Biomaterials for treatment of head and neck cancer

描述（由申请人提供）：当这些药物优先杀死癌细胞或与其他组织相比优先在肿瘤中蓄积时，使用细胞毒性药物的化疗是成功的。然而，这两种情况都不适用于去年被诊断患有头颈部鳞状细胞癌（HNSCC）的52，000名美国人。HNSCC起源于头颈部的粘膜组织，但它迅速转移到整个宫颈系统，这给临床带来了巨大的挑战。用于治疗HNSCC的细胞毒性抗癌药物对这些细胞的渗透性非常差，并且治疗不足的HNSCC将在高达70%的患者中复发。这项工作的主要目标是一种新的聚合物生物材料的合成开发和生物学评价的头部和颈部组织的化疗。这种创新的方法将比任何现有的治疗方法都更好，因为化疗被直接输送到易感组织中，因此脆弱的器官不会受损，并且这是通过第一个专门设计用于在肿瘤周围注射后将药物输送到癌性淋巴结和组织中的纳米颗粒系统来实现的。这种新的生物材料，星星纳米复合物，可以靶向HNSCC肿瘤，而不需要昂贵和不太强大的归巢配体，如抗体或适体。第一个目标是合成一个化疗药物的星星纳米缀合物库，包括标准治疗药物、与现有药物协同作用的新的基于一氧化氮的药物以及第一种光动力一氧化氮治疗。星星纳米复合物是合成的糖基星星聚合物，当与普通抗癌药物结合时，它会塌陷成紧凑的纳米级载体。所得纳米缀合物的生理化学性质可以被合成地定制用于优异的淋巴吸收和保留、肿瘤渗透和肿瘤周围的淋巴内的持续药物释放。在第二个目标中，在啮齿动物中局部注射后纳米缀合物和药物的荧光成像和放射学追踪将证明化疗向HNSCC肿瘤中的上级递送。随后，患有自发性口腔鳞状细胞癌（SCC）的犬的PET/CT成像将在更类似人类的模型中验证该平台的性能。第三，在啮齿动物异种移植的HNSCC中，将用星星纳米缀合物治疗HNSCC的功效和安全性与常规化学疗法进行比较。第四，在自发性口腔SCC癌患者中进行的I期犬试验将在大型动物模型中证明疗效和安全性。在本研究结束时，将在一只疾病与人类HNSCC密切相关的大型动物中证明这种治疗在安全性和有效性方面均上级目前的化疗。基于啮齿动物和犬科动物的广泛初步结果，该平台预计将通过减少对广泛手术和放射治疗的需求来显著影响人类健康，这些治疗会导致永久性毁容并降低生活质量，并为全身化疗提供更安全的替代方案，甚至可以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.