Soumen K. Samanta

Orthogonal actuation of a supramolecular double-porphyrin tweezer.

A supramolecular three-component double-porphyrin tweezer (PT) is prepared quantitatively using heteroleptic complex formation along the HETTAP methodology. Insertion of guest molecules, such as DABCO or pyrazine, into the coupled porphyrin cavities of PT leads to an actuation of the double-porphyrin tweezer function. Evidence from (1)H NMR, VT NMR, and UV-vis titration suggests a rapid association/dissociation of the DABCO molecules at the central porphyrin. Upon addition of an equimolar mixture of DABCO and pyrazine to PT, a dynamic five-component self-assembled structure was furnished exclusively. (1)H NMR and K(assoc) values validate the greater stability of the heteroloaded PT-(DABCO)(py) system in comparison to the two homoloaded systems, PT-(DABCO)(2) and PT-(py)(2). The higher stability of PT-(DABCO)(py) seems to be the result of charge transfer from DABCO to the vacant pi* orbital of pyrazine across the porphyrin plane.

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

Mixed self-assembly of ligands 1, 2, 1,6-hexanediamine (HDA), and Pd(NO3)2 afforded Fujita-type metal organic polyhedron MOP1 (diameter ≈ 8.2 nm), which is covalently functionalized with an average of 18 cucurbit[7]uril (CB[7]) units, as evidenced by 1H NMR, diffusion-ordered spectroscopy NMR, and transmission electron microscopy measurements. By virtue of the host-guest properties of CB[7], the inner cavity of MOP can be rendered hydrophobic by using octadecyl HDA (3) as guest during the self-assembly process. The hydrophobic cavity was successfully utilized to trap the hydrophobic dye Nile Red (NR) and the anticancer drug doxorubicin (DOX). The stimuli-responsive release of encapsulated NR or DOX occurs (1) upon addition of a competitive binder (e.g., adamantane ammonium (ADA)) for CB[7], (2) by a dual pH-chemical stimulus involving the protonation state change of adamantane carboxylate at pH 5.8, and (3) by a dual pH-photochemical stimulus involving photoisomerization of trans-6 to cis-6 at pH 5.8. NR is released from NR@MOP2 within HeLa cancer cells. This body of work suggests that the covalent attachment of cucurbit[n]uril to metal organic polyhedra constitutes a promising vehicle for the development of both diagnostic and therapeutic nanoparticles.

Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors

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.