title: Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors.
abstract: Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-à-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used antihelminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 μM) and poor pharmacokinetics, ABZ is clinically limited as an anticancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability, while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1·ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs.
authors.affiliation: Department of Cell Biology and Molecular Genetics and ‡Department of Chemistry and Biochemistry, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: Gaya
authors.initials: G
authors.lastname: Hettiarachchi
authors.forename: Soumen K
authors.initials: SK
authors.lastname: Samanta
authors.affiliation: Department of Cell Biology and Molecular Genetics and ‡Department of Chemistry and Biochemistry, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: Shane
authors.initials: S
authors.lastname: Falcinelli
authors.forename: Ben
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology and Molecular Genetics and ‡Department of Chemistry and Biochemistry, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: Damien
authors.initials: D
authors.lastname: Moncelet
authors.forename: Lyle
authors.initials: L
authors.lastname: Isaacs
authors.affiliation: Department of Cell Biology and Molecular Genetics and ‡Department of Chemistry and Biochemistry, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: Volker
authors.initials: V
authors.lastname: Briken
mesh_terms: D015766:Albendazole / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage / Q000494:pharmacology*; D001682:Biological Availability; D001952:Bridged-Ring Compounds / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D016503:Drug Delivery Systems; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005079:Excipients / Q000737:chemistry*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D020714:Maximum Tolerated Dose; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012486:Salmonella typhimurium / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D015766:Albendazole; D000871:Anthelmintics; D001952:Bridged-Ring Compounds; D051638:Ether-A-Go-Go Potassium Channels; D005079:Excipients; D007093:Imidazoles; C456276:cucurbit(7)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
keywords: albendazole; cancer; cucurbit[n]uril; drug delivery; excipient; molecular container; solubility