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: 10540811
• 负责人: Susan R Mallery
• 金额: $ 58.37万
• 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 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540811
• 关键词: 17p; ABL1 gene; Address; Adhesives; Adult; Affect; Affinity; Alcohol consumption; Basal Cell; Bathing; Binding; Biological Assay; Biological Availability; Carcinogens; Cells; Cessation of life; Charge; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Cytoskeleton; DNA Repair; Data; Development; Disease; Distant; Dose; Drug Delivery Systems; Drug Kinetics; Eating; Electron Microscopy; Enzymes; Epithelium; 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; Invaded; 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 Transduction; Site; Squamous cell carcinoma; Stromal Cells; Structure; Surface; Therapeutic; Thinness; Time; Tissues; Tobacco use; Toxic effect; Toxicology; Urine; Vitamin A; Xenobiotics; Xenograft procedure; absorption; antagonist; autocrine; 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年美国将新增53,260例口咽癌病例，10,750例死亡。不幸的是，口交 鳞状细胞癌(OSCC)是最具挑战性的人类癌症之一。即使手术切除是 对于功能和美学至关重要的治愈和面部结构被牺牲。然而，口腔鳞状细胞癌并不是从头开始发生的，而是产生 来自启动的角质形成细胞。这一转化前的间隔为继发性口腔鳞癌提供了一个治疗窗口 化学预防。特定情况，如吸烟和/或饮酒或与DNA修复缺陷有关的疾病 例如，范可尼贫血(FA)可使整个口腔面临患口腔鳞状细胞癌的风险。尽管是系统交付的 化学保护剂在概念上应提供全口腔覆盖、生物利用度挑战和药物相关 系统性毒性产生了令人失望的结果。相比之下，本地递送配方可以递送 与治疗相关的化学保护剂水平--相对于全身给药明显较低的剂量--靶向 无药物相关全身副作用的组织。值得注意的是，口腔沐浴在一种保护性的粘弹性粘合剂中 涂层水凝胶(粘液)。虽然粘液会阻碍局部药物的传递，但粘液黏附和粘液穿透纳米颗粒 化学预防配方解决了这个问题。纳米颗粒还可以稳定药物，最大限度地减少偏离目标的副作用 有效，延长化学预防-口腔上皮接触时间，并促进向底层角质形成细胞输送。这个 这项研究的化学保护剂是基于我们的结果和它们互补的作用机制而选择的。IL6， 由口腔角质形成细胞和其他细胞产生，是一种弥漫在口腔包括唾液中的细胞因子。通过ITS IL-6具有促炎症、促增殖和促血管生成的特性，可促进口腔鳞癌的恶性转化 口腔鳞癌的上皮内瘤变。为了抑制这种自分泌-旁分泌环路，IL6受体抑制剂tocilizumab(TCZ) 已被选中。此外，我们的实验室已经表明，合成维生素A衍生物芬维替尼(4HPR)不仅 具有生长调节作用，但也显示高亲和力结合/失活信号转导。 FAK、PYK2、STAT3、Wnt、c-Src和c-Abl在癌变过程中的上调及细胞骨架成分的扰动 是口腔鳞癌细胞侵袭所必需的。我们的数据还表明，虽然单一药物是有益的，但TCZ+4HPR组合 在体外和体内模型中，治疗都提高了这些试剂的化学预防效果。这样做的具体目的是 建议是：1)优化Janus纳米粒(JNPs)，将4HPR和TCZ靶向联合输送到口腔表面上皮细胞， 2)通过基于生物测定的体外研究和体内PK模型鉴定铅JNP配方。3)进行阶段 0健康志愿者的药代动力学/ADME试验。实验方法学将包括：电液动力协同 喷射结合动态光散射、Zeta施胶和电子显微镜制备JNPs，体外 粘附性研究，体外单层和RAFT培养功能分析，LC-MS，IHC(通过图像分析定量)， 并进行了体内(兔模型)和人体临床试验PK分析。