Biomaterials for treatment of head and neck cancer

描述（由申请人提供）：当细胞毒性药物优先杀死癌细胞，或与其他组织相比，这些药物优先在肿瘤中积累时，化疗是成功的。然而，这两种情况都不适用于去年被诊断为头颈部鳞状细胞癌（HNSCC）的52000名美国人。HNSCC起源于头颈部粘膜组织，但它迅速转移到整个颈部淋巴系统，这是一个令人望而生畏的临床挑战。用于治疗HNSCC的细胞毒性抗癌药物对淋巴的渗透性很差，如果治疗不当，高达70%的HNSCC患者会复发。本研究的主要目的是研究一种用于头颈部组织化疗的新型高分子生物材料的合成、开发和生物学评价。这种创新的方法将比任何现有的治疗方法表现得更好，因为化疗是直接输送到易发组织中，因此脆弱的器官不会受到损害，这是通过第一个专门设计的纳米颗粒系统来实现的，该系统用于在肿瘤周围注射后将特殊的药物输送到癌性淋巴结和组织中。这种新的生物材料，星形纳米偶联物，可以靶向HNSCC肿瘤，而不需要昂贵且不那么强大的配体，如抗体或适体。第一个目标是合成化疗药物的星形纳米偶联物库，包括标准治疗药物，与现有药物协同作用的新型一氧化氮药物，以及第一个光动力一氧化氮治疗药物。星形纳米缀合物是合成的糖基星形聚合物，当与普通抗癌药物缀合时，它们会坍塌成紧凑的纳米级载体。由此产生的纳米偶联物的物理化学性质可以被合成为优异的淋巴吸收和保留、肿瘤穿透和肿瘤周围淋巴管内持续的药物释放。在第二个目标中，在局部注射后，对啮齿动物的纳米缀合物和药物的荧光成像和放射学跟踪将证明化疗对HNSCC肿瘤的优越递送。随后，自发性口腔鳞状细胞癌（SCC）犬的PET/CT成像将在更接近人类的模型中验证该平台的性能。第三，将星形纳米偶联物治疗HNSCC的有效性和安全性与常规化疗在啮齿动物异种移植HNSCC中的效果进行比较。第四，一项针对自发性口腔鳞状细胞癌患者的I期犬试验将在大型动物模型中证明其有效性和安全性。在这项研究结束时，将有证据表明，这种治疗方法在安全性和有效性方面都优于目前的化疗方法，因为这种动物的疾病与人类HNSCC非常相似。基于对啮齿动物和犬类的广泛初步结果，该平台预计将显著影响人类健康，减少对广泛手术和放疗（导致永久性毁容和降低生活质量的治疗）的需求，并提供一种比全身化疗更安全的替代方案，甚至可用于严重虚弱和晚期患者。

DESCRIPTION (provided by applicant): Chemotherapy with cytotoxic drugs is successful when these drugs either preferentially kill cancer cells, or preferentially accumulate in tumors compared to other tissues. Yet, neither case holds true for the 52,000 Americans diagnosed last year with head and neck squamous cell carcinoma (HNSCC). HNSCC originates in the mucosal tissues of the head and neck, but it rapidly metastases throughout the cervical lymphatics, which presents a daunting clinical challenge. The cytotoxic anti-cancer drugs used to treat HNSCC have very poor penetration into these lymphatics, and left undertreated the HNSCC will relapse in up to 70% of patients. The primary objective of this work is the synthetic development and biological evaluation of a new polymeric biomaterial for chemotherapy of the head and neck tissues. This innovative approach will perform better than any existing therapy because chemotherapy is delivered directly into prone tissues so delicate organs are not damaged, and this is accomplished with the first nanoparticle system specifically engineered for exceptional drug delivery into cancerous lymph nodes and tissues after peri-tumoral injection. The new biomaterial, star nanoconjugates, can be targeted to HNSCC tumors without expensive and less robust homing ligands, such as antibodies or aptamers. The first aim is to synthesize a library of star nanoconjugates of chemotherapeutics, including both standard-of-care drugs, new nitric oxide-based drugs that synergize with existing drugs, and the first photodynamic nitric oxide treatment. The star nanoconjugates are synthetic sugar-based star polymers that collapse into compact nanoscopic carriers when conjugated to common anticancer drugs. The physiochemical properties of the resulting nanoconjugates can be synthetically tailored for excellent lymphatic uptake and retention, tumor penetration, and sustained drug release within the lymphatics surrounding tumors. In the second aim, fluorescent imaging and radiological tracking of the nanoconjugates and drugs in rodents after locoregional injection will demonstrate the superior delivery of chemotherapy into HNSCC tumors. Subsequently, PET/CT imaging of canines with spontaneous oral squamous cell carcinoma (SCC) will verify performance of this platform in a more man-like model. Third, the efficacy and safety of HNSCC treatment with star nanoconjugates will be compared to conventional chemotherapy in rodent xenografts of HNSCC. Fourth, a Phase I canine trial in patients with spontaneous oral SCC cancer will demonstrate efficacy and safety in a large animal model. At the end of this study, there will be proof in a large animal, whose disease closely models human HNSCC, that this treatment is both superior in safety and more efficacious than current chemotherapies. Based on extensive preliminary results in rodents and canines, this platform is expected to significantly impact human health by reducing the need for extensive surgery and radiotherapy, treatments that cause permanent disfigurement and reduce quality-of-life, and provide a much safer alternative to systemic chemotherapy that can be administered to even severely weaken and advanced patients.