Formulation, Evaluation, and Phase 0 Trial of Nanoparticle Releasing Oral Thin Film for OSCC Chemoprevention

用于口腔鳞癌化学预防的纳米颗粒释放口腔薄膜的配方、评估和 0 期试验

• 批准号: 10359559
• 负责人: Susan R Mallery
• 金额: $ 58.16万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359559
• 关键词: 17p; ABL1 gene; Address; Adhesives; Adult; Affect; Affinity; Alcohol consumption; Basal Cell; Binding; Biological Assay; Biological Availability; Carcinogens; Carcinoma; Cells; Cessation of life; Charge; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Research; Clinical Trials; DNA Repair; Data; Development; Disease; Distant; Dose; Drug Delivery Systems; Drug Kinetics; Eating; Electron Microscopy; Enzymes; Epithelial; Esthetics; Evaluation; Excision; Exposure to; Face; Fanconi' s Anemia; Fenretinide; Film; Formulation; Goals; Growth; High Pressure Liquid Chromatography; Histologic; Human; Hydrogels; IL6 gene; Image Analysis; In Vitro; Inflammatory; Injections; Interleukin 6 Receptor; Intraepithelial Neoplasia; Lead; Lesion; Loss of Heterozygosity; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Metabolism; Methodology; Modality; Modeling; Morbidity - disease rate; Mucous Membrane; Mucous body substance; Nature; Operative Surgical Procedures; Oral; Oral cavity; Oral mucous membrane structure; Oryctolagus cuniculus; Outcome; PTK2 gene; Pathway interactions; Patients; Penetration; Peptides; Persons; Pharmaceutical Preparations; Phase; Phase 0 Trial; Phosphotransferases; Plasma; Primary Neoplasm; Property; Resistance; Risk; Risk Factors; Role; SRC gene; STAT3 gene; Saliva; Shapes; Signal Induction; Signal Transduction; Site; Stromal Cells; Structure; Surface; Therapeutic; Thinness; Time; Tissues; Tobacco use; Toxic effect; Toxicology; Urine; Vitamin A; Xenobiotics; Xenograft procedure; absorption; antagonist; autocrine; base; carcinogenesis; carcinogenicity; cytokine; drug release kinetics; experience; exposure route; healthy volunteer; immunoreactivity; in vivo; in vivo Model; inhibitor; keratinocyte; light scattering; local drug delivery; malignant mouth neoplasm; malignant oropharynx neoplasm; migration; monolayer; mouse model; mouth squamous cell carcinoma; nanocarrier; nanoparticle; oral cavity epithelium; oral lesion; oxidation; paracrine; particle; premalignant; prevent; side effect; social; systemic toxicity; tobacco products; tocilizumab; tumor; viscoelasticity; volunteer; zeta potential

An estimated 53,260 new oropharyngeal cancer cases and 10,750 deaths will occur in U.S. during 2020. Unfortunately, oral squamous cell carcinoma (OSCC) is one of the most challenging-to-treat human cancers. Even if surgical resections are curative, facial structures vital for function and esthetics are sacrificed. OSCC, however, doesn't occur de novo, but arises from initiated keratinocytes. This pre-transformation interval provides a therapeutic window for secondary OSCC chemoprevention. Specific situations such as tobacco and/or alcohol use or diseases associated with DNA repair deficits e.g. Fanconi anemia (FA) can render the entire oral cavity at risk to develop OSCC. Although systemically-delivered chemopreventives should conceptually provide full mouth field-coverage, bioavailability challenges and drug-related systemic toxicities have generated disappointing outcomes. In contrast, local delivery formulations can deliver therapeutically-relevant levels of chemopreventives-at markedly lower doses relative to systemic administration-to target tissue without drug-related systemic side-effects. Notably, the oral cavity is bathed in a protective, viscoelastic, adhesive coating hydrogel (mucous). While mucous can impede local drug delivery, mucoadhesive and mucopenetrating nanoparticle chemopreventive formulations address this issue. Nanoparticles also function to stabilize drugs, minimize off-target side effects, prolong chemopreventive-oral epithelial contact time and facilitate delivery to the underlying keratinocytes. The chemopreventives for this study were selected based on our results and their complementary mechanisms of action. IL6, produced by oral keratinocytes and other cells, is a pervasive cytokine throughout the mouth including saliva. Via its proinflammatory, pro-proliferative and proangiogenic properties, IL6 can facilitate malignant transformation of oral intraepithelial neoplasia to OSCC. To suppress this autocrine-paracrine loop, the IL6 receptor inhibitor, tocilizumab (TCZ) was selected. In addition, our labs have shown that the synthetic vitamin A derivative, fenretinide (4HPR), not only possesses growth modulatory effects, but it also demonstrates high affinity binding/inactivation of signaling kinases upregulated during carcinogenesis i.e. FAK, Pyk2, STAT3, Wnt, c-Src and c-Abl and perturbs cytoskeletal components necessary for OSCC cell invasion. Our data also show that while single agents are beneficial, TCZ+4HPR combination treatment enhances the agents' chemopreventive efficacy in both in vitro and in vivo models. The Specific Aims of this proposal are: 1) Optimize Janus nanoparticles (JNPs) for targeted co-delivery of 4HPR & TCZ to surface oral epithelium, 2) Identify the lead JNP formulation by using bioassay-based in vitro studies and an in vivo PK model., 3) Conduct a Phase 0 pharmacokinetic/ADME trial in healthy volunteers. Experimental methodology will include: electrohydrodynamic co- jetting in conjunction with dynamic light scattering, zeta sizing and electron microscopy to formulate the JNPs, ex vivo mucoadherence studies, in vitro monolayer and raft culture functional assays, LC-MS, IHC (quantified by image analysis), and in vivo (rabbit model) and human clinical trial PK analyses.

据估计，2020年美国将发生53260例新的口咽癌病例和10750例死亡。不幸的是,口语