spectrally matched, co-localized photosensitizers (PS) within the lesion, eliminating the need for an external light source. Although this overcomes a major hurdle, current methods that leverage semiconductor nanoconstructs for BL enzyme delivery are limited in their ability to localize to the disease. Here, we propose a novel method for BL enzyme delivery and BL-PDT: to genetically engineer ultra-bright bioluminescent immune cells (UBLIs) and exploit their disease-homing capabilities, like chemotaxis, to traffic to and accumulate in sites of disease. This approach eliminates the need for complex and potentially toxic nanoconstructs as a component of drug delivery—only the BL substrate and PS administration (both non-toxic compounds) will be required. Recently, we introduced precision photomedicine using a targeted, activatable PS that exhibited cellular selectivity and reduced off-target toxicity in a metastatic cancer model. We will pair the proposed novel light delivery platform with precision photomedicine for maximal benefit. First, we will optimize the BL-PDT platform in 3D cancer–immune cell co- cultures across biologically and clinically relevant parameter spaces informed by Monte Carlo simulations. Then we will demonstrate the approach in vivo by intravenous injection of UBLIs into an in vivo xenograft model of cancer metastases informed by in vitro results. These proof-of-concept studies will enable comprehensive safety and efficacy studies in multiple disease models in future funding periods. Ultimately, we envision clinical translation involving extraction and engineering of patient immune cells, similar to chimeric antigen redirected (CAR) T cell therapy, followed by reinfusion and administration of photomedicine. This new therapeutic paradigm has potential to benefit many diseases in cancer and beyond, which justifies the high- risk, high-reward nature of the proposal.

项目概要光动力疗法 (PDT) 提供独特的细胞死亡机制，用于治疗多种癌症诊所光疗的原理是将光活性化学物质输送到疾病部位以转化事件。光子能量转化为局部化学毒性，避免了全身性休克，这与传统药物无关。耐药途径并且不会引起严重的合并症，使其作为单一疗法或作为一种有吸引力的疗法然而，PDT 的一个主要批评是需要外部光源。这限制了 PDT 应用于浅表病变或可通过光纤到达的病变。最近出现了 PDT 光传输机制的范式转变：生物发光 (BL) 介导的 PDT (BL-PDT)，因此 BL 酶激活光谱匹配的共定位光敏剂 (PS) 尽管这克服了一个主要障碍，目前利用半导体纳米结构进行 BL 酶传递的方法的能力有限在这里，我们提出了一种 BL 酶递送和 BL-PDT 的新方法：对超亮生物发光免疫细胞 (UBLI) 进行基因改造并利用其疾病归巢这种方法消除了需要，例如趋化性，以在疾病部位积累。对于复杂且具有潜在毒性的纳米结构作为药物输送的组成部分——仅 BL 底物和最近，我们引入了精确性，需要 PS 管理（均为无毒化合物）。使用具有细胞选择性和降低脱靶毒性的靶向、可激活 PS 进行光医学我们将在转移性癌症模型中将所提出的新型光传输平台与精确配对。首先，我们将优化 3D 癌症-免疫细胞协同治疗中的 BL-PDT 平台。通过蒙特卡罗模拟了解生物学和临床相关参数空间的文化。然后我们将通过将 UBLI 静脉注射到体内异种移植物中来演示该方法这些概念验证研究将使癌症转移模型成为可能。最终，我们在未来的资助期内对多种疾病模型进行全面的安全性和有效性研究。设想临床转化涉及患者免疫细胞的提取和改造，类似于嵌合体抗原重定向（CAR）T 细胞疗法，然后进行回输和光药物治疗。该治疗模式有可能使癌症及其他疾病的许多疾病受益，这证明了高该提案具有风险、高回报的性质。