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

项目摘要 通过在蛋白质工程、生物结合化学和复杂的 随着纳米技术的发展，靶向纳米治疗的创新在增加 抗癌纳米药物的特异性。然而，由于模块化目标的复杂性， 纳米缀合物（TNCs）、体内选择性和随后的治疗结果经常遭受挫折。 准确分辨体内肿瘤内TNCs的分子和细胞选择性的能力通常是 受到宏观生理因素的阻碍。这些因素包括跨国公司的宏观规模量化 肿瘤递送，其提供了对微尺度癌细胞特异性分子结合事件的很少了解， 跨国公司的内在化存在于企业内部。其他因素包括不同的药代动力学 非选择性纳米缀合物对照，以及靶向无效肿瘤的无与伦比的生理学;这两者都阻碍了 评估新型跨国公司所需的精确实验比较。为此，Dual-Tracer 将部署荧光成像（DT-FI），可提供肿瘤靶点的准确体内定量 通过结合势度量，结合亲和力和结合强度的组合测量， 相应的肿瘤靶受体浓度。头颈部鳞状细胞癌（HNSCC）是 使人衰弱，并在关键解剖部位出现，需要高度选择性治疗以保留功能 和美学。除了不加选择的手术、化疗和放疗， HNSCC的细胞毒性可以通过光动力疗法（PDT）来赋予，光动力疗法是一种用于管理HNSCC的有前途的方式。 通过光敏剂（PS）的光活化来治疗癌症。为了提高细胞的选择性， HNSCC治疗，PS包埋的，化学负载的脂质体将在本提案中作为模型使用 纳米平台与表面接枝工程化的重组靶向部分。DT-FI将作为关键的 指导光活性跨国公司的工程设计以改善基于PDT的治疗结果的手段， HNSCC。为了指导奥贝德博士向独立过渡，组建了一个指导委员会， 补充了他在纳米化学方面的训练Tayyaba Hasan博士的指导将培训Obaid博士 基于PDT的癌症纳米药物和肿瘤生物学反应。Brian Pogue博士的共同指导将培训 博士Obaid体内定量DT-FI。其他杰出成员包括布赖恩种子博士，专家在 蛋白质工程，Andrew Tsourkas博士，纳米结合专家，Eben Rosenthal博士，耳鼻喉科医生 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 和向独立的明显过渡，在指导阶段建立的基础设施将进行调整， 多特异性光化学治疗纳米平台的工程设计， HNSCC模型。在K99/R 00机制中建立的方法将使未来的各种 在体内DT-FI的指导下，具有靶向动态疾病特异性分子靶点的能力的跨国公司。

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.