Biomaterials for treatment of head and neck cancer

用于治疗头颈癌的生物材料

• 批准号: 9022438
• 负责人: Marcus Laird Forrest
• 金额: $ 28.46万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9022438
• 关键词: American; Animal Model; Animals; Antibodies; Antineoplastic Agents; Biocompatible; Biocompatible Materials; Biological; Blood Vessels; Cancerous; Canis familiaris; Caring; Cervical; Cervical lymph node group; Charge; Clinic; Clinical; Cytotoxic agent; Deglutition; Deposition; Dermatologist; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Disease-Free Survival; Disseminated Malignant Neoplasm; Distant; Dose; Drug Carriers; Drug Delivery Systems; Drug usage; Dyes; Engineering; Evaluation; Excision; Generations; Goals; Head; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Health; Homing; Human; Image; Injection of therapeutic agent; Kidney; Knowledge; Larynx; Left; Libraries; Ligands; Liver; Lung; Lymph; Lymph Node Mapping; Lymph Node Tissue; Lymphatic; Malignant Neoplasms; Measures; Metastatic Neoplasm to Lymph Nodes; Mission; Modeling; Mucous Membrane; Nanoconjugate; Neck; Necrosis; Neoplasm Metastasis; Nitric Oxide; Nodal; Operative Surgical Procedures; Oral cavity; Organ; Outcome; PET/CT scan; Pain; Patients; Pattern; Penetration; Performance; Pharmaceutical Preparations; Pharmacotherapy; Pharyngeal structure; Phase; Physicians; Pilot Projects; Plasma; Polymers; Property; Public Health; Quality of life; Radiation; Radiation therapy; Rattus; Recurrence; Relapse; Research; Research Personnel; Rodent; Route; Safety; Site; Surgeon; Survival Rate; System; Systemic Therapy; Technology; Thinking; Time; Tissues; Toxic effect; Toxicity due to chemotherapy; Translating; Treatment Efficacy; Work; Xenograft Model; Xenograft procedure; aptamer; base; cancer cell; cancer therapy; chemotherapy; clinical toxicology; comparative; cytotoxic; fluorescence imaging; gene therapy; imaging agent; imaging probe; innovation; killings; lymph nodes; man; mouth squamous cell carcinoma; nanomaterials; nanoparticle; novel therapeutics; oncology; phase I trial; pilot trial; prevent; sarcoma; standard of care; sugar; systemic toxicity; trafficking; tumor; uptake

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.

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优先在肿瘤中积聚时，使用细胞毒性药物的化疗是成功的。然而，对于去年诊断出患有头颈鳞状细胞癌 (HNSCC) 的 52,000 名美国人来说，这两种情况均不成立。 HNSCC起源于头颈部的粘膜组织，但它会迅速转移到整个颈部淋巴管，这给临床带来了严峻的挑战。用于治疗 HNSCC 的细胞毒性抗癌药物对这些淋巴管的渗透性非常差，如果治疗不充分，多达 70% 的患者 HNSCC 会复发。这项工作的主要目标是用于头颈部组织化疗的新型聚合生物材料的合成开发和生物学评估。这种创新方法将比任何现有疗法表现更好，因为化疗直接输送到易受攻击的组织中，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，该系统可在肿瘤周围将特殊的药物输送到癌性淋巴结和组织中注射。这种新型生物材料——星形纳米缀合物，可以靶向 HNSCC 肿瘤，而无需昂贵且不太坚固的归巢配体，例如抗体或适体。第一个目标是合成化疗药物的明星纳米缀合物库，包括标准护理药物、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。星形纳米缀合物是合成的糖基星形聚合物，当与常见的抗癌药物缀合时，它们会塌陷成致密的纳米级载体。所得纳米缀合物的理化性质可以综合定制，以实现出色的淋巴吸收和保留、肿瘤渗透以及肿瘤周围淋巴管内的持续药物释放。第二个目标是，局部注射后对啮齿类动物的纳米缀合物和药物进行荧光成像和放射学追踪，将证明化疗药物能够卓越地递送至 HNSCC 肿瘤中。随后，对患有自发性口腔鳞状细胞癌 (SCC) 的犬科动物进行 PET/CT 成像，将在更像人类的模型中验证该平台的性能。第三，将在啮齿动物 HNSCC 异种移植物中比较星形纳米缀合物治疗 HNSCC 的疗效和安全性与常规化疗。第四，对自发性口腔鳞状细胞癌患者进行的 I 期犬试验将在大型动物模型中证明疗效和安全性。在这项研究结束时，将在一种大型动物身上证明这种治疗方法比目前的化疗方法更安全，而且更有效，这种动物的疾病与人类头颈部鳞状细胞癌非常相似。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大量手术和放射治疗以及导致永久性毁容和降低生活质量的治疗的需要，从而显着影响人类健康，并提供比全身治疗更安全的替代方案甚至可以对严重虚弱和晚期患者进行化疗。