Acyclic Cucurbit n uril Molecular Containers for Drug Solubilization and Delivery

用于药物溶解和递送的无环葫芦脲分子容器

• 批准号: 9033081
• 负责人: VOLKER BRIKEN
• 金额: $ 36.74万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-26 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033081
• 关键词: Address; Affect; Albumins; Ames Assay; Antineoplastic Agents; Binding; Biological Assay; Biological Availability; Biopharmaceutics; Blood; Camptothecin; Cell Line; Cells; Characteristics; Charge; Chemistry; Cholesterol; Chromosome abnormality; Classification; Complex; Core Facility; Cyclodextrins; Dendrimers; Development; Disease; Drug Combinations; Drug Compounding; Drug Containers; Drug Delivery Systems; Drug Industry; Drug Kinetics; Electrostatics; Erythrocytes; Ethers; Evaluation; Excipients; FDA approved; Fenofibrate; Fibrinogen; Formulation; Genes; Geometry; Health; Heart; Hepatocyte; Histopathology; Human; In Vitro; Injection of therapeutic agent; Ion Channel; Ions; Itraconazole; Kidney; Kinetics; Length; Liver; Lung; Maximum Tolerated Dose; Measures; Methods; Modeling; Molecular; Monitor; Mus; Nature; Nude Mice; Paclitaxel; Performance; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Polyethylene Glycols; Positioning Attribute; Prize; Process; Property; Public Health; Roentgen Rays; Safety; Series; Shapes; Solubility; Spleen; Staging; Structure-Activity Relationship; System; Technology; Thermodynamics; Time; Toxic effect; Toxicogenetics; Ursidae Family; Vertebral column; Water; Work; Xenograft Model; analog; aqueous; arm; base; biomaterial compatibility; cancer therapy; cell type; chemical synthesis; clopidogrel; cytotoxicity; design; drug candidate; drug development; drug structure; glycoluril; hydroxypropyl-beta-cyclodextrin; improved; in vitro testing; in vivo; in vivo Model; intravenous injection; kidney cell; medical schools; mouse model; novel therapeutics; receptor; research study; stoichiometry; success; tool; tumor xenograft; water solubility

DESCRIPTION (provided by applicant): A major problem affecting the pharmaceutical industry is that 40-70% of new drug compounds belong to the biopharmaceutics classification system (BCS) class II with such poor aqueous solubility that they cannot be formulated on their own. Accordingly, the pharmaceutical industry devotes significant time and effort toward the formulation of BCS class II drugs. Although a number of methods for the formulation of BCS Class II drugs are available - including solubilization by cyclodextrin molecular containers - none is a general purpose solution. Accordingly, new tools to help address these solubility / bioavailability issues are highly prized. Our central hypothesis is that highly soluble acyclic cucurbit[n]uril-type (CB[n]) molecular containers will dramatically increase the aqueous solubility of BCS class II drugs and thereby improve their bioavailability. Dr. Isaacs' lab is a leading innovator in the creation of CB[n] type receptors and thus is uniquely positioned to develop acyclic CB[n] for drug delivery applications. Specific Aim 1 presents the design and synthesis of new acyclic CB[n] molecules that differ in the nature of their aromatic walls, glycoluril oligomer backbone, and solubilizing arms. Subsequent evaluation of their capacity to increase the aqueous solubility of FDA approved poorly soluble drugs (e.g. paclitaxel, clopidogrel, fenofibrate, cinnarizine, itraconazole) as well as drugs in various stages of development by our academic and pharmaceutical collaborators and will be assessed by phase solubility diagrams and compared with that achievable with hydroxypropyl-beta-cyclodextrin. We will use 1H NMR to determine the self-association of each container, monitor container-drug complex release kinetics, and elucidate the geometry of the container-drug complexes. The influence of electrostatic and size/shape match as well as the presence of competitors on the association constants of the container-drug complexes will be determined. In Specific Aim 2 the toxicity of the acyclic CB[n]-type containers and their capacity to increase the bioactivity of insoluble cancer drugs will be evaluated using in vitro and in vivo models. For example, in vitro toxicity in human kidney, liver, and erythrocytes as well as interference with the human Ether-a-go-go related gene ion channel, Ames tests, and chromosomal aberration assays will be performed. In vivo maximal tolerated dose studies including histopathology for the most promising containers will be performed. The pharmacokinetics for drugs (e.g. paclitaxel) solubilized with the acyclic CB[n]-type containers will be measured and compared with alternate solubilization methods (e.g. Cremophore). Lastly, in vivo bioactivity of the container-paclitaxel complexes will be studied using appropriate mouse xenograft models in comparison to established technology (e.g. Cremophore). The proposed work is significant because it promises to improve established drugs (e.g. improved bioavailability and reduced toxicity) and further advance drug candidates in the drug development pipeline. Therefore, the work is poised to have a major impact on the treatment of cancer and other disease states.

描述（由申请人提供）：影响制药工业的一个主要问题是40-70%的新药化合物属于生物药剂学分类系统（BCS）II类，其水溶性很差，无法自行配制。因此，制药工业将大量时间和精力投入到BCS II类药物的配制中。尽管有许多用于配制BCS II类药物的方法-包括通过环糊精分子容器增溶-但没有一种方法是有效的。 是一种通用解决方案。因此，帮助解决这些溶解度/生物利用度问题的新工具受到高度重视。 我们的中心假设是，高度可溶的无环葫芦[n]脲型（CB[n]）分子容器将显着增加水溶性 BCS II类药物，从而提高其生物利用度。Isaacs博士的实验室是CB[n]型受体的领先创新者，因此在开发用于药物递送应用的无环CB[n]方面具有独特的优势。具体目标1提出了新的无环CB[n]分子的设计和合成，其芳香族壁，甘脲低聚物骨架和增溶臂的性质不同。随后，我们的学术和制药合作者将评估其增加FDA批准的难溶性药物（如紫杉醇、氯吡格雷、非诺贝特、桂利嗪、伊曲康唑）以及处于不同开发阶段的药物的水溶性的能力，并将通过相溶解度图进行评估，并与羟丙基-β-环糊精进行比较。我们将使用1H NMR来确定每个容器的自缔合，监测容器-药物复合物的释放动力学，并阐明容器-药物复合物的几何形状。将确定静电和大小/形状匹配以及竞争对手的存在对容器-药物复合物的缔合常数的影响。在具体目标2中，将使用体外和体内模型评价无环CB[n]型容器的毒性及其增加不溶性癌症药物生物活性的能力。例如，体外毒性在 将进行人肾脏、肝脏和红细胞以及干扰人Ether-a-go-go相关基因离子通道、艾姆斯试验和染色体畸变试验。将对最有希望的容器进行体内最大耐受剂量研究，包括组织病理学研究。将测量用无环CB[n]型容器增溶的药物（例如紫杉醇）的药代动力学，并与替代增溶方法（例如Cremophore）进行比较。最后，将使用适当的小鼠异种移植模型与已建立的技术（例如Cremophore）进行比较，研究容器-紫杉醇复合物的体内生物活性。 拟议的工作是重要的，因为它有望改善已建立的药物（例如提高生物利用度和降低毒性），并进一步推进药物开发管道中的候选药物。因此，这项工作有望对癌症和其他疾病的治疗产生重大影响。