Targeting Fluid Stress-induced Chemoresistance in a 3D Carcinomatosis Perfusion Model Using Mechanism-based Photo-immunoconjugate Nanoparticles

使用基于机制的光免疫缀合物纳米颗粒在 3D 癌病灌注模型中靶向流体应激诱导的化疗耐药性

• 批准号: 10587481
• 负责人: Huang Chiao Huang
• 金额: $ 56.54万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-12 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587481
• 关键词: 3-Dimensional; Abdomen; Abscopal effect; Address; Adhesions; Animal Model; Animals; Antibody Activation; Artificial nanoparticles; Ascites; Biodistribution; Biometry; Cancer Biology; Cancer Patient; Carboplatin; Carcinomatosis; Cause of Death; Cell Death; Cell Line; Cell physiology; Cells; Characteristics; Chemoresistance; Chemosensitization; Cisplatin; Clinic; Clinical; Cytoskeleton; DNA; Development; Diffuse; Disease Resistance; Dose; Drug Kinetics; Effectiveness; Engineering; Epidermal Growth Factor Receptor; Female Genital Neoplasms; Goals; Greater sac of peritoneum; Gynecologic Oncology; Image; Immune; Immune mediated destruction; Immunocompetent; Immunoconjugates; Knowledge; Leadership; Light; Liquid substance; Malignant Neoplasms; Malignant neoplasm of ovary; Mitochondria; Modeling; Modification; Molecular; Molecular Profiling; Monitor; Mus; Nanotechnology; Neoplasm Metastasis; Nodule; Operative Surgical Procedures; Optics; Outcome; Ovarian; Pathway interactions; Patients; Perfusion; Peritoneal; Peritoneal Fluid; Pharmaceutical Preparations; Phenotype; Photosensitizing Agents; Physiological; Platinum; Platinum Compounds; Play; Proliferating; Recurrence; Regimen; Research; Residual state; Resistance; Role; Route; Safety; Signal Transduction; Stress; Surface; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Tumor Burden; Tumor Debulking; Tumor Immunity; Tumor-associated macrophages; Xenograft procedure; anti-tumor immune response; cancer cell; cancer therapy; cancer type; chemotherapy; density; design; dosimetry; fluorescence imaging; image guided; image-guided drug delivery; immunogenic cell death; immunoregulation; improved; in vivo; individual patient; insight; intraperitoneal; light dosimetry; malignant ascites; migration; mouse model; multidisciplinary; nano; nanoparticle; nanoscale; nanotechnology platform; ovarian neoplasm; patient derived xenograft model; patient prognosis; photoimmunotherapy; receptor; response; safety assessment; shear stress; standard care; targeted biomarker; targeted delivery; targeted treatment; taxane; three-dimensional modeling; tumor; tumor immunology; uptake; 3-Dimensional; Abdomen; Abscopal effect; Address; Adhesions; Animal Model; Animals; Antibody Activation; Artificial nanoparticles; Ascites; Biodistribution; Biometry; Cancer Biology; Cancer Patient; Carboplatin; Carcinomatosis; Cause of Death; Cell Death; Cell Line; Cell physiology; Cells; Characteristics; Chemoresistance; Chemosensitization; Cisplatin; Clinic; Clinical; Cytoskeleton; DNA; Development; Diffuse; Disease Resistance; Dose; Drug Kinetics; Effectiveness; Engineering; Epidermal Growth Factor Receptor; Female Genital Neoplasms; Goals; Greater sac of peritoneum; Gynecologic Oncology; Image; Immune; Immune mediated destruction; Immunocompetent; Immunoconjugates; Knowledge; Leadership; Light; Liquid substance; Malignant Neoplasms; Malignant neoplasm of ovary; Mitochondria; Modeling; Modification; Molecular; Molecular Profiling; Monitor; Mus; Nanotechnology; Neoplasm Metastasis; Nodule; Operative Surgical Procedures; Optics; Outcome; Ovarian; Pathway interactions; Patients; Perfusion; Peritoneal; Peritoneal Fluid; Pharmaceutical Preparations; Phenotype; Photosensitizing Agents; Physiological; Platinum; Platinum Compounds; Play; Proliferating; Recurrence; Regimen; Research; Residual state; Resistance; Role; Route; Safety; Signal Transduction; Stress; Surface; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Tumor Burden; Tumor Debulking; Tumor Immunity; Tumor-associated macrophages; Xenograft procedure; anti-tumor immune response; cancer cell; cancer therapy; cancer type; chemotherapy; density; design; dosimetry; fluorescence imaging; image guided; image-guided drug delivery; immunogenic cell death; immunoregulation; improved; in vivo; individual patient; insight; intraperitoneal; light dosimetry; malignant ascites; migration; mouse model; multidisciplinary; nano; nanoparticle; nanoscale; nanotechnology platform; ovarian neoplasm; patient derived xenograft model; patient prognosis; photoimmunotherapy; receptor; response; safety assessment; shear stress; standard care; targeted biomarker; targeted delivery; targeted treatment; taxane; three-dimensional modeling; tumor; tumor immunology; uptake

ABSTRACT The prognosis for patients with advanced stage and recurrent ovarian cancer has remained dismal for decades. The poor response rates result in part from resistance to chemotherapy, particularly platinum- and taxane-based agents. Ovarian cancer often metastasizes via transcoelomic routes along currents of ascitic fluid in the peritoneal cavity. We have engineered a 3D adherent perfusion model to mimic ovarian nodules that stud peritoneal surfaces and recapitulate resistant disease, thereby providing a unique platform to develop targeted therapies. Our studies showed that physiologically relevant fluid shear stress (FSS) induces a pro- metastatic phenotype and confers resistance to platinum agents. Photoimmunotherapy (PIT) has shown promise in selectively imaging and treating disseminated tumors, and it can resensitize chemoresistant cancer cells to platinum agents. However, the high thresholds of intracellular photoimmunoconjugate required for cell death have hindered the effectiveness of PIT in physiologically relevant models. Therefore, the main goal of this proposal is to develop a multi-purpose nanoplatform that breaks the selectivity-uptake trade-off of photoimmunoconjugates and enables multi-tier cancer targeting under peritoneal FSS. We have recently shown that successful conjugation of photoimmunoconjugates onto nanoparticles can effectively enhance intratumoral photoimmunoconjugate delivery and improve PIT outcomes in mice. We hypothesize that nanoscale engineering enables high-payload co-delivery of photoimmunoconjugate and chemotherapy in a manner that is safe and efficacious in overcoming FSS-induced chemoresistance. This approach will significantly enhance the therapeutic index of platinum agents for ovarian cancer patients. In Aim 1, a panel of photoimmunoconjugate-nanoconstructs (PICNC) will be developed to target biomarkers altered by FSS in a 3D perfusion model of ovarian cancer. In Aim 2, we will assess the effects on chemosensitization, T cell sparing, and destruction of immune supporting tumor-associated macrophages following PICNC-PIT under FSS in 3D perfusion models. In Aim 3, to improve the safety and consistency of the treatment, we will develop image- guided strategies to inform the timing and dosing of PICNC-PIT in mouse models. In Aim 4, the anti-tumor efficacy of PICNC-PIT will be evaluated in cell line-based syngeneic (immunocompetent) and xenograft mouse models, as well as PDX models, for ovarian cancer. The PIs envision a simple and feasible modification to the standard treatment framework, where PICNC will be delivered intraperitoneally after surgical debulking, and activated by light, triggering PIT and releasing chemotherapy. The knowledge gained could play a transformative role in the development of improved therapeutic regimens tailored to the molecular profile of disseminated tumors in individual patients. To accomplish these aims, we will deploy our multi-disciplinary team of nanoparticle engineering, 3D tumor perfusion model, cancer biology, tumor immunology, biostatistics, and gynecologic oncology experts to examine the impact of our technology on ovarian cancer treatment.

抽象的 晚期和复发性卵巢癌患者的预后仍然令人沮丧 几十年。反应率较差，部分原因是从耐药到化学疗法，尤其是铂和 基于紫杉烷的代理。卵巢癌通常通过沿腹电流的转换路线转移 腹膜腔中的液体。我们已经设计了一个3D辅助灌注模型，以模仿卵巢结节 该螺柱腹膜表面并概括了抗性疾病，从而提供了一个独特的平台来发展 靶向疗法。我们的研究表明，与生理相关的液体剪应力（FSS）引起了促进 转移表型并赋予对铂剂的抗性。摄影（PIT）已显示 有选择性成像和治疗散布的肿瘤的承诺，并且可以使化学抗性癌症敏感 细胞到铂剂。然而，细胞内需要的细胞内摄影剂的高阈值是细胞所需的 死亡阻碍了PIT在生理相关模型中的有效性。因此，主要目标 该建议是开发一种多功能纳米板，打破了选择性摄取权衡的权衡 在腹膜FSS下，摄影节二轭并实现了多层癌的靶向。我们最近有 表明，成功的摄影偶联物在纳米颗粒上的成功结合可以有效地增强 肿瘤内摄影偶联物的递送并改善小鼠的凹坑结局。我们假设这一点 纳米级工程可以使高付额的摄影和化学疗法的高付费共同递送 在克服FSS诱导的化学抗性方面安全有效的方式。这种方法会 显着增强了卵巢癌患者铂药的治疗指数。在AIM 1中，一个面板 将开发摄影膜缀合物 - 纳米结构（PITNC），以靶向3D中FSS改变的生物标志物 卵巢癌的灌注模型。在AIM 2中，我们将评估对化学敏化，T细胞保留的影响， 在3D中的FSS下，在PITNC-PIT之后，在picnc-pit之后遭​​到免疫支持的免疫销毁 灌注模型。在AIM 3中，为了提高治疗的安全性和一致性，我们将发展形象 - 指导策略，以告知鼠标模型中PITNC-PIT的时间和剂量。在AIM 4中，抗肿瘤 PICNC-PIT的疗效将在基于细胞系的合成元（免疫能力）和异种移植小鼠中评估 用于卵巢癌的模型以及PDX模型。 PIS设想了对 标准治疗框架，在手术剪裁后将腹膜内picnc腹膜内交付，并且 被光激活，触发坑并释放化学疗法。获得的知识可以发挥 在改善根据分子特征的改善治疗方案的发展中的变革作用 在个别患者中传播肿瘤。为了实现这些目标，我们将部署我们的多学科 纳米颗粒工程团队，3D肿瘤灌注模型，癌症生物学，肿瘤免疫学，生物统计学， 以及妇科肿瘤学专家研究我们技术对卵巢癌治疗的影响。