Dataset Information

In Vitro and In Vivo Sequestration of Phencyclidine by Me₄ Cucurbit[8]uril*.

ABSTRACT: We report investigations of the use of cucurbit[8]uril (CB[8]) macrocycles as an antidote to counteract the in vivo biological effects of phencyclidine. We investigate the binding of CB[8] and its derivative Me₄ CB[8] toward ten drugs of abuse (3-9, 12-14) by a combination of ¹ H NMR spectroscopy and isothermal titration calorimetry in phosphate buffered water. We find that the cavity of CB[8] and Me₄ CB[8] are able to encapsulate the 1-amino-1-aryl-cyclohexane ring system of phencyclidine (PCP) and ketamine as well as the morphinan skeleton of morphine and hydromorphone with K_d values ≤50 nm. In vitro cytotoxicity (MTS metabolic and adenylate kinase cell death assays in HEK293 and HEPG2 cells) and in vivo maximum tolerated dose studies (Swiss Webster mice) which were performed for Me₄ CB[8] indicated good tolerability. The tightest host⋅guest pair (Me₄ CB[8]⋅PCP; K_d =2 nm) was advanced to in vivo efficacy studies. The results of open field tests demonstrate that pretreatment of mice with Me₄ CB[8] prevents subsequent hyperlocomotion induction by PCP and also that treatment of animals previously dosed with PCP with Me₄ CB[8] significantly reduces the locomotion levels.

SUBMITTER: Murkli S

PROVIDER: S-EPMC7902406 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

In Vitro and In Vivo Sequestration of Phencyclidine by Me4 Cucurbit[8]uril*.

Murkli Steven S Klemm Jared J Brockett Adam T AT Shuster Michael M Briken Volker V Roesch Matthew R MR Isaacs Lyle L

Chemistry (Weinheim an der Bergstrasse, Germany) 20210119 9

We report investigations of the use of cucurbit[8]uril (CB[8]) macrocycles as an antidote to counteract the in vivo biological effects of phencyclidine. We investigate the binding of CB[8] and its derivative Me4 CB[8] toward ten drugs of abuse (3-9, 12-14) by a combination of 1 H NMR spectroscopy and isothermal titration calorimetry in phosphate buffered water. We find that the cavity of CB[8] and Me4 CB[8] are able to encapsulate the 1-amino-1-aryl-cyclohexane r ...[more]

PMID: 33206421

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Project description:Mesoporous silica nanoparticles (MSNs) are promising solid supports for controlled anticancer drug delivery. Herein, we report biocompatible layer-by-layer (LbL) coated MSNs (LbL-MSNs) that are designed and crafted to release encapsulated anticancer drugs, e.g., doxorubicin hydrochloride (DOX), by changing the pH or by adding competitive agents. The LbL coating process comprises bis-aminated poly(glycerol methacrylate)s (BA-PGOHMAs) and cucurbit[7]uril (CB[7]), where CB[7] serves as a molecular bridge holding two different bis-aminated polymeric layers together by means of host-guest interactions. This integrated nanosystem is tuned to respond under specific acidic conditions or by adding adamantaneamine hydrochloride (AH), attributed to the competitive binding of hydronium ions or AH to CB[7] with BA-PGOHMAs. These LbL-MSN hybrids possess excellent biostability, negligible premature drug leakage at pH 7.4, and exceptional stimuli-responsive drug release performance. The pore sizes of the MSNs and bis-aminated compounds (different carbon numbers) of BA-PGOHMAs have been optimized to provide effective integrated nanosystems for the loading and release of DOX. Significantly, the operating pH for the controlled release of DOX matches the acidifying endosomal compartments of HeLa cancer cells, suggesting that these hybrid nanosystems are good candidates for autonomous anticancer drug nanocarriers actuated by intracellular pH changes without any invasive external stimuli. The successful cellular uptake and release of cargo, e.g., propidium iodide (PI), in human breast cancer cell line MDA-231 from PI-loaded LbL-MSNs have been confirmed by confocal laser scanning microscopy (CLSM), while the cytotoxicities of DOX-loaded LbL-MSNs have been quantified by the Cell Counting Kit-8 (CCK-8) viability assay against HeLa cell lines and fibroblast L929 cell lines. The uptake of DOX-loaded LbL-MSNs by macrophages can be efficiently reduced by adding biocompatible hydrophilic poly(ethylene glycol) or CB[7] without destroying the capping. In vivo tumor-growth inhibition experiments with BALB/c nude mice demonstrated a highly efficient tumor-growth inhibition rate of DOX-loaded LbL-MSNs, suggesting that the novel type of LbL-MSN materials hold great potentials in anticancer drug delivery.

Dataset Information

In Vitro and In Vivo Sequestration of Phencyclidine by Me₄ Cucurbit[8]uril*.

Publications

In Vitro and In Vivo Sequestration of Phencyclidine by Me<sub>4</sub> Cucurbit[8]uril*.

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