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.

预计 2020 年美国将新增 53,260 例口咽癌病例，10,750 例死亡。不幸的是，口腔癌 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 牺牲了对功能和美观至关重要的治疗性面部结构。然而，OSCC 并不是从头发生的，而是出现的 来自起始的角质形成细胞。该转化前间隔为继发性 OSCC 提供了治疗窗口 化学预防。特定情况，例如吸烟和/或饮酒或与 DNA 修复缺陷相关的疾病 例如范可尼贫血 (FA) 会使整个口腔面临发生 OSCC 的风险。虽然系统地交付 化学预防从概念上讲应提供全口腔覆盖、生物利用度挑战和药物相关 全身毒性产生了令人失望的结果。相比之下，局部递送制剂可以递送 化学预防剂的治疗相关水平 - 相对于全身给药的剂量明显较低 - 达到目标 组织没有药物相关的全身副作用。值得注意的是，口腔沐浴在一种保护性的、粘弹性的、粘性的物质中。 涂层水凝胶（粘液）。虽然粘液会阻碍局部药物输送，但粘膜粘附和粘膜穿透纳米颗粒 化学预防制剂解决了这个问题。纳米颗粒还可以稳定药物，最大限度地减少脱靶副作用 作用，延长化学预防-口腔上皮接触时间并促进递送至下面的角质形成细胞。这 本研究的化学预防剂是根据我们的结果及其补充作用机制选择的。白细胞介素6, 由口腔角质形成细胞和其他细胞产生，是一种遍及整个口腔（包括唾液）的普遍细胞因子。通过其 IL6 具有促炎、促增殖和促血管生成特性，可促进口腔癌的恶性转化 上皮内瘤变至 OSCC。为了抑制这种自分泌-旁分泌环路，可使用 IL6 受体抑制剂托珠单抗 (TCZ) 被选中。此外，我们的实验室已证明合成维生素 A 衍生物芬维A胺 (4HPR) 不仅 具有生长调节作用，但它也表现出信号激酶的高亲和力结合/失活 在癌变过程中上调，即 FAK、Pyk2、STAT3、Wnt、c-Src 和 c-Abl，并扰乱细胞骨架成分 OSCC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 治疗增强了药物在体外和体内模型中的化学预防功效。本次活动的具体目标 建议是：1) 优化 Janus 纳米颗粒 (JNP)，以将 4HPR 和 TCZ 靶向共同递送至口腔表面上皮， 2) 通过使用基于生物测定的体外研究和体内 PK 模型来确定主要 JNP 配方。, 3) 进行一个阶段 0 在健康志愿者中进行的药代动力学/ADME 试验。实验方法将包括：电流体动力合作 喷射与动态光散射、zeta 尺寸测定和电子显微镜相结合，离体配制 JNP 粘膜粘附研究、体外单层和筏培养功能测定、LC-MS、IHC（通过图像分析量化）、 以及体内（兔模型）和人体临床试验 PK 分析。