Enhanced Solubility and Targeted Delivery of Drugs using Cucurbit[n]uril-Type Compounds

dc.contributor.advisorBriken, Volkeren_US
dc.contributor.authorHettiarachchi, Gaya Kamelikaen_US
dc.contributor.departmentMolecular and Cell Biologyen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.description.abstractThere is a significant decrease in the productivity of the drug development pipeline due to low drug solubility and high toxicity. Promising solutions to these issues are to use solubilizing excipients and targeted drug delivery systems (DDS). There is a constant demand for an increased diversity of excipients and DDSs because no one host molecule can encapsulate all drugs. Here we study the use of three novel cucurbit[n]uril (CB[n])-type compounds synthesized by Dr. Lyle Isaacs. Motor1 and Motor2 are highly soluble (105 mM and 14 mM) and unique in acyclic structure. The targeted delivery of drugs was explored using biotin functionalized CB[7]. Phase solubility experiments evaluated improvements to drug solubility. Host biocompatibility was assessed both in vitro and in vivo. In vitro bioactivity studies were conducted using Motor1 complexed with several anticancer drugs and biotin functionalized CB[7] complexed with oxaliplatin. Studies with Motor1 were repeated in vivo using NUDE mice baring human cervical cancer cell tumors. Motor1 and 2 significantly increased the solubility of drugs from many different therapeutic fields, such as paclitaxel (anticancer), cinnarizine (antihistamine), and 17a-ethynyl estradiol (hormone). CB[7] and Motor1 were non-toxicity up to 10 mM in human liver and kidney cell lines. Female Swiss Webster mice continued to gain weight and appeared healthy after three intravenous doses of Motor1 up to 1230 mg/kg. Bioactivity assays using anticancer drugs paclitaxel albendazole, camptothecin and PBS-1086 complexed in Motor1 resulted in significant cytotoxicity in HeLa cells. A pilot in vivo tumor treatment study showed tumor growth stabilization with these treatments. Biotin functionalized CB[7] showed cytotoxicity specifically in cells overexpressing the biotin receptor upon targeted delivery of oxaliplatin. The CB-type compounds significantly increased the solubility of a large variety of drugs across therapeutic fields. This coupled with host toxicity and drug bioactivity data indicate that these CB[n]-type compounds may be invaluable contributions to the toolbox of excipients and DDSs currently available.en_US
dc.subject.pqcontrolledCellular biologyen_US
dc.titleEnhanced Solubility and Targeted Delivery of Drugs using Cucurbit[n]uril-Type Compoundsen_US


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