EGFR-targeted Polymeric Micelles for Targeted Pc 4-PDT of Oropharyngeal Tumors

描述(申请人提供)：我广泛的长期研究目标是开发一种有效的纳米药物平台，将光敏剂药物Pc4靶向输送到头颈部癌症的部位，以增强Pc4诱导的光动力疗法(PDT)在这些恶性肿瘤中的临床疗效。口腔癌、头颈癌、喉癌、咽癌和鼻/鼻道癌是美国癌症死亡的第七大常见原因。在这些癌症中，由于身体和情感创伤、功能衰弱和美学损害的限制，常规放疗和化疗后新的原发肿瘤的局部区域发生使得重复这些治疗或手术是不可行的。在这种情况下，光动力疗法可以在保护组织功能和美观的同时有效地治疗这些癌症。PDT涉及光敏剂(PS)药物的给药和光激活，这会导致单态原子氧的产生，从而导致细胞死亡。由于操作简单、损伤小和成本效益好，目前该方法正在研究中，用于治疗多种癌症，结果令人振奋。我提出的研究基础是，由于表皮生长因子受体(EGFR)的过度表达与这些恶性肿瘤的侵袭性有关，包裹Pc4的EGFR靶向生物相容胶束可以增强Pc4在头颈部(包括口咽癌)部位的选择性传递和摄取，从而实现位置选择性Pc4-PDT。其具体目的是：(1)测定Pc4在生物相容嵌段共聚胶束中的包封率和释放动力学；(2)用EGFR特异性配体或抗体修饰胶束表面，并在体外研究表面修饰胶束的癌细胞靶向性；(3)研究Pc4-EGFR靶向胶束在体外对SCC细胞的靶向性PDT效应和合适的动物模型。这项研究与国家牙科和颅面研究所(NIDCR)的使命相关，因为它涉及生物医学领域的基础和应用研究，将帮助我增强研究专业知识和经验，以便进一步发展我的事业，进入癌症治疗领域的医疗研究。我提出的开发新的口咽癌治疗策略的研究恰好符合NIDCR促进所有人的口腔健康和支持科学研究以促进国家福祉的愿景。 与公共卫生的相关性：这项研究可能会以手稿和发明披露的形式产生洞察力，从而促进知识的及时转让，以改善公共卫生。由于这类癌症占美国所有恶性肿瘤的6%，是癌症死亡的第七大常见原因，特别是在50岁以上的人群中，拟议的治疗系统如果成功，将对公众健康产生重大好处。

DESCRIPTION (provided by applicant): My broad long-term research objective is to develop an effective nanomedicine platform for targeted delivery of the photosensitizer drug Pc 4 to sites of head and neck cancer to enhance the clinical repertoire of Pc 4- induced photodynamic therapy (PDT) in these malignancies. Cancers of the buccal cavity, head and neck subset, larynx, pharynx, and nose/nasal passages is the seventh most common cause of cancer death in the US. In these cancers, the locoregional occurrence of new primary tumors after conventional radiotherapy and chemotherapy makes repetition of these therapies or surgery non-feasible, due to limitations of physical and emotional trauma, functional debilitation and aesthetic damage. In such cases, PDT may enable treating these cancers effectively while preserving tissue functionality and aesthetics. PDT involves administration and photoactivation of a photosensitizer (PS) drug, which leads to generation of singlet atomic oxygen that induces cell death. Due to simplicity, minimal damage and cost-effectiveness, this approach is currently being investigated for treatment of a variety of cancers, with promising results. My proposed research rationale is that, since overexpression of Epidermal Growth Factor Receptors (EGFR) is implicated in the aggressiveness of these malignancies, EGFR-targeted biocompatible micelles encapsulating Pc 4 can enhance the selective delivery and uptake of Pc 4 at sites of head & neck (including oropharyngeal) cancers, thereby enabling site- selective Pc 4-PDT. The specific aims are to: (1) Determine encapsulation and release kinetics of Pc 4 in biocompatible block-copolymer micelles, (2) Modify micelle surface with EGFR-specific ligands or antibodies and investigate cancer cell targeting of the surface-modified micelles in vitro, and, (3) Investigate targeted PDT effects on SCC cell lines in vitro and suitable animal models in vivo with Pc 4- loaded EGFR-targeted micelle formulations. The research is relevant to the mission of National Institute of Dental and Craniofacial Research (NIDCR), since it involves basic and applicative research in the biomedical area that will help me enhance my research expertise and experience for further progressing my career into healthcare research in the area of cancer therapy. My proposed research of developing novel therapeutic strategies for oropharyngeal malignancies appropriately complies with the vision of NIDCR for advancing oral health of all people and supporting scientific investigations for promoting well-being of the Nation. PUBLIC HEALTH RELEVANCE: The research will potentially generate insight in the form of manuscripts and invention disclosures that will facilitate timely transfer of knowledge for the betterment of public health. Since this class of cancers form 6% of all malignancies in the US and the seventh most common cause of cancer death, especially in people over 50, the proposed therapeutic system, if successful, can have significant benefit to public health.