Research Supplements for R35 to Promote Diversity in Health-Related Research, PA-21-071

R35 研究补充剂促进健康相关研究的多样性，PA-21-071

• 批准号: 10612236
• 负责人: Xiaowei Dong
• 金额: $ 5.58万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612236
• 关键词: African American; American; Amphotericin B; Antifungal Agents; Award; Biodistribution; Biological Availability; Blood; Blood specimen; Cremophor; Cytoplasmic Granules; Data; Data Analyses; Developed Countries; Development Plans; Discipline; Dosage Forms; Dose; Drug Administration Routes; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug or chemical Tissue Distribution; Excipients; Experimental Designs; Fellowship; Formulation; Goals; Grant; Growth; Head; Health; Hydrophobicity; Immunocompromised Host; In Vitro; Individual; Injections; Intravenous; Intravenous infusion procedures; Knowledge; Laboratories; Leadership; Learning; Libraries; Life; Lipids; Measurement; Measures; Mentors; Micelles; Mycoses; National Institute of General Medical Sciences; Oral; Oral Administration; Oral Characters; Outcome; Parents; Patients; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Plague; Powder dose form; Preparation; Principal Investigator; Questionnaires; Rattus; Research; Research Personnel; Research Project Grants; Resolution; Savings; Science; Scientist; Site; Solid; Solubility; Steroids; Structure; System; Tail; Techniques; Technology; Testing; Therapeutic; Tissues; Training; Tweens; Underrepresented Students; Water; Work; Writing; absorption; amphiphilicity; base; bile salts; biomaterial compatibility; career; career development; commercialization; design; doctoral student; effective therapy; experience; hydrophilicity; improved; innovation; insight; intravenous injection; novel; parent grant; research and development; skills; solid state; surfactant; translational approach; water solubility

Amphotericin B (AmB) is a first option therapy against life-threatening invasive fungal infections. However, as of now administration of AmB is limited to intravenous infusions because of poor solubility and poor permeability, which severely impacts patient accessibility. Although oral AmB medication is a highly sought-after resolution, oral AmB formulations have yet not to be achieved even after 6 decades of commercialization. Our lab has discovered novel stable binary lipid systems (BLS) that consist of one lipid and one water-soluble surfactant to enhance oral bioavailability of water insoluble drugs. In 2020, we were awarded a Maximizing Investigators’ Research Award (R35) from NIGMS to further study this new formulation technology. The goal of the parent R35 grant is to develop a novel formulation technology by bringing our unique findings of new colloidal BLS into solid dosage forms to improve oral absorption of insoluble drugs. One of studies in the parent grant is to build a library of stable BLS using lipids and traditional surfactants. AmB represents a type of amphiphilic molecules that have big ring structure with both hydrophobic and hydrophilic regions. The traditional surfactants with a polar head group conjugated to non-polar tails are not suitable for AmB. Bile salts are desirable biosurfactants due to their biocompatibility and unique structure with planar steroidal moiety. A commercial AmB injection is made of bile salt micelles. However, bile salts have not been used in oral solid dosage forms because they are water-soluble and normally do not like lipids. With our novel findings in the BLS, we hypothesize that the BLS containing bile salts is an effective formulation strategy to enhance oral absorption of AmB. Thus, the goal of this Diversity Supplement is to develop novel oral granules for AmB by using BLS containing one lipid and one bile salt as well as train an African American PhD student to become a biomedical researcher. We will develop oral AmB granules and evaluate pharmacokinetics and tissue distribution. We anticipate the outcome of the Supplement will establish bile salt based BLS, which will be incorporated into the parent questionnaire to expand the library and test our new formulation technology. This proposed Diversity Supplement will support an African American PhD student for his dissertation research. The proposed research plan aligns with the candidate’s long-term career goals and individual development plan (IDP). The principal investigator/mentor has extensive mentoring experiences, especially for underrepresented students. This project has been designed around improving the candidate’s skills, as per the candidate’s IDP, as well as training the candidate to be able to take the next steps along the path of an independent pharmaceutical scientist. The proposed training plan and specific aims outline a path for structured learning of new pharmaceutical techniques, conceptual discipline specific knowledge, experimental design, data analysis and also account for great opportunities to grow in terms of presentation, writing and leadership skills. In all, this project is well designed to enhance the parent grant in addition to bolstering the candidate’s capability and skills in preparation for future research grant and career development.

两性霉素B（AMB）是针对威胁生命的侵入性真菌感染的第一种选择疗法。但是，到底 现在，由于溶解度差和渗透性差，AMB的给药仅限于静脉输注。 严重影响患者的可及性。尽管口服AMB药物是一种备受追捧的解决方案，但 即使经过6年的商业化，口服AMB公式仍无法实现。我们的实验室有 发现了一种新型稳定的二进制脂质系统（BLS），由一种脂质和一种水溶性表面活性剂组成 增强缺水药物的口服生物利用度。 2020年，我们被授予最大化调查人员的授予 研究奖（R35）来自Nigms，以进一步研究这种新的公式技术。父母R35的目标 格兰特（Grant）是通过将我们新的新胶体BLS的独特发现来开发一种新颖的公式技术 剂型以改善口服滥用不溶的药物。父母赠款中的研究之一是建立图书馆 使用脂质和传统表面活性剂的稳定BL。 AMB代表一种具有的两亲性分子 大环结构具有疏水区和亲水区域。具有极性头部的传统表面活性剂 连接到非极性尾巴的组不适合AMB。胆汁盐是理想的生物表面活性剂 生物相容性和带有平面类固醇部分的独特结构。商业AMB注射是由胆汁进行的 盐胶束。但是，胆汁盐尚未用于口服固体剂型，因为它们是水溶性的 通常不喜欢脂质。随着BLS中的新颖发现，我们假设包含胆汁的BLS 盐是增强对AMB的口服滥用的有效公式策略。那是这种多样性的目标 补充剂是通过使用含有一种脂质和一个胆汁盐的BLS来开发AMB的新型口服颗粒 作为培训非裔美国人博士生的学生，成为一名生物医学研究员。我们将开发口服AMB颗粒 并评估药代动力学和组织分布。我们预计补充的结果将会 建立基于胆汁的BLS，该BLS将纳入父级问卷以扩展图书馆，并 测试我们的新公式技术。提出的多样性补充剂将支持非裔美国人博士 学生的论文研究。拟议的研究计划与候选人的长期职业保持一致 目标和个人发展计划（IDP）。首席调查员/导师具有广泛的心理 经验，特别是对于代表性不足的学生。该项目的设计旨在改善 根据候选人的IDP，候选人的技能，以及培训候选人能够采取下一步的步骤 沿着独立的药物科学家的道路。拟议的培训计划和特定目的大纲 新药技术的结构化学习途径，概念学科特定的知识， 实验设计，数据分析，还考虑了在演示方面成长的巨大机会， 写作和领导能力。总的来说，该项目的设计旨在增强父母的赠款。 加强候选人的能力和技能，为未来的研究赠款和职业发展做准备。