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.

Public Health Relevance

Many promising drug candidates ultimately fail because of their poor solubility characteristics in water. In this project we develop a promising new class of molecular containers - acyclic cucurbit[n]uril type containers - that dramatically enhance the water solubility of established and candidate pharmaceutical agents. The project promises to impact human health by enabling the advancement or re-introduction of promising drugs in the drug development pipeline.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA168365-02
Application #
8656316
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fu, Yali
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland College Park
Department
Chemistry
Type
Earth Sciences/Resources
DUNS #
City
College Park
State
MD
Country
United States
Zip Code
20742
Hettiarachchi, Gaya; Samanta, Soumen K; Falcinelli, Shane et al. (2016) Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors. Mol Pharm 13:809-18
Samanta, Soumen K; Moncelet, Damien; Briken, Volker et al. (2016) Metal-Organic Polyhedron Capped with Cucurbit[8]uril Delivers Doxorubicin to Cancer Cells. J Am Chem Soc 138:14488-14496
Ganapati, Shweta; Zavalij, Peter Y; Eikermann, Matthias et al. (2016) In Vitro selectivity of an acyclic cucurbit[n]uril molecular container towards neuromuscular blocking agents relative to commonly used drugs. Org Biomol Chem 14:1277-87
Diaz-Gil, Daniel; Haerter, Friederike; Falcinelli, Shane et al. (2016) A Novel Strategy to Reverse General Anesthesia by Scavenging with the Acyclic Cucurbit[n]uril-type Molecular Container Calabadion 2. Anesthesiology 125:333-45
She, Nengfang; Moncelet, Damien; Gilberg, Laura et al. (2016) Glycoluril-Derived Molecular Clips are Potent and Selective Receptors for Cationic Dyes in Water. Chemistry 22:15270-15279
Sigwalt, David; Zavalij, Peter Y; Isaacs, Lyle (2016) Cationic acyclic cucurbit[n]uril-type containers: synthesis and molecular recognition toward nucleotides. Supramol Chem 28:825-834
Sigwalt, David; Moncelet, Damien; Falcinelli, Shane et al. (2016) Acyclic Cucurbit[n]uril-Type Molecular Containers: Influence of Linker Length on Their Function as Solubilizing Agents. ChemMedChem 11:980-9
Sigwalt, David; Ahlbrand, Sarah; Zhang, Mingming et al. (2015) Acyclic Cucurbit[n]uril Dendrimers. Org Lett 17:5914-7
Robinson, Elizabeth L; Zavalij, Peter Y; Isaacs, Lyle (2015) Synthesis of a Disulfonated Derivative of Cucurbit[7]uril and Investigations of its Ability to Solubilize Insoluble Drugs. Supramol Chem 27:288-297
Haerter, Friederike; Simons, Jeroen Cedric Peter; Foerster, Urs et al. (2015) Comparative Effectiveness of Calabadion and Sugammadex to Reverse Non-depolarizing Neuromuscular-blocking Agents. Anesthesiology 123:1337-49

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