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.

项目摘要光动力疗法（PDT）提供了细胞死亡的独特机制，用于治疗许多癌症诊所。光疗的主席是传递到疾病现场转换事件的光活性化学物质光子能量到局部化学毒性，避免全身性休克。 PDT对经典药物不可知 - 阻力途径，不会引起关键的合并症，使其作为单一疗法或作为一种多模式疗法的成分。但是，PDT的主要关键是需要外部光源，这限制了PDT应用于表面病变或光纤可通过光学损伤的应用。为了克服这一点，最近出现了PDT光传递机理的范式转移：生物发光（BL）介导的PDT（BL-PDT），其中BL酶激活了频谱匹配的共定位光敏剂（PS）在病变中，消除了对外部光源的需求。尽管这克服了一个重大障碍，但当前利用半导体纳米构造进行BL酶输送的方法有限要定位于疾病。在这里，我们提出了一种新颖的方法，用于BL酶输送和BL-PDT：遗传工程师超光彩的生物发光免疫池（UBLIS）并利用其疾病的疾病像趋化性一样的能力，可以在疾病部位访问和积累。这种方法消除了需求对于复杂且潜在的有毒纳米结构作为药物输送的组成部分 - 仅BL底物和 PS给药（两种无毒化合物）将需要。最近，我们介绍了精度使用靶向的，可激活的PS的光学医学，该PS暴露了细胞选择性并降低了靶向毒性在转移性癌症模型中。我们将精确地将拟议的新型轻型递送平台与摄影医学可获得最大收益。首先，我们将优化3D癌 - 免疫细胞中的BL-PDT平台通过蒙特卡洛模拟告知的生物学和临床相关参数空间的培养。然后，我们将通过将UBLIS静脉注射到体内特种谱系中来证明体内的方法癌症转移的模型以体外结果告知。这些概念验证研究将使未来资助期间多种疾病模型中的全面安全和效率研究。最终，我们设想涉及患者免疫细胞提取和工程的临床翻译，类似于嵌合抗原重定向（CAR）T细胞疗法，然后再灌注和给予光学医学。这个新治疗范式有可能使许多癌症及其他疾病受益，这证明了高级疾病风险，提案的高回报。