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:
  • 金额:
    $ 58.37万
  • 依托单位:
  • 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

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.
据估计,2020年美国将发生53,260例新的口咽癌病例和10,750例死亡。不幸的是, 鳞状细胞癌(OSCC)是最具挑战性的治疗人类癌症之一。即使手术切除 牺牲了对功能和美学至关重要的治疗性面部结构。然而,口腔鳞状细胞癌不是从头发生的,而是在口腔癌的发生过程中, 从初始角质形成细胞。这个转化前的间隔期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修复缺陷相关的疾病 例如范可尼贫血(FA)可使整个口腔处于发展OSCC的风险中。虽然系统性地 化学预防应在概念上提供全面的口腔领域覆盖,生物利用度的挑战和药物相关的 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 治疗相关水平的化学预防-在相对于全身给药显著较低的剂量下-以靶向 没有药物相关的全身副作用。值得注意的是,口腔是沐浴在一个保护,粘弹性,粘合剂 涂布水凝胶(粘液)。虽然粘液可以阻碍局部药物递送,但粘膜粘附和粘液渗透纳米颗粒 化学预防制剂解决了这个问题。纳米颗粒还具有稳定药物,最大限度地减少脱靶侧的功能 效果,延长化学预防性口腔上皮接触时间,并促进传递到下面的角质形成细胞。的 本研究的化学预防剂是根据我们的结果及其互补的作用机制选择的。IL6, 由口腔角化细胞和其它细胞产生,是遍布口腔包括唾液的细胞因子。通过其 IL 6具有促炎、促增殖和促血管生成的特性,可促进口腔癌的恶性转化。 上皮内瘤变到OSCC。为了抑制这种自分泌-旁分泌循环,IL 6受体抑制剂托珠单抗(TCZ) 被选中了此外,我们的实验室已经表明,合成的维生素A衍生物芬维A胺(4 HPR),不仅 具有生长调节作用,但也显示出高亲和力结合/失活信号激酶 在癌发生过程中上调,即FAK、Pyk 2、STAT 3、Wnt、c-Src和c-Abl,并干扰细胞骨架组分 OSCC细胞的侵袭。我们的数据还表明,虽然单药是有益的,但TCZ+4 HPR组合 在体外和体内模型中,治疗增强了药剂的化学预防功效。具体目标是 建议是:1)优化Janus纳米颗粒(JNPs)用于将4 HPR和TCZ靶向共递送至表面口腔上皮, 2)通过使用基于生物测定的体外研究和体内PK模型确定JNP的主要制剂。3)执行阶段 0健康志愿者的药代动力学/ADME试验。实验方法将包括:电流体动力学共- 喷射结合动态光散射、zeta尺寸测定和电子显微镜以配制JNPs,离体 粘膜粘附研究,体外单层和筏培养功能测定,LC-MS,IHC(通过图像分析定量), 以及体内(兔模型)和人体临床试验PK分析。

项目成果

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Susan R Mallery其他文献

Susan R Mallery的其他文献

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{{ truncateString('Susan R Mallery', 18)}}的其他基金

Multidisciplinary Research Training in Dental, Oral, and Craniofacial Sciences (MARTDOCS)
牙科、口腔和颅面科学多学科研究培训 (MARTDOCS)
  • 批准号:
    10711411
  • 财政年份:
    2023
  • 资助金额:
    $ 58.37万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 58.37万
  • 项目类别:
Assessment of Chemopreventive Effects of a Mucoadhesive Fenretinide Patch on Premalignant Oral Epithelial Lesions
粘膜粘附芬维A胺贴剂对口腔癌前上皮病变的化学预防作用评估
  • 批准号:
    10321591
  • 财政年份:
    2019
  • 资助金额:
    $ 58.37万
  • 项目类别:
Assessment of Chemopreventive Effects of a Mucoadhesive Fenretinide Patch on Premalignant Oral Epithelial Lesions
粘膜粘附芬维A胺贴剂对口腔癌前上皮病变的化学预防作用评估
  • 批准号:
    10542711
  • 财政年份:
    2019
  • 资助金额:
    $ 58.37万
  • 项目类别:
Evaluation of locally-delivered fenretinide and black raspberries for oral cancer
局部给药芬维A胺和黑树莓治疗口腔癌的评价
  • 批准号:
    8523810
  • 财政年份:
    2012
  • 资助金额:
    $ 58.37万
  • 项目类别:
Evaluation of locally-delivered fenretinide and black raspberries for oral cancer
局部给药芬维A胺和黑树莓治疗口腔癌的评价
  • 批准号:
    8392351
  • 财政年份:
    2012
  • 资助金额:
    $ 58.37万
  • 项目类别:
Evaluation of locally-delivered fenretinide and black raspberries for oral cancer
局部给药芬维A胺和黑树莓治疗口腔癌的评价
  • 批准号:
    9091491
  • 财政年份:
    2012
  • 资助金额:
    $ 58.37万
  • 项目类别:
Evaluation of locally-delivered fenretinide and black raspberries for oral cancer
局部给药芬维A胺和黑树莓治疗口腔癌的评价
  • 批准号:
    8867171
  • 财政年份:
    2012
  • 资助金额:
    $ 58.37万
  • 项目类别:
Evaluation of locally-delivered fenretinide and black raspberries for oral cancer
局部给药芬维A胺和黑树莓治疗口腔癌的评价
  • 批准号:
    8686793
  • 财政年份:
    2012
  • 资助金额:
    $ 58.37万
  • 项目类别:
Chemoprevention of Head & Neck Cancer Using Controlled Release Polymers
头部化学预防
  • 批准号:
    8197246
  • 财政年份:
    2009
  • 资助金额:
    $ 58.37万
  • 项目类别:

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Leukemogenicity of the RCSD1-ABL1 gene
RCSD1-ABL1 基因的致白血病性
  • 批准号:
    26461434
  • 财政年份:
    2014
  • 资助金额:
    $ 58.37万
  • 项目类别:
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