Molecular imaging-directed bioengineering of nanoconjugates as adaptable tumor targeting platforms

分子成像引导的纳米缀合物生物工程作为适应性肿瘤靶向平台

• 批准号: 10177878
• 负责人: Girgis Obaid
• 金额: $ 24.44万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-12 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177878
• 关键词: Affinity; Alanine; Anatomy; Antibody-drug conjugates; Attenuated; Binding; Binding Sites; Biodistribution; Biomedical Engineering; Carboplatin; Cells; Cetuximab; Chemicals; Chemistry; Complement; Complex; Custom; Disease; Drug Carriers; Drug Kinetics; ERBB2 gene; Engineering; Environment; Epidermal Growth Factor Receptor; Equilibrium; Esthetics; Event; Failure; Functional disorder; Future; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human; Image; In Vitro; Infrastructure; Ligands; Light; Liposomes; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Mentors; Mentorship; Methodology; Modality; Modeling; Molecular; Molecular Target; Mus; Mutagenesis; Nanoconjugate; Nanotechnology; Operative Surgical Procedures; Otolaryngologist; Outcome; PUVA Photochemotherapy; Penetration; Permeability; Phase; Photosensitizing Agents; Phototherapy; Physiology; Platinum; Protein Engineering; Radiation therapy; Recombinants; Research; Scanning; Seeds; Specialist; Specificity; Spectrum Analysis; Surface; Surface Plasmon Resonance; Tracer; Training; Trastuzumab; Treatment Efficacy; Treatment outcome; Tumor Biology; anti-cancer; attenuation; base; cancer cell; cellular targeting; cohesion; cytotoxicity; density; design; fluorescence imaging; improved; improved outcome; in vivo; innovation; insight; member; molecular imaging; nanomedicine; nanoparticle; nanoparticle drug; nanoscience; nanotechnology platform; nanotherapeutic; novel; preservation; primary endpoint; programs; receptor; response; spatiotemporal; success; synergism; targeted treatment; treatment response; tumor; tumor heterogeneity; tumor microenvironment; uptake

PROJECT SUMMARY Through cohesive advancements in protein engineering, bioconjugation chemistry and sophisticated nanotechnology, innovations in targeted nanotherapeutics have made significant progress in increasing the specificity of anticancer nanomedicines. However, as a consequence of the complexity of modular targeted nanoconjugates (TNCs), in vivo selectivity, and subsequent treatment outcomes, frequently suffer setbacks. The capacity to accurately resolve intratumoral molecular and cellular selectivity of TNCs in vivo is oftentimes thwarted by dominant macrophysiological factors. Such factors include macro-scale quantification of TNC tumor delivery, which provides little insight into micro-scale cancer cell-specific molecular binding events and internalization of TNCs present within the interstitium. Additional factors include variable pharmacokinetics of non-selective nanoconjugate controls, and unparalleled physiologies of target-null tumors; both which hamper the accurate experimental comparisons needed to evaluate novel TNCs. To this end, Dual-Tracer Fluorescence Imaging (DT-FI) will be deployed, which provides accurate in vivo quantitation of tumor target molecular binding of TNCs via a Binding Potential metric, a combined measure of binding affinity and respective tumor target receptor concentration. Head and neck squamous cell carcinoma (HNSCC) is debilitating and manifests at critical anatomical sites, requiring highly selective treatments to preserve function and aesthetics. Aside from indiscriminate surgery, chemo- and radiotherapy, confined spatiotemporal control of cytotoxicity of HNSCC can be imparted by photodynamic therapy (PDT), a promising modality used to manage cancers by the light-activation of photosensitizer (PS) agents. In an effort to improve the cellular selectivity of HNSCC therapy, PS-embedded, chemo-loaded liposomes will be employed in this proposal as a model nanoplatform to surface-graft engineered recombinant targeting moieties. DT-FI will be leveraged as a critical means of directing the engineering of the photoactive TNCs to improve outcomes of PDT-based treatments in HNSCC. To guide Dr. Obaid's transition to independence, a mentoring committee has been assembled to complement his training in chemical nanoscience. Mentorship by Dr. Tayyaba Hasan will train Dr. Obaid on PDT-based cancer nanomedicines and tumor biology response. Co-mentorship by Dr. Brian Pogue will train Dr. Obaid in quantitative in vivo DT-FI. Additional distinguished members include Dr. Brian Seed, a specialist in protein engineering, Dr. Andrew Tsourkas, a nanoconjugation expert, Dr. Eben Rosenthal, Otolaryngologist and pioneer in HNSCC imaging, and Dr. William Faquin, a HNSCC pathophysiology expert. As a well-defined and distinct transition to independence, the infrastructure established in the mentored phase will be adapted to the engineering of multi-specific photo-chemotherapeutic nanoplatforms tailored for in vivo heterogeneity of HNSCC models. The approach established in this K99/R00 mechanism will enable future designs of various TNCs, as directed by in vivo DT-FI, with the capacity for targeting dynamic disease-specific molecular targets.

项目总结 通过在蛋白质工程、生物偶联化学和尖端技术方面的凝聚进步 在纳米技术方面，靶向纳米疗法的创新在增加 抗癌纳米药物的特异性。然而，由于模块化目标的复杂性， 纳米结合物(TNCs)、体内选择性和随后的治疗结果经常受挫。 在活体内准确分辨肿瘤内跨国公司分子和细胞选择性的能力往往是 被占主导地位的宏观生理因素所阻碍。这些因素包括跨国公司的宏观量化 肿瘤递送，这几乎没有提供对微尺度癌细胞特异性分子结合事件的洞察和 组织内存在的跨国公司的内部化。其他因素包括可变的药代动力学 非选择性纳米结合对照，以及靶标缺失肿瘤的无与伦比的生理学；两者都阻碍了 评估新型跨国公司所需的准确的实验比较。为此，双追踪器 将部署荧光成像(DT-FI)，提供准确的体内肿瘤靶点定量 通过结合潜力指标、结合亲和力和 相应的肿瘤靶标受体浓度。头颈部鳞状细胞癌是 在关键的解剖部位出现虚弱和表现，需要高度选择性的治疗才能保留功能 和审美观。除了不分青红皂白的手术、化疗和放射治疗，有限的时空控制 HNSCC的细胞毒性可以通过光动力疗法(PDT)来传递，光动力疗法是一种有前途的治疗方法 通过光敏剂(PS)的光激活而致癌。在努力提高细胞选择性的同时 HNSCC治疗，PS包埋，化学负载的脂质体将在本方案中用作模型 纳米平台表面接枝工程重组靶向部分。DT-FI将被用作关键的 指导光活性跨国公司的工程以改善基于光动力疗法的治疗结果的方法 HNSCC。为了指导奥贝德博士向独立的过渡，已经成立了一个指导委员会来 补充他在化学纳米科学方面的训练。塔亚巴·哈桑博士的指导将对奥贝德博士进行培训 基于光动力疗法的肿瘤纳米药物与肿瘤生物学反应。布莱恩·波格博士的共同导师将进行培训 奥贝德博士在体内定量DT-FI。其他杰出的成员包括布莱恩·塞德博士，一位 蛋白质工程，纳米连接专家安德鲁·图尔卡斯博士，耳鼻咽喉科医生埃本·罗森塔尔 和HNSCC成像的先驱，以及HNSCC病理生理学专家William Faquin博士。作为一个定义明确的 和明显的向独立的过渡，在指导阶段建立的基础设施将适应 为体内异质性定制的多特异性光化学治疗纳米平台的工程 HNSCC型号。在K99/R00机制中建立的方法将使各种不同的未来设计 由体内DT-FI指导的跨国公司，具有靶向动态疾病特异性分子靶点的能力。