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) 是对抗危及生命的侵袭性真菌感染的首选疗法。然而，截至 由于AmB的溶解度和渗透性较差，目前AmB的给药仅限于静脉输注， 这严重影响了患者的可及性。尽管口服 AmB 药物是一种备受追捧的解决方案， 口服AmB制剂在商业化6年后仍未实现。我们实验室有 发现了新型稳定的二元脂质系统（BLS），该系统由一种脂质和一种水溶性表面活性剂组成， 提高水不溶性药物的口服生物利用度。 2020 年，我们被授予“最大化调查员奖” NIGMS 颁发的研究奖（R35）用于进一步研究这种新的配方技术。母R35的目标 赠款旨在通过将我们对新型胶体 BLS 的独特发现转化为固体来开发一种新颖的配方技术 改善难溶性药物口服吸收的剂型。家长资助的其中一项研究是建立一个图书馆 使用脂质和传统表面活性剂制备稳定的 BLS。 AmB 代表一类两亲分子，具有 具有疏水性和亲水性区域的大环结构。传统的极性头表面活性剂 与非极性尾部缀合的基团不适合 AmB。胆盐是理想的生物表面活性剂，因为它们具有 生物相容性和具有平面甾体部分的独特结构。商业化的 AmB 注射液由胆汁制成 盐胶束。然而，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。根据我们在 BLS 中的新发现，我们假设 BLS 含有胆汁 盐是增强 AmB 口服吸收的有效制剂策略。因此，这种多样性的目标 补充剂是利用含有一种脂质和一种胆盐的 BLS 开发新型 AmB 口服颗粒剂 培训一名非裔美国博士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。我们预计补充协议的结果将 建立基于胆汁盐的 BLS，将其纳入家长调查问卷中以扩大图书馆和 测试我们的新配方技术。拟议的多样性补充计划将支持非裔美国博士 学生进行论文研究。拟议的研究计划与候选人的长期职业生涯相一致 目标和个人发展计划（IDP）。首席研究员/导师有广泛的指导 经验，特别是对于代表性不足的学生。该项目旨在改善 候选人的技能，根据候选人的 IDP，以及培训候选人能够采取后续步骤 沿着独立药物科学家的道路。拟议的培训计划和具体目标概述 结构化学习新制药技术、概念学科特定知识的途径， 实验设计、数据分析以及在演示方面也有很大的发展机会， 写作和领导能力。总而言之，该项目经过精心设计，除了 增强候选人的能力和技能，为未来的研究资助和职业发展做好准备。