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）：与其他组织相比，这些药物优先杀死癌细胞，或优先积聚在肿瘤中时，用细胞毒性药物进行化学疗法是成功的。然而，对于去年诊断出患有头颈部鳞状细胞癌（HNSCC）的52,000名美国人而言，这两种情况都没有。 HNSCC起源于头颈的粘膜组织，但在整个宫颈淋巴管中迅速转移，这带来了艰巨的临床挑战。用于治疗HNSCC的细胞毒性抗癌药物对这些淋巴管的渗透非常差，并且治疗不足的HNSCC将在多达70％的患者中复发。这项工作的主要目的是对头颈组织化学疗法的新聚合物生物材料的合成开发和生物学评估。这种创新的方法的表现将比任何现有疗法都更好，因为化学疗法直接递送到容易发生的组织中，因此不损坏了细腻的器官，并且使用专门设计的第一个纳米颗粒系统来实现，专门设计用于肿瘤周期后的癌性淋巴结和组织中的特殊药物。新的生物材料恒星纳米缀合物可以针对HNSCC肿瘤，而没有昂贵且健壮的归巢配体（例如抗体或适体）。第一个目的是合成化学治疗剂的星纳米偶联物的库，包括护理标准药物，新的基于一氧化氮的药物，与现有药物协同作用以及第一个光动力一氧化氮治疗。恒星纳米缀合物是合成糖基的星星聚合物，当结合到常见的抗癌药物中时，将其塌陷成紧凑的纳米载体。可以根据肿瘤周围的淋巴管内的淋巴管摄取和保留率，肿瘤渗透和持续的药物释放来量身定制所得纳米偶联物的生理化学特性。在第二个目标中，局部注射后的纳米偶联物和啮齿动物的荧光成像和放射学跟踪将证明化学疗法在HNSCC肿瘤中的出色递送。随后，具有自发性口服鳞状细胞癌（SCC）犬类的PET/CT成像将以更类似人的模型来验证该平台的性能。第三，将HNSCC治疗用星纳米偶联物治疗的功效和安全性将与HNSCC啮齿动物异种移植物中的常规化学疗法进行比较。第四，对自发口腔SCC癌患者的I期犬试验将在大型动物模型中表现出功效和安全性。在这项研究结束时，将有一个大型动物的证据，该动物的疾病对人类HNSCC进行了密切模型，表明这种治疗既优越，又比当前的化学疗法更高。基于啮齿动物和犬的广泛初步结果，该平台有望通过减少广泛的手术和放射疗法的需求，导致永久性毁容并降低生活质量的治疗方法，从而显着影响人类健康，并为可以严重削弱和高级患者提供的全身化学疗法提供更安全的替代方案。