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

基本信息

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
项目类别：
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&apos 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

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&apos 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

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项目摘要

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.

估计在2020年美国将在美国发生53,260例新的口咽癌病例和10,750例死亡。不幸的是，口服鳞状细胞癌（OSCC）是最具挑战性的人类癌症之一。即使手术切除是牺牲了对功能和美学至关重要的治疗性面部结构。但是，OSCC并未从头开始，但出现从开始的角质形成细胞。此前转化间隔为次级OSCC提供了一个治疗窗口化学预防。特定情况，例如烟草和/或酒精使用或与DNA修复缺陷相关的疾病例如Fanconi贫血（FA）可以使整个口腔有风险开发OSCC。虽然是系统地交付的化学预防应在概念上提供全口覆盖，生物利用度挑战和与药物有关的系统性毒性引起了令人失望的结果。相比之下，本地交付配方可以交付与全身给药到目标相对于剂量明显降低剂量的化学反应水平与治疗水平相关的水平没有药物相关的全身副作用的组织。值得注意的是，口腔以保护性，粘弹性，粘合剂沐浴涂层水凝胶（粘液）。虽然粘液会阻碍局部药物递送，但粘附和粘液粘膜纳米颗粒化学预防配方解决了这个问题。纳米颗粒还起作用可稳定药物，最大程度地减少目标范围效果，延长化学预防的口腔上皮接触时间，并促进到基础角质形成细胞。这根据我们的结果及其互补作用机理选择了本研究的化学预防剂。 IL6，口服角质形成细胞和其他细胞产生的是整个口腔中普遍的细胞因子，包括唾液。通过它的促炎，促增殖和促血管生成特性，IL6可以促进口服的恶性转化上皮内肿瘤至OSCC。为了抑制这种自分泌 - 二循环，IL6受体抑制剂Tocilizumab（TCZ）被选中。此外，我们的实验室表明，合成维生素A衍生物fenretinide（4HPR），不仅具有生长调节作用，但也表明了信号激酶的高亲和力结合/灭活在致癌过程中上调，即FAK，PYK2，STAT3，WNT，C-SRC和C-ABL，以及perturbs细胞骨架成分 OSCC细胞入侵所需的。我们的数据还表明，尽管单个代理是有益的，但TCZ+4HPR组合治疗在体外和体内模型中都增强了药物的化学预防功效。这个特定的目的提案为：1）优化Janus纳米颗粒（JNP），以靶向4HPR和TCZ的靶向共递送以表面口服上皮， 2）通过使用基于生物测定的体外研究和体内PK模型来确定铅JNP公式。3）进行相位 0健康志愿者的药代动力学/ADME试验。实验方法将包括：电水力动力学共同与动态光散射，Zeta尺寸和电子显微镜一起喷射，以形成JNP，离体粘附研究，体外单层和筏培养功能分析，LC-MS，IHC（通过图像分析进行量化），和体内（兔模型）和人类临床试验PK分析。