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

两性霉素B（AmB）是治疗威胁生命的侵袭性真菌感染的首选药物。但截至 现在AmB的给药由于溶解性差和渗透性差而限于静脉内输注， 这严重影响了患者的可及性。虽然口服AmB药物是一种非常受欢迎的解决方案， 口服AmB制剂即使在60年的商业化之后也尚未实现。我们的实验室 发现了由一种脂质和一种水溶性表面活性剂组成的新型稳定二元脂质系统（BLS）， 提高水不溶性药物的口服生物利用度。2020年，我们获得了“最大化调查者”奖。 研究奖（R35）从NIGMS进一步研究这种新的配方技术。父R35的目标 格兰特是开发一种新的配方技术，把我们独特的发现，新的胶体BLS到固体 剂型以改善不溶性药物的口服吸收。家长资助的研究项目之一是建立一个图书馆 稳定的BLS使用脂质和传统的表面活性剂。AmB代表一种两亲性分子， 具有疏水和亲水区域的大环结构。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。胆汁盐是理想的生物表面活性剂，这是由于它们的 生物相容性和具有平面甾族部分独特结构。商业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 而且通常不喜欢脂质。根据我们在BLS中的新发现，我们假设含胆汁的BLS 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 培养一名非裔美国博士生成为生物医学研究员。我们将开发口服AmB颗粒剂 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 建立基于胆盐的BLS，将其纳入家长问卷以扩大库， 测试我们的新配方技术。这项拟议的多样性补充将支持非洲裔美国人博士学位 学生为他的论文研究。拟议的研究计划与候选人的长期职业生涯相一致 个人发展计划（IDP）。主要研究者/导师有广泛的指导 经验，特别是对代表性不足的学生。该项目的设计是围绕改善 候选人的技能，根据候选人的IDP，以及培训候选人能够采取下一步 沿着独立制药科学家的道路。拟议的培训计划和具体目标大纲 新制药技术的结构化学习路径，概念学科特定知识， 实验设计，数据分析，也占了很大的机会，在演示方面的增长， 写作和领导能力。总之，这个项目是精心设计的，以提高家长补助金，除了 提升候选人的能力和技能，为未来的研究补助金和职业发展做好准备。

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.