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

我广泛的长期研究目标是开发一种有效的纳米医学平台，用于将光敏剂药物Pc 4靶向递送到头颈部癌症部位，以增强Pc 4诱导的光动力疗法（PDT）在这些恶性肿瘤中的临床功能。口腔癌、头颈癌、喉癌、咽癌和鼻/鼻腔癌是美国第七大常见癌症死亡原因。在这些癌症中，常规放疗和化疗后局部出现新的原发性肿瘤，由于身体和情感创伤、功能衰弱和美学损害的限制，重复这些治疗或手术是不可行的。在这种情况下，PDT可以有效地治疗这些癌症，同时保持组织功能和美观。PDT涉及光敏剂（PS）药物的施用和光活化，其导致诱导细胞死亡的单线态原子氧的产生。由于简单，最小的损害和成本效益，这种方法目前正在研究用于治疗各种癌症，并取得了可喜的成果。我提出的研究原理是，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，因此包裹Pc 4的EGFR靶向生物相容性胶束可以增强Pc 4在头颈部（包括口咽部）癌症部位的选择性递送和摄取，从而实现位点选择性Pc 4-PDT。具体目标是：（1）确定Pc 4在生物相容性嵌段共聚物胶束中的包封和释放动力学，（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的胶束的癌细胞靶向，和（3）用负载Pc 4的EGFR靶向胶束制剂在体外研究靶向PDT对SCC细胞系的作用和在体内研究合适的动物模型。这项研究与国家牙科和颅面研究所（NIDCR）的使命有关，因为它涉及生物医学领域的基础和应用研究，这将帮助我提高我的研究专业知识和经验，进一步推进我在癌症治疗领域的医疗保健研究。我提出的开发口咽恶性肿瘤新治疗策略的研究符合NIDCR的愿景，即促进所有人的口腔健康，并支持促进国家福祉的科学研究。

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.