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

基本信息

批准号：
9245629
负责人：
VOLKER BRIKEN
金额：
$ 36.52万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-26 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9245629
关键词：
Address Affect Albumins Ames Assay Antineoplastic Agents Binding Biological Assay Biological Availability Biological Products Blood Camptothecin Cell Line Cells Characteristics Charge Chemicals 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 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 clopidogrel cytotoxicity design drug candidate drug development experimental study glycoluril hydroxypropyl-beta-cyclodextrin improved in vivo in vivo Model innovation intravenous injection kidney cell medical schools mouse model novel therapeutics public health relevance receptor stoichiometry success tool tumor xenograft water solubility

项目摘要

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（申请人提供）：影响制药行业的一个主要问题是，40-70%的新药化合物属于生物制药分类系统（BCS）II类，其水溶性很差，无法单独配制。因此，制药行业投入了大量的时间和精力来配制 BCS II 类药物。尽管有多种 BCS II 类药物的配制方法（包括通过环糊精分子容器进行增溶）可用，但没有一种方法可以用于配制 BCS II 类药物。是一个通用解决方案。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，高溶解度的无环葫芦[n]脲型（CB[n]）分子容器将显着提高水溶性 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] 型受体创建领域的领先创新者，因此在开发用于药物输送应用的无环 CB[n] 方面具有独特的优势。具体目标 1 介绍了新的无环 CB[n] 分子的设计和合成，这些分子的芳香壁、甘脲低聚物主链和增溶臂的性质不同。随后由我们的学术和制药合作者评估其增加 FDA 批准的难溶性药物（例如紫杉醇、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，并将通过相溶解度进行评估图表并与羟丙基-β-环糊精可实现的结果进行比较。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。将确定静电和尺寸/形状匹配以及竞争者的存在对容器-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估无环 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，体外毒性将进行人体肾脏、肝脏和红细胞以及干扰人体 Ether-a-go-go 相关基因离子通道、Ames 试验和染色体畸变测定。将进行体内最大耐受剂量研究，包括最有希望的容器的组织病理学研究。将测量用无环 CB[n] 型容器溶解的药物（例如紫杉醇）的药代动力学，并与替代溶解方法（例如 Cremophore）进行比较。最后，将使用适当的小鼠异种移植模型与现有技术（例如 Cremophore）进行比较，研究容器-紫杉醇复合物的体内生物活性。拟议的工作意义重大，因为它有望改进现有药物（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，这项工作将对癌症和其他疾病的治疗产生重大影响。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metal Organic Polyhedra: A Click-and-Clack Approach Toward Targeted Delivery.

DOI：
10.1002/hlca.201800057
发表时间：
2018-06
期刊：
Helvetica chimica acta
影响因子：
1.8
作者：
S. Samanta;Damien Moncelet;B. Vinciguerra;V. Briken;L. Isaacs
通讯作者：
S. Samanta;Damien Moncelet;B. Vinciguerra;V. Briken;L. Isaacs

Synthesis of a Disulfonated Derivative of Cucurbit[7]uril and Investigations of its Ability to Solubilize Insoluble Drugs.

DOI：
10.1080/10610278.2014.940952
发表时间：
2015-05-01
期刊：
Supramolecular chemistry
影响因子：
3.3
作者：
Robinson EL;Zavalij PY;Isaacs L
通讯作者：
Isaacs L

Cucurbit[7]uril Enables Multi-Stimuli-Responsive Release from the Self-Assembled Hydrophobic Phase of a Metal Organic Polyhedron.

DOI：
10.1021/jacs.7b05154
发表时间：
2017-07-05
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Samanta SK;Quigley J;Vinciguerra B;Briken V;Isaacs L
通讯作者：
Isaacs L

New small-molecule inhibitors effectively blocking picornavirus replication.

新型小分子抑制剂可有效阻止小核糖核酸病毒复制。

DOI：
10.1128/jvi.01877-14
发表时间：
2014
期刊：
Journal of virology
影响因子：
5.4
作者：
FordSiltz,LaurenA;Viktorova,EkaterinaG;Zhang,Ben;Kouiavskaia,Diana;Dragunsky,Eugenia;Chumakov,Konstantin;Isaacs,Lyle;Belov,GeorgeA
通讯作者：
Belov,GeorgeA

Acyclic cucurbit[n]uril-type molecular containers: influence of glycoluril oligomer length on their function as solubilizing agents.