Development of a drug-release strategy based on the reductive fragmentation of benzyl carbamate disulfides

Senter, Peter D.; Pearce, Walter E.; Greenfield, Robert S.

doi:10.1021/jo00296a082

Cited by 69 publications

(81 citation statements)

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“…Therefore, the rate-limiting step for bioavailability in such a system is actually the activation of prodrug rather than the release of drug from the liposome. In the current system, any thiol-containing agent can cleave the dithiobenzyl linker and generate free MMC (22,38). Although thiols are ubiquitously present in biological systems (39), these are mostly polar molecules (e.g., glutathione and cysteine) or macromolecules (e.g., albumin).…”

Section: Discussionmentioning

confidence: 99%

“…This conjugate (known as JNJ-27548547, ALZA Corporation, Mountain View, CA) is highly lipophilic and compatible with liposomal bilayers. Upon thiolytic cleavage of the disulfide-substituted benzyl urethane, MMC is released and becomes bioavailable (22). We hypothesized that the kinetics of liposome localization in tumor tissue will be faster than the kinetics of prodrug thiolytic activation in vivo, thus enabling selective tumor drug delivery in the prodrug form and reduced systemic toxicity.…”

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confidence: 99%

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Reduced Toxicity and Superior Therapeutic Activity of a Mitomycin C Lipid-Based Prodrug Incorporated in Pegylated Liposomes

Gabizón

Tzemach

Horowitz³

et al. 2006

Clinical Cancer Research

114

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Purpose: A lipid-based prodrug of mitomycin C [MMC; 2,3-(distearoyloxy)propane-1-dithio-4V-benzyloxycarbonyl-MMC] was designed for liposome formulation. The purpose of this study was to examine the in vitro cytotoxicity, pharmacokinetics, in vivo toxicity, and in vivo antitumor activity of this new lipid-based prodrug formulated in polyethylene glycol^coated (pegylated) liposomes. Experimental Design: MMC was released from the MMC lipid^based prodrug (MLP) by thiolytic-induced cleavage with a variety of thiol-containing reducing agents. MLP was incorporated with nearly 100% efficiency in cholesterol-free pegylated liposomes with hydrogenated phosphatidylcholine as the main component and a mean vesicle size of f90 nm.This formulation was used for in vitro and in vivo tests in rodents. Results: In vitro, the cytotoxic activity of pegylated liposomal MLP (PL-MLP) was drastically reduced compared with free MMC. However, in the presence of reducing agents, such as cysteine or N-acetyl-cysteine, its activity increased to nearly comparable levels to those of free MMC. Intravenous administration of PL-MLP in rats resulted in a slow clearance indicating stable prodrug retention in liposomes and long circulation time kinetics, with a pharmacokinetic profile substantially different from that of free MMC. In vivo, PL-MLP was f3-fold less toxic than free MMC.The therapeutic index and absolute antitumor efficacy of PL-MLP were superior to that of free MMC in the three tumor models tested. In addition, PL-MLP was significantly more active than a formulation of doxorubicin in pegylated liposomes (DOXIL) in the M109R tumor model, a mouse tumor cell line with a multidrug-resistant phenotype. Conclusions: Delivery of MLP in pegylated liposomes is a potential approach for effective treatment of multidrug-resistant tumors while significantly buffering the toxicity of MMC.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Reduced Toxicity and Superior Therapeutic Activity of a Mitomycin C Lipid-Based Prodrug Incorporated in Pegylated Liposomes

Gabizón

Tzemach

Horowitz³

et al. 2006

Clinical Cancer Research

114

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“…46, 47 The 7- O -thiobenzyl derivative 5 was designed to undergo reductive cleavage from the AuNP by glutathione in the reducing tumor environment and to release native paclitaxel. 48 Glutathione is the most abundant intracellular thiol, with concentrations ranging from 0.2–10 mM, 49 and with concentration in tumors higher than in normal tissue. 50 And, this range of concentrations is far higher than the 2.09 ± 1.14 μM found in human plasma, 51 indicating that a compound such as 5 should be reasonably stable in plasma but should undergo reductive cleavage in the tumor.…”

Section: Resultsmentioning

confidence: 99%

“…Paclitaxel analog 5 was prepared (Scheme 3) by coupling precursor 12 53 with the corresponding alcohol 13 , 48 followed by deprotection of the resulting TBDMS ether 14 .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of Paclitaxel-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery

et al. 2016

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The synthesis of a series of thiolated paclitaxel analogs is described as part of a novel nanomedicine program aimed at developing formulations of paclitaxel that will bind to gold nanoparticles for tumor targeted drug delivery. Preliminary evaluation of the new nanomedicine comprised of 27 nm gold nanoparticles, tumor necrosis factor alpha (TNFα), thiolated polyethylene glycol (PEG-Thiol) and one of several thiolated paclitaxel analogs is presented.

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“…1–4 In these cases, the released substrate is either a phenol (R′ = Ar) or an aniline derivative so that the intramolecular cyclization occurs rapidly at physiological temperature, 5 generally with a half-life from minutes to one hour. 6 Intramolecular cyclizations of this type also have been used to unmask aromatic hydroxyl, 7 amine 8 or thiol 9 moieties as mechanisms to initiate electron cascade reactions or for release of polymer-bound drugs. 10 Again the focus was to use the intramolecular cyclization for rapid drug release at physiological temperature, and this required R′ to be aromatic.…”

Section: Introductionmentioning

confidence: 99%

Thermally induced substrate release via intramolecular cyclizations of Amino esters and Amino carbonates

et al. 2014

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The relative cleavage of an alcohol from a panel of amino esters and amino carbonates via intramolecular cyclization was examined as a mechanism for substrate release. Thermal stability at 37 °C was observed only for the 7-membered ring progenitors. Applicability of the approach was illustrated by δ-lactam formation within a poly(dimethylsiloxane) microchannel for release of a captured fluorescent probe.

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Development of a drug-release strategy based on the reductive fragmentation of benzyl carbamate disulfides

Cited by 69 publications

References 0 publications

Reduced Toxicity and Superior Therapeutic Activity of a Mitomycin C Lipid-Based Prodrug Incorporated in Pegylated Liposomes

Reduced Toxicity and Superior Therapeutic Activity of a Mitomycin C Lipid-Based Prodrug Incorporated in Pegylated Liposomes

Synthesis and Evaluation of Paclitaxel-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery

Thermally induced substrate release via intramolecular cyclizations of Amino esters and Amino carbonates

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