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Sample records for donor prodrug protects

  1. Development and characterization of glutamyl-protected N-hydroxyguanidines as reno-active nitric oxide donor drugs with therapeutic potential in acute renal failure.

    PubMed

    Zhang, Qingzhi; Milliken, Philip; Kulczynska, Agnieszka; Slawin, Alex M Z; Gordon, Adele; Kirkby, Nicholas S; Webb, David J; Botting, Nigel P; Megson, Ian L

    2013-07-11

    Acute renal failure (ARF) has high mortality and no effective treatment. Nitric oxide (NO) delivery represents a credible means of preventing the damaging effects of vasoconstriction, central to ARF, but design of drugs with the necessary renoselectivity is challenging. Here, we developed N-hydroxyguanidine NO donor drugs that were protected against spontaneous NO release by linkage to glutamyl adducts that could be cleaved by γ-glutamyl transpeptidase (γ-GT), found predominantly in renal tissue. Parent NO donor drug activity was optimized in advance of glutamyl adduct prodrug design. A lead compound that was a suitable substrate for γ-GT-mediated deprotection was identified. Metabolism of this prodrug to the active parent compound was confirmed in rat kidney homogenates, and the prodrug was shown to be an active vasodilator in rat isolated perfused kidneys (EC50 ~50 μM). The data confirm that glutamate protection of N-hydroxyguanidines is an approach that might hold promise in ARF.

  2. Cephalosporin-NO-donor prodrug PYRRO-C3D shows β-lactam-mediated activity against Streptococcus pneumoniae biofilms.

    PubMed

    Allan, Raymond N; Kelso, Michael J; Rineh, Ardeshir; Yepuri, Nageshwar R; Feelisch, Martin; Soren, Odel; Brito-Mutunayagam, Sanjita; Salib, Rami J; Stoodley, Paul; Clarke, Stuart C; Webb, Jeremy S; Hall-Stoodley, Luanne; Faust, Saul N

    2017-05-01

    Bacterial biofilms show high tolerance towards antibiotics and are a significant problem in clinical settings where they are a primary cause of chronic infections. Novel therapeutic strategies are needed to improve anti-biofilm efficacy and support reduction in antibiotic use. Treatment with exogenous nitric oxide (NO) has been shown to modulate bacterial signaling and metabolic processes that render biofilms more susceptible to antibiotics. We previously reported on cephalosporin-3'-diazeniumdiolates (C3Ds) as NO-donor prodrugs designed to selectively deliver NO to bacterial infection sites following reaction with β-lactamases. With structures based on cephalosporins, C3Ds could, in principal, also be triggered to release NO following β-lactam cleavage mediated by transpeptidases/penicillin-binding proteins (PBPs), the antibacterial target of cephalosporin antibiotics. Transpeptidase-reactive C3Ds could potentially show both NO-mediated anti-biofilm properties and intrinsic (β-lactam-mediated) antibacterial effects. This dual-activity concept was explored using Streptococcus pneumoniae, a species that lacks β-lactamases but relies on transpeptidases for cell-wall synthesis. Treatment with PYRRO-C3D (a representative C3D containing the diazeniumdiolate NO donor PYRRO-NO) was found to significantly reduce viability of planktonic and biofilm pneumococci, demonstrating that C3Ds can elicit direct, cephalosporin-like antibacterial activity in the absence of β-lactamases. While NO release from PYRRO-C3D in the presence of pneumococci was confirmed, the anti-pneumococcal action of the compound was shown to arise exclusively from the β-lactam component and not through NO-mediated effects. The compound showed similar potency to amoxicillin against S. pneumoniae biofilms and greater efficacy than azithromycin, highlighting the potential of C3Ds as new agents for treating pneumococcal infections.

  3. Protecting the interests of the child bone marrow donor.

    PubMed

    Terry, Louise M; Campbell, Anne

    2004-01-01

    At a time when designer babies have been created to act as cord blood donors to sick siblings, ethical debate has focused predominantly on the extent to which it is acceptable to create one human being to assist another. However, children are frequently used this way, by their families and doctors who extract their bone marrow, to try to save the life of another, usually a sibling. With any life-threatening illness, there is the possibility that the urgency of the sick sibling's need means that the short-term welfare of the donor child receives less attention than it should by parents and doctors. This article suggests ways to protect the interests of such children and empower them within the decision-making process and concludes that the drive to save life must be tempered by recognition of the intrinsic worth of donor children and their rights not to be exploited.

  4. Stabilization of the nitric oxide (NO) prodrugs and anticancer leads, PABA/NO and Double JS-K, through incorporation into PEG-protected nanoparticles.

    PubMed

    Kumar, Varun; Hong, Sam Y; Maciag, Anna E; Saavedra, Joseph E; Adamson, Douglas H; Prud'homme, Robert K; Keefer, Larry K; Chakrapani, Harinath

    2010-02-01

    We report the stabilization of the nitric oxide (NO) prodrugs and anticancer lead compounds, PABA/NO (O(2)-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) and "Double JS-K" 1,5-bis-{1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diol-2-ato}-2,4-dinitrobenzene, through their incorporation into polymer-protected nanoparticles. The prodrugs were formulated in block copolymer-stabilized nanoparticles with sizes from 220 to 450 nm by a novel rapid precipitation process. The block copolymers, with polyethylene glycol (PEG) soluble blocks, provide a steric barrier against NO prodrug activation by glutathione. Too rapid activation and NO release has been a major barrier to effective administration of this class of compounds. The nanoparticle stabilized PABA/NO are protected from attack by glutathione as evidenced by a significant increase in time taken for 50% decomposition from 15 min (unformulated) to 5 h (formulated); in the case of Double JS-K, the 50% decomposition time was extended from 4.5 min (unformulated) to 40 min (formulated). The more hydrophobic PABA/NO produced more stable nanoparticles and correspondingly more extended release times in comparison with Double JS-K. The hydrophobic blocks of the polymer were either polystyrene or polylactide. Both blocks produced nanoparticles of approximately the same size and release kinetics. This combination of PEG-protected nanoparticles with sizes appropriate for cancer targeting by enhanced permeation and retention (EPR) and delayed release of NO may afford enhanced therapeutic benefit.

  5. Stabilization of the Nitric Oxide (NO) Prodrugs and Anti-Cancer Leads, PABA/NO and Double JS-K through Incorporation into PEG-Protected Nanoparticles

    PubMed Central

    Kumar, Varun; Hong, Sam Y.; Maciag, Anna E.; Saavedra, Joseph E.; Adamson, Douglas H.; Prud'homme, Robert K.; Keefer, Larry K.; Chakrapani, Harinath

    2009-01-01

    Here we report the stabilization of the nitric oxide (NO) prodrugs and anti-cancer lead compounds, PABA/NO (O2-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) and “Double JS-K” (1,5-bis{[1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diol-2-ato]-2,4-dinitrobenzene), through their incorporation into polymer-protected nanoparticles. The prodrugs were formulated in block copolymer-stabilized nanoparticles with sizes from 220 to 450 nm by a novel rapid precipitation process. The block copolymers, with polyethylene glycol (PEG) soluble blocks, provide a steric barrier against NO prodrug activation by glutathione. Too rapid activation and NO release has been a major barrier to effective administration of this class of compounds. The nanoparticle stabilized PABA/NO from attack by glutathione as evidenced by a significant increase in time taken for 50% decomposition from 15 min (unformulated) to 5 h (formulated); in the case of Double JS-K, the 50% decomposition time was extended from 4.5 min (unformulated) to 40 min (formulated). The more hydrophobic PABA/NO produced more stable nanoparticles and correspondingly more extended release times in comparison with Double JS-K. The hydrophobic blocks of the polymer were either polystyrene or polylactide. Both blocks produced nanoparticles of approximately the same size and release kinetics. This combination of PEG-protected nanoparticles with sizes appropriate for cancer targeting by enhanced permeation and retention (EPR) and delayed release of NO may afford enhanced therapeutic benefit. PMID:20000791

  6. Keeping mum about dad: "contracts" to protect gamete donor anonymity.

    PubMed

    Rees, Anne

    2012-06-01

    This article considers the legal status of so-called contracts for anonymity between fertility clinics and donors of gametes that were made in the period before legislation authorising disclosure. It notes that while clinics frequently cite the existence of these "contracts" to argue against retrospective legislation authorising disclosure of the donor's identity, they may be nothing more than one-sided statements of informed consent. However, the article notes that even if an agreement between a donor and a clinic is not contractual, it does not follow that a person conceived through assisted reproductive technology has any right of access to the identity of the donor. The writer has not been able to locate examples of written promises by the clinics promising anonymity. There are written promises by the donors not to seek the identity of the recipients. These promises do not bind the resulting offspring nor do they appear to be supported by consideration. The article suggests that the basis for any individual donor to restrain a clinic from revealing their identity may be found in promissory estoppel. Nevertheless, there is no real issue in Australia concerning clinics revealing these details absent legislative authority. The issue is whether parliaments will legislate to authorise the disclosure. The article notes that it would be rare for parliaments to legislate to overturn existing legal contracts but suggests that the contract argument may not be as strong as has been thought.

  7. New prodrugs against tuberculosis.

    PubMed

    Mori, Giorgia; Chiarelli, Laurent Roberto; Riccardi, Giovanna; Pasca, Maria Rosalia

    2017-03-01

    The term 'prodrug' was first introduced by Albert in 1958. Generally, prodrugs can be utilized for improving active drug solubility and bioavailability, increasing drug permeability and absorption, modifying the distribution profile, preventing fast metabolism and excretion, and reducing toxicity. Previously, the prodrug approach was a final resort during the drug discovery process only after all other approaches had been exhausted. However, this strategy is now considered during the early stages of the drug development process. Most antitubercular agents are defined as 'prodrugs', including isoniazid and ethionamide. Thus, the prodrug approach could provide novel targets for the rational design of more effective treatments for tuberculosis (TB).

  8. BLISS: a computer program for the protection of blood donors. Technical report

    SciTech Connect

    Catsimpoolas, N.; Cooke, C.; Valeri, C.R.

    1982-06-28

    A BASIC program has been developed for the Hewlett-Packard Model 9845 desk-top computer which allows the creation of blood donor files for subsequent retrieval, update, and correction. A similar modified version was developed for hte HP 9835 Model. This software system has been called BLISS which stands for Blood Information and Security System. In addition to its function as a file management system, BLISS provides warnings before a donation is performed to protect the donor from excessive exposure to radioactivity and DMSO levels, from too frequent of donations of blood, and from adverse reactions. The program can also be used to select donors who have participated in specific studies and to list the experimental details which have been stored in the file. The BLISS system has been actively utilized at the Naval Blood Research Laboratory in Boston and contains the files of over 750 donors.

  9. Photoactivatable Caged Prodrugs of VEGFR-2 Kinase Inhibitors.

    PubMed

    Pinchuk, Boris; Horbert, Rebecca; Döbber, Alexander; Kuhl, Lydia; Peifer, Christian

    2016-04-29

    In this study, we report on the design, synthesis, photokinetic properties and in vitro evaluation of photoactivatable caged prodrugs for the receptor tyrosine kinase VEGFR-2. Highly potent VEGFR-2 inhibitors 1 and 3 were caged by introduction of a photoremovable protecting group (PPG) to yield the caged prodrugs 4 and 5. As expected, enzymatic and cellular proliferation assays showed dramatically diminished efficacy of caged prodrugs in vitro. Upon ultraviolet (UV) irradiation of the prodrugs original inhibitory activity was completely restored and even distinctly reinforced, as was the case for the prodrug 4. The presented results are a further evidence for caging technique being an interesting approach in the protein kinase field. It could enable spatial and temporal control for the inhibition of VEGFR-2. The described photoactivatable prodrugs might be highly useful as biological probes for studying the VEGFR-2 signal transduction.

  10. Esterase-Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide.

    PubMed

    Zheng, Yueqin; Yu, Bingchen; Ji, Kaili; Pan, Zhixiang; Chittavong, Vayou; Wang, Binghe

    2016-03-24

    Prodrugs that release hydrogen sulfide upon esterase-mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H2 S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H2 S donors. Additionally, such prodrugs can easily be conjugated to another non-steroidal anti-inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H2 S prodrugs, the anti-inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS-induced TNF-α production in RAW 264.7 cells. This type of H2 S prodrugs shows great potential as both research tools and therapeutic agents.

  11. [Radiation Anticarcinogenesis by Thiazolidine Pro-drug

    NASA Technical Reports Server (NTRS)

    Warters, Raymond L.; Roberts, Jeanette C.; Fain, Heidi

    1999-01-01

    The original goal of this work was to determine the capacity of selected aminothiols to modulate radiation induced cytotoxicity, mutagenesis and carcinogenesis in a human mammary epithelial cell line. The conclusions from this work are that WR-1065 is the "gold standard" for protection against radiation induced cytotoxicity, mutagenesis and carcinogenesis. While a potent radiation protector, WR-1065 is cytotoxic in vitro and in vivo. Our rationale for a study of the thiazolidine pro-drugs was that these compounds are neither toxic in vitro or in vivo. The results obtained during this funding period indicate that the thiazolidine pro-drugs are as potent as WR-1065 as protectors against radiation induced mutation induction, and thus presumably against radiation induced carcinogenesis. Our results indicate that the thiazolidine prodrugs are excellent candidates to test as non-toxic anticarcinogens for protecting astronauts from cancer induction during space travel.

  12. Multiqubit gates protected by adiabaticity and dynamical decoupling applicable to donor qubits in silicon

    NASA Astrophysics Data System (ADS)

    Witzel, Wayne M.; Montaño, Inès; Muller, Richard P.; Carroll, Malcolm S.

    2015-08-01

    We present a strategy for producing multiqubit gates that promise high fidelity with minimal tuning requirements. Our strategy combines gap protection from the adiabatic theorem with dynamical decoupling in a complementary manner. Energy-level transition errors are protected by adiabaticity and remaining phase errors are mitigated via dynamical decoupling. This is a powerful way to divide and conquer the various error channels. In order to accomplish this without violating a no-go theorem regarding black-box dynamically corrected gates [Phys. Rev. A 80, 032314 (2009), 10.1103/PhysRevA.80.032314], we require a robust operating point (sweet spot) in control space where the qubits interact with little sensitivity to noise. There are also energy gap requirements for effective adiabaticity. We apply our strategy to an architecture in Si with P donors where we assume we can shuttle electrons between different donors. Electron spins act as mobile ancillary qubits and P nuclear spins act as long-lived data qubits. This system can have a very robust operating point where the electron spin is bound to a donor in the quadratic Stark shift regime. High fidelity single qubit gates may be performed using well-established global magnetic resonance pulse sequences. Single electron-spin preparation and measurement has also been demonstrated. Putting this all together, we present a robust universal gate set for quantum computation.

  13. Multi-qubit gates protected by adiabaticity and dynamical decoupling applicable to donor qubits in silicon

    DOE PAGES

    Witzel, Wayne; Montano, Ines; Muller, Richard P.; ...

    2015-08-19

    In this paper, we present a strategy for producing multiqubit gates that promise high fidelity with minimal tuning requirements. Our strategy combines gap protection from the adiabatic theorem with dynamical decoupling in a complementary manner. Energy-level transition errors are protected by adiabaticity and remaining phase errors are mitigated via dynamical decoupling. This is a powerful way to divide and conquer the various error channels. In order to accomplish this without violating a no-go theorem regarding black-box dynamically corrected gates [Phys. Rev. A 80, 032314 (2009)], we require a robust operating point (sweet spot) in control space where the qubits interactmore » with little sensitivity to noise. There are also energy gap requirements for effective adiabaticity. We apply our strategy to an architecture in Si with P donors where we assume we can shuttle electrons between different donors. Electron spins act as mobile ancillary qubits and P nuclear spins act as long-lived data qubits. Furthermore, this system can have a very robust operating point where the electron spin is bound to a donor in the quadratic Stark shift regime. High fidelity single qubit gates may be performed using well-established global magnetic resonance pulse sequences. Single electron-spin preparation and measurement has also been demonstrated. Thus, putting this all together, we present a robust universal gate set for quantum computation.« less

  14. Multi-qubit gates protected by adiabaticity and dynamical decoupling applicable to donor qubits in silicon

    SciTech Connect

    Witzel, Wayne; Montano, Ines; Muller, Richard P.; Carroll, Malcolm S.

    2015-08-19

    In this paper, we present a strategy for producing multiqubit gates that promise high fidelity with minimal tuning requirements. Our strategy combines gap protection from the adiabatic theorem with dynamical decoupling in a complementary manner. Energy-level transition errors are protected by adiabaticity and remaining phase errors are mitigated via dynamical decoupling. This is a powerful way to divide and conquer the various error channels. In order to accomplish this without violating a no-go theorem regarding black-box dynamically corrected gates [Phys. Rev. A 80, 032314 (2009)], we require a robust operating point (sweet spot) in control space where the qubits interact with little sensitivity to noise. There are also energy gap requirements for effective adiabaticity. We apply our strategy to an architecture in Si with P donors where we assume we can shuttle electrons between different donors. Electron spins act as mobile ancillary qubits and P nuclear spins act as long-lived data qubits. Furthermore, this system can have a very robust operating point where the electron spin is bound to a donor in the quadratic Stark shift regime. High fidelity single qubit gates may be performed using well-established global magnetic resonance pulse sequences. Single electron-spin preparation and measurement has also been demonstrated. Thus, putting this all together, we present a robust universal gate set for quantum computation.

  15. Two absorption furosemide prodrugs.

    PubMed

    Mombrú, A W; Mariezcurrena, R A; Suescun, L; Pardo, H; Manta, E; Prandi, C

    1999-03-15

    The structures of two absorption furosemide prodrugs, hexanoyloxymethyl 4-chloro-N-furfuryl-5-sulfamoyl-anthranilate (C19H23CIN2O7S), (I), and benzoyloxymethyl 4-chloro-N-furfuryl-5-sulfamoylanthranilate (C20H17CIN2O7S), (II), are described in this paper and compared with furosemide and four other prodrugs. The molecular conformations of both compounds are similar to those of the other prodrugs; the packing and the crystal system are the primary differences. Compound (I) crystallizes in the trigonal space group R3 and compound (II) in the monoclinic space group P2(1)/n. The packing of both structures is stabilized by a three-dimensional hydrogen-bond network.

  16. Cytochrome P450-activated prodrugs

    PubMed Central

    Ortiz de Montellano, Paul R

    2013-01-01

    A prodrug is a compound that has negligible, or lower, activity against a specified pharmacological target than one of its major metabolites. Prodrugs can be used to improve drug delivery or pharmacokinetics, to decrease toxicity, or to target the drug to specific cells or tissues. Ester and phosphate hydrolysis are widely used in prodrug design because of their simplicity, but such approaches are relatively ineffective for targeting drugs to specific sites. The activation of prodrugs by the cytochrome P450 system provides a highly versatile approach to prodrug design that is particularly adaptable for targeting drug activation to the liver, to tumors or to hypoxic tissues. PMID:23360144

  17. Adaptive cellular protection against UVA-1-induced lipid peroxidation in human dermal fibroblasts shows donor-to-donor variability and is glutathione dependent.

    PubMed

    Schneider, Lars Alexander; Dissemond, Joachim; Brenneisen, Peter; Hainzl, Adelheid; Briviba, Karlis; Wlaschek, Meinhard; Scharffetter-Kochanek, Karin

    2006-01-01

    Photo-oxidative stress and subsequent lipid peroxidation (LPO) is one of the major mechanisms of UVA-related skin pathology. The skin's protection system against photo-oxidative stress involves low molecular scavengers as well as highly specialised antioxidant enzymes like glutathione peroxidase (GPX). Against repetitive UVA-1 exposures in vitro it is partly adaptive, as recent studies have shown exemplarily for antioxidant enzymes. We now investigated in vitro by repetitively irradiating human dermal fibroblasts with UVA-1 whether this adaptive response might reflect itself in reduced cellular membrane damage, that is, LPO. Our experiments show that the degree of cellular protection against LPO and the adaptive potential of the cells against a repetitive UVA-1 exposure varies from donor-to-donor and depends highly on glutathione.

  18. Prodrugs: design and clinical applications.

    PubMed

    Rautio, Jarkko; Kumpulainen, Hanna; Heimbach, Tycho; Oliyai, Reza; Oh, Dooman; Järvinen, Tomi; Savolainen, Jouko

    2008-03-01

    Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

  19. High preoperative bilirubin values protect against reperfusion injury after live donor liver transplantation.

    PubMed

    Spetzler, Vinzent N; Goldaracena, Nicolas; Kaths, Johann M; Marquez, Max; Selzner, Nazia; Cattral, Mark S; Greig, Paul D; Lilly, Les; McGilvray, Ian D; Levy, Gary A; Ghanekar, Anand; Renner, Eberhard L; Grant, David R; Selzner, Markus

    2015-11-01

    Heme Oxygenase-1 and its product biliverdin/bilirubin have been demonstrated to protect against ischemia/reperfusion injury (IRI). We investigated whether increased preoperative bilirubin values of transplant recipients decrease IRI. Preoperative bilirubin levels of live donor liver recipients were correlated to postoperative liver transaminase as a marker of IRI. Additionally, two recipient groups with pretransplant bilirubin levels >24 μmol/l (n = 348) and ≤24 μmol/l (n = 118) were compared. Post-transplant liver function, complications, length of hospital stay, and patient and graft survival were assessed. Preoperative bilirubin levels were negatively correlated to the postoperative increase in transaminases suggesting a protective effect against IRI. The maximal rise of ALT after transplantation in high versus low bilirubin patients was 288 (-210-2457) U/l vs. 375 (-11-2102) U/l, P = 0.006. Bilirubin remained a significant determining factor in a multivariate linear regression analysis. The MELD score and its individual components as a marker of severity of chronic liver disease were significantly higher in the high versus low bilirubin group (P < 0.001). Despite this, overall complication rate (21.0% vs. 21.2%, P = 0.88), hospital stay [13 (4-260) vs. 14 (6-313) days, P = 0.93), and 1-year graft survival (90.8% vs. 89.0%, P = 0.62) were similar in both groups. High bilirubin levels of liver recipients before live donor transplantation is associated with decreased postoperative IRI.

  20. Prodrug approaches for CNS delivery.

    PubMed

    Rautio, Jarkko; Laine, Krista; Gynther, Mikko; Savolainen, Jouko

    2008-01-01

    Central nervous system (CNS) drug delivery remains a major challenge, despite extensive efforts that have been made to develop novel strategies to overcome obstacles. Prodrugs are bioreversible derivatives of drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which subsequently exerts the desired pharmacological effect. In both drug discovery and drug development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents that overcome barriers to a drug's usefulness. This review provides insight into various prodrug strategies explored to date for CNS drug delivery, including lipophilic prodrugs, carrier- and receptor-mediated prodrug delivery systems, and gene-directed enzyme prodrug therapy.

  1. Aid for health in times of political unrest in Mali: does donors' way of intervening allow protecting people's health?

    PubMed

    Paul, Elisabeth; Samaké, Salif; Berthé, Issa; Huijts, Ini; Balique, Hubert; Dujardin, Bruno

    2014-12-01

    Mali has long been a leader in francophone Africa in developing systems aimed at improving aid effectiveness, especially in the health sector. But following the invasion of the Northern regions of the country by terrorist groups and a coup in March 2012, donors suspended official development assistance, except for support to NGOs and humanitarian assistance. They resumed aid after transfer of power to a civil government, but this was not done in a harmonized framework. This article describes and analyses how donors in the health sector reacted to the political unrest in Mali. It shows that despite its long sector-wide approach experience and international agreements to respect aid effectiveness principles, donors have not been able to intervene in view of safeguarding the investments of co-operation in the past decade, and of protecting the health system's functioning. They reacted to the political unrest on a bilateral basis, stopped working with their ministerial partners, interrupted support to the health system which was still expected to serve populations' needs and took months before organizing alternative and only partial solutions to resume aid to the health sector. The Malian example leads to a worrying conclusion: while protecting the health system's achievements and functioning for the population should be a priority, and while harmonizing donors' interventions seems the most appropriate way for that purpose, donors' management practices do not allow for reacting adequately in times of unrest. The article concludes by a number of recommendations.

  2. Toxicity induced by cumene hydroperoxide in PC12 cells: protective role of thiol donors.

    PubMed

    Vimard, F; Saucet, M; Nicole, O; Feuilloley, M; Duval, D

    2011-01-01

    Oxidative shock and production of reactive oxygen species are known to play a major role in situations leading to neuron degeneration, but the precise mechanisms responsible for cell degeneration remain uncertain. In the present article, we have studied in PC 12 cells the effect of cumene hydroxyperoxide on both cell metabolism and morphology. We observed that relatively low concentrations of the drug (100 μM) led to a significant decrease in the cellular content of ATP and reduced glutathione as well as to a decreased mitochondrial potential. These metabolic alterations were followed by an important increase in intracellular free calcium and membrane disruption and death. In parallel, we observed profound changes in cell morphology with a shortening of cell extensions, the formation of ruffles and blebs at the cell surface, and a progressive detachment of the cells from the surface of the culture flasks. We also showed that addition of thiol donors such as N-acetylcysteine or β-mercaptoethanol, which were able to enhance cell glutathione content, almost completely protected PC 12 cells from the toxic action of cumene hydroperoxide whereas pretreatment by buthionine sulfoximine, a selective inhibitor of GSH synthesis, enhanced its action.

  3. Prodrug Strategies for Paclitaxel

    PubMed Central

    Meng, Ziyuan; Lv, Quanxia; Lu, Jun; Yao, Houzong; Lv, Xiaoqing; Jiang, Feng; Lu, Aiping; Zhang, Ge

    2016-01-01

    Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective. PMID:27223283

  4. Abate Cytochrome C induced apoptosome to protect donor liver against ischemia reperfusion injury on rat liver transplantation model

    PubMed Central

    Zhuang, Zhuonan; Lian, Peilong; Wu, Xiaojuan; Shi, Baoxu; Zhuang, Maoyou; Zhou, Ruiling; Zhao, Rui; Zhao, Zhen; Guo, Sen; Ji, Zhipeng; Xu, Kesen

    2016-01-01

    Objective: Aim of this study is to protect donor liver against ischemia-reperfusion injury by abating Cytochrome C induced apoptosome on rat model. Methods: A total of 25 clean SD inbred male rats were used in this research. The rats in ischemia-reperfusion injury group (I/R group, n=5) were under liver transplantation operation; rats in dichloroacetate diisopropylamine group (DADA group, n=5) were treated DADA before liver transplantation; control group (Ctrl group, n=5); other 10 rats were used to offer donor livers. Results: In DADA therapy group, Cytochrome C expression in donor hepatocellular cytoplasm was detected lower than that in I/R group. And the Cytochrome C induced apoptosome was also decreased in according to the lower expressions of Apaf-1 and Caspase3. Low level of cleaved PARP expression revealed less apoptosis in liver tissue. The morphology of donor liver mitochondria in DADA group was observed to be slightly edema but less than I/R group after operation 12 h. The liver function indexes of ALT and AST in serum were tested, and the results in DADA group showed it is significantly lower than I/R group after operation 12 h. The inflammation indexes of IL-6 and TNF-α expressions in DADA group were significantly lower than that in I/R group after operation 24 h. Conclusion: The dichloroacetate diisopropylamine treatment could protect the hepatocellular mitochondria in case of the spillage of Cytochrome C induced apoptosome, and protect the liver against ischemia-reperfusion injury. Thus, it may be a method to promote the recovery of donor liver function after transplantation. PMID:27186297

  5. Cytomegalovirus protease targeted prodrug development.

    PubMed

    Sabit, Hairat; Dahan, Arik; Sun, Jing; Provoda, Chester J; Lee, Kyung-Dall; Hilfinger, John H; Amidon, Gordon L

    2013-04-01

    Human cytomegalovirus (HCMV) is a prevalent virus that infects up to 90% of the population. The goal of this research is to determine if small molecular prodrug substrates can be developed for a specific HCMV encoded protease and thus achieve site-specific activation. HCMV encodes a 256 amino acid serine protease that is responsible for capsid assembly, an essential process for herpes virus production. The esterase activity of the more stable HCMV A143T/A144T protease mutant was evaluated with model p-nitrophenol (ONp) esters, Boc-Xaa-ONp (Ala, Leu, Ile, Val, Gln, Phe at the Xaa position). We demonstrate that the A143T/A144T mutant has esterase activity toward specific small ester compounds, e.g., Boc-L-Ala-ONp. Mono amino acid and dipeptide prodrugs of ganciclovir (GCV) were also synthesized and evaluated for hydrolysis by the A143T/A144T protease mutant in solution. Hydrolysis of these prodrugs was also evaluated in Caco-2 cell homogenates, human liver microsomes (HLMs), and rat and human plasma. For the selectivity potential of the prodrugs, the hydrolysis ratio was evaluated as a percentage of prodrug hydrolyzed by the HCMV protease over the percentages of prodrug hydrolyses by Caco-2 cell homogenates, HLMs, and human/rat plasma. A dipeptide prodrug of ganciclovir, Ac-l-Gln-l-Ala-GCV, emerged as a potential selective prodrug candidate. The results of this research demonstrate that targeting prodrugs for activation by a specific protease encoded by the infectious HCMV pathogen may be achievable.

  6. Two Simple Leg Net Devices Designed to Protect Lower-Extremity Skin Grafts and Donor Sites and Prevent Decubitus Ulcer

    DTIC Science & Technology

    2007-02-01

    Two Simple Leg Net Devices Designed to Protect Lower-Extremity Skin Grafts and Donor Sites and Prevent Decubitus Ulcer Travis L. Hedman, MPT, OCS... decubitus . Pressure ulcer is a serious health prob- lem and can cause pain, suffering, disability, and even death.1,2 The cost of treatment for a...single pressure decubitus has been estimated to be as high as $70,000.3 Therefore, prevention is paramount. The prevention of pressure ulcers is far less

  7. Thiazolidine prodrugs of cysteamine and cysteine as radioprotective agents

    SciTech Connect

    Roberts, J.C.; Koch, K.E.; Detrick, S.R.

    1995-08-01

    The need for protection against the toxic effects of ionizing radiation comes from many different directions: occupational exposure, nuclear accidents, environmental sources and protection of normal tissue during the therapeutic irradiation of cancer. Sulfhydryl-containing compounds, including cysteamine and L-cysteine, have long been known to possess radioprotective properties, but their therapeutic utility is limited by their side effects at radioprotective doses. To avoid this drawback, thiazolidine prodrugs of cysteamine and L-cysteine were prepared by the condensation of each thiolamine with the aldose monosaccharides, D-ribose and D-glucose, producing RibCyst, GlcCyst, Rib-Cys and GlcCys. The prodrugs were designed to liberate the parent thiolamine nonenzymatically, after ring opening and hydrolysis, which is then available e to function as a radioprotective agent. Cysteamine`s inherent toxicity, measured using Chinese hamster V79 cells growing in culture, was completely eliminated, even at concentrations as high as 25 mM, by providing the thiolamine in the form of a prodrug. Good protection against radiation-induced lethality was demonstrated by the cysteamine prodrugs using a clonogenic assay. Protection against radiation-induced DNA single-strand breaks, as measured by alkaline elution, was also shown by both RibCyst and GlcCyst; this activity was higher than that exhibited by either cysteamine or WR-1065. The L-cysteine prodrugs, RibCys and GlcCys, also possessed radioprotective abilities under most of the conditions studied. Protection against DNA damage was comparable between L-cystein, WR-1065 and RibCys. 42 refs., 7 figs., 2 tabs.

  8. A prodrug approach involving in situ depot formation to achieve localized and sustained action of diclofenac after joint injection.

    PubMed

    Thing, Mette; Ågårdh, Li; Larsen, Susan; Rasmussen, Rune; Pallesen, Jakob; Mertz, Nina; Kristensen, Jesper; Hansen, Martin; Ostergaard, Jesper; Larsen, Claus Selch

    2014-12-01

    Long-acting nonsteroidal anti-inflammatory drug formulations for intra-articular injection might be effective in the management of joint pain and inflammation associated sports injuries and osteoarthritis. In this study, a prodrug-based delivery system was evaluated. The synthesized diclofenac ester prodrug, a weak base (pKa 7.52), has relatively high solubility at low pH (6.5 mg mL(-1) at pH 4) and much lower solubility at physiological pH (4.5 μg mL(-1) at pH 7.4) at 37°C. In biological media including 80% (v/v) human synovial fluid (SF), the prodrug was cleaved to diclofenac mediated by esterases. In situ precipitation of the prodrug was observed upon addition of a concentrated slightly acidic prodrug solution to phosphate buffer or SF at pH 7.4. The degree of supersaturation accompanying the precipitation process was more pronounced in SF than in phosphate buffer. In the rotating dialysis cell model, a slightly acidic prodrug solution was added to the donor cell containing 80% SF resulting in a continuous appearance of diclofenac in the acceptor phase for more than 43 h after an initial lag period of 8 h. Detectable amounts of prodrug were found in the rat joint up to 8 days after knee injection of the acidic prodrug solution.

  9. Prodrugs--from serendipity to rational design.

    PubMed

    Huttunen, Kristiina M; Raunio, Hannu; Rautio, Jarkko

    2011-09-01

    The prodrug concept has been used to improve undesirable properties of drugs since the late 19th century, although it was only at the end of the 1950s that the actual term prodrug was introduced for the first time. Prodrugs are inactive, bioreversible derivatives of active drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then elicit its desired pharmacological effect in the body. In most cases, prodrugs are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the active parent drug. However, some prodrugs lack an obvious carrier or promoiety but instead result from a molecular modification of the prodrug itself, which generates a new active compound. Numerous prodrugs designed to overcome formulation, delivery, and toxicity barriers to drug utilization have reached the market. In fact, approximately 20% of all small molecular drugs approved during the period 2000 to 2008 were prodrugs. Although the development of a prodrug can be very challenging, the prodrug approach represents a feasible way to improve the erratic properties of investigational drugs or drugs already on the market. This review introduces in depth the rationale behind the use of the prodrug approach from past to present, and also considers the possible problems that can arise from inadequate activation of prodrugs.

  10. Why Prodrugs and Propesticides Succeed.

    PubMed

    Casida, John E

    2017-04-07

    What are the advantages of bioactivation in optimizing drugs and pesticides? Why are there so many prodrugs and propesticides? These questions are examined here by considering compounds selected on the basis of economic value or market success in 2015. The 100 major drugs and 90 major pesticides are divided into ones acting directly and those definitely or possibly requiring bioactivation. Established or candidate prodrugs accounted for 19% of the total drug sales, with corresponding values of 20, 37, and 17% for proinsecticides, proherbicides, and profungicides. The 19 prodrugs acting in humans generally had better pharmacodynamic/pharmacokinetic properties for target enzyme, receptor, tissue, or organ specificity due to their physical properties (lipophilicity and stabilization). Bioactivation usually involved hydrolases or cytochrome P450 oxidation or reduction. Prodrugs considered are neuroactive aripiprazole, eletriptan, desvenlafaxin, lisdexamfetamine, quetiapine, and fesoterodine; cholesterol-lowering atorvastatin, ezetimibe, and fenofibrate; various prodrugs activated by esterases or sulfatases, ciclesonide, oseltamivir, dabigatran; omega-3 fatty acid ethyl esters and esterone sulfate; and five others with various targets (sofosbuvir, fingolimod, clopidogrel, dapsone, and sildenafil). The proinsecticides are the neuroactive chlorpyrifos, thiamethoxam, and indoxacarb, two spiro enol ester inhibitors of acetyl CoA carboxylase (ACCase), and the bacterial protein delta-endotoxin. The proherbicides considered are five ACCase inhibitors including pinoxaden and clethodim, three protox inhibitors (saflufenacil, flumioxazin, and canfentrazone-ethyl), and three with various targets (fluroxypyr, isoxaflutole, and clomazone). The profungicides are prothioconazole, mancozeb, thiophanate-methyl, dazomet, and fosetyl-aluminum. The prodrug and propesticide concept is broadly applicable and has created some of the most selective pharmaceutical and pest control agents

  11. Duocarmycin-based prodrugs for cancer prodrug monotherapy.

    PubMed

    Tietze, Lutz F; Schuster, Heiko J; Schmuck, Kianga; Schuberth, Ingrid; Alves, Frauke

    2008-06-15

    The synthesis and biological evaluation of novel prodrugs based on the cytotoxic antibiotic duocarmycin SA (1) for a selective treatment of cancer using a prodrug monotherapy (PMT) are described. Transformation of the phenol 8 with the glucuronic acid benzyl ester trichloroacetimidate 9b followed by reaction with DMAI x HCl (10) gives the glucuronide 11b, which is deprotected to afford the desired prodrug 4a containing a glucuronic acid moiety. In addition, the prodrug 4b with a glucuronic methyl ester unit is prepared. The cytotoxicity of the glucuronides is determined using a HTCFA-assay with IC(50) values of 610 nM for 4a and 3300 nM for 4b. In the presence of beta-glucuronidase, 4a expresses an IC(50) value of 0.9 nM and 4b of 2.1 nM resulting in QIC(50) values of about 700 for 4a and 1600 for 4b.

  12. A functional model for the role of cytochrome b559 in the protection against donor and acceptor side photoinhibition.

    PubMed Central

    Barber, J; De Las Rivas, J

    1993-01-01

    A quinone-independent photoreduction of the low potential form of cytochrome b559 has been studied using isolated reaction centers of photosystem II. Under anaerobic conditions, the cytochrome can be fully reduced by exposure to strong illumination without the addition of any redox mediators. Under high light conditions, the extent and rate of the reduction is unaffected by addition of the exogenous electron donor Mn2+ and, during this process, no irreversible damage occurs to the reaction center. However, prolonged illumination in strong light brings about irreversible bleaching of chlorophyll, indicative of photoinhibitory damage. When the cytochrome is fully reduced and excess Mn2+ is present, the effect of moderate light is to facilitate the photoaccumulation of reduced pheophytin. The dark reoxidation of the reduced cytochrome is very slow under anaerobic conditions but significantly speeded up on addition of oxidized 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone. From these results it is suggested that the low potential form of cytochrome b559 can accept electrons directly from reduced pheophytin and in so doing help to protect the reaction center against acceptor side photoinhibition as suggested by Nedbal et al. [Nedbal, J., Samson, G. & Whitmarsh, J. (1992) Proc. Natl. Acad. Sci. USA 89, 7929-7933]. This conclusion has been incorporated into a model that further suggests that in its high potential form the cytochrome primarily acts to protect against donor side photoinhibition due to increased lifetime of highly oxidized species as previously proposed by Thompson and Brudvig [Thompson, L. & Brudvig, G. W. (1988) Biochemistry 27, 6653-6658]. The particular feature of our scheme is that it incorporates reversible interconversion between the two redox forms so as to protect against either type of photoinhibition. PMID:8248195

  13. Prodrug applications for targeted cancer therapy.

    PubMed

    Giang, Irene; Boland, Erin L; Poon, Gregory M K

    2014-09-01

    Prodrugs are widely used in the targeted delivery of cytotoxic compounds to cancer cells. To date, targeted prodrugs for cancer therapy have achieved great diversity in terms of target selection, activation chemistry, as well as size and physicochemical nature of the prodrug. Macromolecular prodrugs such as antibody-drug conjugates, targeted polymer-drug conjugates and other conjugates that self-assemble to form liposomal and micellar nanoparticles currently represent a major trend in prodrug development for cancer therapy. In this review, we explore a unified view of cancer-targeted prodrugs and highlight several examples from recombinant technology that exemplify the prodrug concept but are not identified as such. Recombinant "prodrugs" such as engineered anthrax toxin show promise in biological specificity through the conditionally targeting of multiple cellular markers. Conditional targeting is achieved by structural complementation, the spontaneous assembly of engineered inactive subunits or fragments to reconstitute functional activity. These complementing systems can be readily adapted to achieve conditionally bispecific targeting of enzymes that are used to activate low-molecular weight prodrugs. By leveraging strengths from medicinal chemistry, polymer science, and recombinant technology, prodrugs are poised to remain a core component of highly focused and tailored strategies aimed at conditionally attacking complex molecular phenotypes in clinically relevant cancer.

  14. Additive-controlled stereoselective glycosylations of 2,3-oxazolidinone protected glucosamine or galactosamine thioglycoside donors with phenols based on preactivation protocol.

    PubMed

    Qin, Qi; Xiong, De-Cai; Ye, Xin-Shan

    2015-02-11

    Stereo-controllable glycosylation reactions of 2,3-oxazolidinone protected glucosamine thioglycoside donor with different phenol acceptors based on preactivation protocol, are described. It was found that BF3·Et2O worked as α-directing additive, while TTBP acted as β-directing additive. Simply by altering additives, either α-aryl glycosides or β-aryl glycosides were achieved in a stereoselective manner. The additives were also applied to the stereoselective glycosylation reactions of 2,3-oxazolidinone protected galactosamine donor with phenol substrates.

  15. Beta-galactoside prodrugs of doxorubicin for application in antibody directed enzyme prodrug therapy/prodrug monotherapy.

    PubMed

    Devalapally, HariKrishna; Navath, Raghavendra Swamy; Yenamandra, Venkateshwarlu; Akkinepally, RaghuRam Rao; Devarakonda, Rama Krishna

    2007-06-01

    Anthracycline antibiotics, particularly doxorubicin and daunorubicin, have been used exten sively in the treatment of human malignancies. However cardiotoxicity and multidrug resistance are significant problems that limit the clinical efficacy of such agents. Rational design to avoid these side effects includes strategies such as drug targeting and prodrug synthesis. Described here are the synthesis and preliminary biological evaluation of the enzymatically activated two new prodrugs (6 & 11) of doxorubicin. These prodrugs were designed as potential candidates for selective chemotherapy in ADEPT or PMT strategies. They are constituted of a galactose moiety, a spacer and the cytotoxic drug and they differ by the type of spacer. The prodrugs were stable in a buffer, and the in vitro studies showed good detoxification and hydrolysis kinetics. As prodrug 11 was readily hydrolyzed, this could be a valuable candidate for further development.

  16. Prodrug approach: An overview of recent cases.

    PubMed

    Abet, Valentina; Filace, Fabiana; Recio, Javier; Alvarez-Builla, Julio; Burgos, Carolina

    2017-02-15

    In this review we highlight the most modern trends in the prodrug strategy. In drug research and development, the prodrug concept has found a number of useful applications. Selected examples of this approach are provided in this paper and they are classified according to the aim of their design.

  17. Insight into Prodrugs of Quinolones and Fluoroquinolones.

    PubMed

    Sharma, Prabodh Chander; Piplani, Mona; Mittal, Monika; Pahwa, Rakesh

    2016-01-01

    Quinolones and fluoroquinolones are principal weapons against variety of bacterial infections and exert their antibacterial potential by interfering the activities of bacterial enzymes. As these agents are associated with some limitations, an important approach to overcome these major constraints is to prepare covalent derivatives, i.e. prodrugs. Prodrug design has been employed to improve the limitations of these drugs such as less aqueous solubility, poor absorption and distribution, toxicity, disagreeable taste, poor lipophilicity etc and for improving their pharmacological profile. This paper highlights the utility of various prodrug strategies in optimizing the therapeutic index of these antibacterial agents and their recent patents. Some of their prodrugs being utilized at preclinical and clinical levels have also been discussed. Hence, this paper has been prepared to present the significant findings of various research papers that would be helpful in motivating scientific researchers to forward the research in direction of utilization of prodrugs in clinical therapy.

  18. Prodrug behaviour of nicotinoylmorphine esters.

    PubMed

    Broekkamp, C L; Oosterloo, S K; Rijk, H W

    1988-06-01

    Morphine and its nicotinoyl esters, dinicotinoylmorphine (nicomorphine), 6-mononicotinoylmorphine (6-MNM) and 3-mononicotinoylmorphine (3-MNM) were tested in mice for central activity to obtain time-effect profiles of these compounds in rats. Two effects, analgesia with the hot plate test and locomotor stimulation in activity cages were measured and nicomorphine, 6-MNM and 3-MNM were found to have a faster onset of action compared with morphine. The effects of 3-MNM and morphine lasted longer than the effect of nicomorphine and 6-MNM. The prodrug behaviour of 3-MNM and nicomorphine for morphine and 6-MNM, respectively, is discussed.

  19. Novel double prodrugs of the iron chelator N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED): Synthesis, characterization, and investigation of activation by chemical hydrolysis and oxidation.

    PubMed

    Thiele, Nikki A; Abboud, Khalil A; Sloan, Kenneth B

    2016-08-08

    The development of iron chelators suitable for the chronic treatment of diseases where iron accumulation and subsequent oxidative stress are implicated in disease pathogenesis is an active area of research. The clinical use of the strong chelator N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) and its alkyl ester prodrugs has been hindered by poor oral bioavailability and lack of conversion to the parent chelator, respectively. Here, we present novel double prodrugs of HBED that have the carboxylate and phenolate donors of HBED masked with carboxylate esters and boronic acids/esters, respectively. These double prodrugs were successfully synthesized as free bases (7a-f) or as dimesylate salts (8a-c,e), and were characterized by (1)H, (13)C, and (11)B NMR; MP; MS; and elemental analysis. The crystal structure of 8a was solved. Three of the double prodrugs (8a-c) were selected for further investigation into their abilities to convert to HBED by stepwise hydrolysis and H2O2 oxidation. The serial hydrolysis of the pinacol and methyl esters of N,N'-bis(2-boronic acid pinacol ester benzyl)ethylenediamine-N,N'-diacetic acid methyl ester dimesylate (8a) was verified by LC-MS. The macro half-lives for the hydrolyses of 8a-c, measured by UV, ranged from 3.8 to 26.3 h at 37 °C in pH 7.5 phosphate buffer containing 50% MeOH. 9, the product of hydrolysis of 8a-c and the intermediate in the conversion pathway, showed little-to-no affinity for iron or copper in UV competition experiments. 9 underwent a serial oxidative deboronation by H2O2 in N-methylmorpholine buffer to generate HBED (k = 10.3 M(-1) min(-1)). The requirement of this second step, oxidation, before conversion to the active chelator is complete may confer site specificity when only localized iron chelation is needed. Overall, these results provide proof of principle for the activation of the double prodrugs by chemical hydrolysis and H2O2 oxidation, and merit further investigation into the

  20. Protection by the NO-Donor SNAP and BNP against Hypoxia/Reoxygenation in Rat Engineered Heart Tissue.

    PubMed

    Görbe, A; Eder, A; Varga, Z V; Pálóczi, J; Hansen, A; Ferdinandy, P; Eschenhagen, T

    2015-01-01

    In vitro assays could replace animal experiments in drug screening and disease modeling, but have shortcomings in terms of functional readout. Force-generating engineered heart tissues (EHT) provide simple automated measurements of contractile function. Here we evaluated the response of EHTs to hypoxia/reoxygenation (H/R) and the effect of known cardiocytoprotective molecules. EHTs from neonatal rat heart cells were incubated for 24 h in EHT medium. Then they were subjected to 180 min hypoxia (93% N2, 7% CO2) and 120 min reoxygenation (40% O2, 53% N2, 7% CO2), change of medium and additional follow-up of 48 h. Time-matched controls (40% O2, 53% N2, 7% CO2) were run for comparison. The following conditions were applied during H/R: fresh EHT medium (positive control), the NO-donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 10(-7), 10(-6), 10(-5) M) or the guanylate cyclase activator brain type natriuretic peptide (BNP, 10(-9), 10(-8), 10(-7) M). Frequency and force of contraction were repeatedly monitored over the entire experiment, pH, troponin I (cTnI), lactate dehydrogenase (LDH) and glucose concentrations measured in EHT medium. Beating activity of EHTs in 24 h-medium ceased during hypoxia, partially recovered during reoxygenation and reached time-control values during follow-up. H/R was accompanied by a small increase in LDH and non-significant increase in cTnI. In fresh medium, some EHTs continued beating during hypoxia and all EHTs recovered faster during reoxygenation. SNAP and BNP showed small but significant protective effects during reoxygenation. EHTs are applicable to test potential cardioprotective compounds in vitro, monitoring functional and biochemical endpoints, which otherwise could be only measured by using in vivo or ex vivo heart preparations. The sensitivity of the model needs improvement.

  1. Prodrug Strategies in Ocular Drug Delivery

    PubMed Central

    Barot, Megha; Bagui, Mahuya; Gokulgandhi, Mitan R.; Mitra, Ashim K.

    2015-01-01

    Poor bioavailability of topically instilled drug is the major concern in the field of ocular drug delivery. Efflux transporters, static and dynamic ocular barriers often possess rate limiting factors for ocular drug therapy. Different formulation strategies like suspension, ointment, gels, nanoparticles, implants, dendrimers and liposomes have been employed in order to improve drug permeation and retention by evading rate limiting factors at the site of absorption. Chemical modification such as prodrug targeting various nutrient transporters (amino acids, peptide and vitamin) has evolved a great deal ofintereSt to improve ocular drug delivery. In this review, we have discussed various prodrug strategies which have been widely applied for enhancing therapeutic efficacy of ophthalmic drugs. The purpose of this review is to provide an update on the utilization of prodrug concept in ocular drug delivery. In addition, this review will highlight ongoing academic and industrial research and development in terms of ocular prodrug design and delivery. PMID:22530907

  2. Synthesis and Evaluation as Prodrugs of Hydrophilic Carbamate Ester Analogues of Resveratrol.

    PubMed

    Azzolini, Michele; Mattarei, Andrea; La Spina, Martina; Marotta, Ester; Zoratti, Mario; Paradisi, Cristina; Biasutto, Lucia

    2015-09-08

    Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is an unfulfilled promise for health care: its exploitation is hindered by rapid conjugative metabolism in enterocytes and hepatocytes; low water solubility is a serious practical problem. To advantageously modify the physicochemical properties of the compound we have developed prodrugs in which all or part of the hydroxyl groups are linked via an N-monosubstituted carbamate ester bond to promoieties derived from glycerol or galactose, conferring higher water solubility. Kinetic studies of hydrolysis in aqueous solutions and in blood indicated that regeneration of resveratrol takes place in an appropriate time frame for delivery via oral administration. Despite their hydrophilicity some of the synthesized compounds were absorbed in the gastrointestinal tract of rats. In these cases the species found in blood after administration of a bolus consisted mainly of partially deprotected resveratrol derivatives and of the products of their glucuronidation, thus providing proof-of-principle evidence of behavior as prodrugs. The soluble compounds largely reached the lower intestinal tract. Upon administration of resveratrol, the major species found in this region was dihydroresveratrol, produced by enzymes of the intestinal flora. In experiments with a fully protected (trisubstituted) deoxygalactose containing prodrug, the major species were the prodrug itself and partially deprotected derivatives, along with small amounts of dihydroresveratrol. We conclude that the N-monosubstituted carbamate moiety is suitable for use in prodrugs of polyphenols.

  3. Biocatalytic approaches applied to the synthesis of nucleoside prodrugs.

    PubMed

    Iglesias, Luis E; Lewkowicz, Elizabeth S; Medici, Rosario; Bianchi, Paola; Iribarren, Adolfo M

    2015-01-01

    Nucleosides are valuable bioactive molecules, which display antiviral and antitumour activities. Diverse types of prodrugs are designed to enhance their therapeutic efficacy, however this strategy faces the troublesome selectivity issues of nucleoside chemistry. In this context, the aim of this review is to give an overview of the opportunities provided by biocatalytic procedures in the preparation of nucleoside prodrugs. The potential of biocatalysis in this research area will be presented through examples covering the different types of nucleoside prodrugs: nucleoside analogues as prodrugs, nucleoside lipophilic prodrugs and nucleoside hydrophilic prodrugs.

  4. Synthesis and in vitro Evaluation of Polymeric Prodrug of Ibuprofen with Amino Acid Spacer.

    PubMed

    Redasani, Vivekkumar K; Bari, Sanjay B

    2015-01-01

    The present work is an agreement with simple and efficient method of improving the therapeutic efficacy of ibuprofen by masking its acidic moiety. It aims to reduce gastrointestinal side effects by controlling the rate, duration and site of release. This is achieved by synthesis and evaluation of polymeric prodrug of ibuprofen with natural polymer sodium alginate. The synthesis was supported by N-protected serine as spacer due to chemical incompatibility of drug and polymer. Synthesized prodrug was characterized for confirmation of said structures. The in-vitro dissolution profile of ibuprofen-alginate prodrug showed that the release of the drug is significantly higher in case of pH 7.2 buffer as compared to ibuprofen, which might be due to ester group adjacent to drug get hydrolyzed. The hydrolysis was found to be with faster rate in alkaline media than that of in acidic media.

  5. Water-soluble nitric-oxide-releasing acetylsalicylic acid (ASA) prodrugs.

    PubMed

    Rolando, Barbara; Lazzarato, Loretta; Donnola, Monica; Marini, Elisabetta; Joseph, Sony; Morini, Giuseppina; Pozzoli, Cristina; Fruttero, Roberta; Gasco, Alberto

    2013-07-01

    A series of water-soluble (benzoyloxy)methyl esters of acetylsalicylic acid (ASA), commonly known as aspirin, are described. The new derivatives each have alkyl chains containing a nitric oxide (NO)-releasing nitrooxy group and a solubilizing moiety bonded to the benzoyl ring. The compounds were synthesized and evaluated as ASA prodrugs. After conversion to the appropriate salt, most of the derivatives are solid at room temperature and all possess good water solubility. They are quite stable in acid solution (pH 1) and less stable at physiological pH. In human serum, these compounds are immediately metabolized by esterases, producing a mixture of ASA, salicylic acid (SA), and of the related NO-donor benzoic acids, along with other minor products. Due to ASA release, the prodrugs are capable of inhibiting collagen-induced platelet aggregation of human platelet-rich plasma. Simple NO-donor benzoic acids 3-hydroxy-4-(3-nitrooxypropoxy)benzoic acid (28) and 3-(morpholin-4-ylmethyl)-4-[3-(nitrooxy)propoxy]benzoic acid (48) were also studied as representative models of the whole class of benzoic acids formed following metabolism of the prodrugs in serum. These simplified derivatives did not trigger antiaggregatory activity when tested at 300 μM. Only 28 displays quite potent NO-dependent vasodilatatory action. Further in vivo evaluation of two selected prodrugs, {[2-(acetyloxy)benzoyl]oxy}methyl-3-[(3-[aminopropanoyl)oxy]-4-[3-(nitrooxy)propoxy]benzoate⋅HCl (38) and {[2-(acetyloxy)benzoyl]oxy}methyl 3-(morpholin-4-ylmethyl)-4-[3-(nitrooxy)propoxy]benzoate oxalate (49), revealed that their anti-inflammatory activities are similar to that of ASA when tested in the carrageenan-induced paw edema assay in rats. The gastrotoxicity of the two prodrugs was also determined to be lower than that of ASA in a lesion model in rats. Taken together, these results indicated that these NO-donor ASA prodrugs warrant further investigation for clinical application.

  6. In situ bioremediation of nitrate and perchlorate in vadose zone soil for groundwater protection using gaseous electron donor injection technology.

    PubMed

    Evans, Patrick J; Trute, Mary M

    2006-12-01

    When present in the vadose zone, potentially toxic nitrate and perchlorate anions can be persistent sources of groundwater contamination. Gaseous electron donor injection technology (GEDIT), an anaerobic variation of petroleum hydrocarbon bioventing, involves injecting electron donor gases, such as hydrogen or ethyl acetate, into the vadose zone, to stimulate biodegradation of nitrate and perchlorate. Laboratory microcosm studies demonstrated that hydrogen and ethanol promoted nitrate and perchlorate reduction in vadose zone soil and that moisture content was an important factor. Column studies demonstrated that transport of particular electron donors varied significantly; ethyl acetate and butyraldehyde were transported more rapidly than butyl acetate and ethanol. Nitrate removal in the column studies, up to 100%, was best promoted by ethyl acetate. Up to 39% perchlorate removal was achieved with ethanol and was limited by insufficient incubation time. The results demonstrate that GEDIT is a promising remediation technology warranting further validation.

  7. Amino Acid Carbamates As Prodrugs Of Resveratrol

    PubMed Central

    Mattarei, Andrea; Azzolini, Michele; La Spina, Martina; Zoratti, Mario; Paradisi, Cristina; Biasutto, Lucia

    2015-01-01

    Resveratrol (3, 5, 4′-trihydroxy-trans-stilbene), a plant polyphenol, has important drug-like properties, but its pharmacological exploitation in vivo is hindered by its rapid transformation via phase II conjugative metabolism. One approach to bypass this problem relies on prodrugs. We report here the synthesis, characterization, stability and in vivo pharmacokinetic behaviour of prodrugs of resveratrol in which the OH groups are engaged in an N-monosubstituted carbamate ester (-OC(O)NHR) linkage with a natural amino acid (Leu, Ile, Phe, Thr) to prevent conjugation and modulate the physicochemical properties of the molecule. We also report a convenient, high-yield protocol to obtain derivatives of this type. The new carbamate ester derivatives are stable at pH 1, while they undergo slow hydrolysis at physiological pH and hydrolyse with kinetics suitable for use in prodrugs in whole blood. After administration to rats by oral gavage the isoleucine-containing prodrug was significantly absorbed, and was present in the bloodstream as non-metabolized unaltered or partially deprotected species, demonstrating effective shielding from first-pass metabolism. We conclude that prodrugs based on the N-monosubstituted carbamate ester bond have the appropriate stability profile for the systemic delivery of phenolic compounds. PMID:26463125

  8. Lactic acid oligomers (OLAs) as prodrug moieties.

    PubMed

    Kruse, J; Lachmann, B; Lauer, R; Eppacher, S; Noe, C R

    2013-02-01

    In this paper we propose the use of lactic acid oligomers (OLAs) as prodrug moieties. Two synthetic approaches are presented, on the one hand a non selective oligomerisation of lactic acid and on the other hand a block synthesis to tetramers of lactic acid. Dimers of lactic acid were investigated with respect to their plasma stability and their adsorption to albumine. Ibuprofen was chosen as the first drug for OLAylation. The ester 19 of LA(1)-ibuprofen was evaluated with respect to the degradation to human plasma and the adsorption to albumine. All results indicate that lactic acid oligomers are promising prodrug moieties.

  9. [In vitro metabolism of fenbendazole prodrug].

    PubMed

    Wen, Ai-Dan; Duan, Li-Ping; Liu, Cong-Shan; Tao, Yi; Xue, Jian; Wu, Ning-Bo; Jiang, Bin; Zhang, Hao-Bing

    2013-02-01

    Synthesized fenbendazole prodrug N-methoxycarbonyl-N'-(2-nitro-4-phenylthiophenyl) thiourea (MPT) was analyzed in vitro in artificial gastric juice, intestinal juice and mouse liver homogenate model by using HPLC method, and metabolic curve was then generated. MPT was tested against Echinococcus granulosus protoscolices in vitro. The result showed that MPT could be metabolized in the three biological media, and to the active compound fenbendazole in liver homogenate, with a metabolic rate of 7.92%. Besides, the prodrug showed a weak activity against E. granulosus protoscolices with a mortality of 45.9%.

  10. Evaluating Prodrug Strategies for Esterase-Triggered Release of Alcohols

    PubMed Central

    Perez, Christian; Daniel, Kevin B.

    2013-01-01

    Prodrugs are effective tools in overcoming drawbacks typically associated with drug formulation and delivery. Those employing esterase-triggered functional groups are frequently utilized to mask polar carboxylic acids and phenols, increasing drug-like properties such as lipophilicity. Herein we detail a comprehensive assessment for strategies that effectively release hydroxyl and phenolic moieties in the presence of an esterase. Matrix metalloproteinases (MMPs) serve as our proof-of-concept target. Three distinct ester-responsive protecting groups are incorporated into MMP proinhibitors containing hydroxyl moieties. Analytical evaluation of the proinhibitors demonstrates that the use of a benzyl ether group appended to the esterase trigger leads to considerably faster kinetics of conversion and enhanced aqueous stability when compared to more conventional approaches where the trigger is directly attached to the inhibitor. Biological assays confirm that all protecting groups effectively cleave in the presence of esterase to generate the active inhibitor. PMID:23929690

  11. Novel prodrugs with a spontaneous cleavable guanidine moiety.

    PubMed

    Hamada, Yoshio

    2016-04-01

    Water-soluble prodrug strategy is a practical alternative for improving the drug bioavailability of sparingly-soluble drugs with reduced drug efficacy. Many water-soluble prodrugs of sparingly-soluble drugs, such as the phosphate ester of a drug, have been reported. Recently, we described a novel water-soluble prodrug based on O-N intramolecular acyl migration. However, these prodrug approaches require a hydroxy group in the structure of their drugs, and other prodrug approaches are often restricted by the structure of the parent drugs. To develop prodrugs with no restriction in the structure, we focused on a decomposition reaction of arginine methyl ester. This reaction proceeds at room temperature under neutral conditions, and we applied this reaction to the prodrug strategy for drugs with an amino group. We designed and synthesized novel prodrugs of representative sparingly soluble drugs phenytoin and sulfathiazole. Phenytoin and sulfathiazole were obtained as stable salt that were converted to parent drugs under physiological conditions. Phenytoin prodrug 3 showed a short half-life (t1/2) of 13min, whereas sulfathiazole prodrug 7 had a moderate t1/2 of 40min. Prodrugs 3 and 7 appear to be suitable for use as an injectable formulation and orally administered drug, respectively.

  12. Modern prodrug design for targeted oral drug delivery.

    PubMed

    Dahan, Arik; Zimmermann, Ellen M; Ben-Shabat, Shimon

    2014-10-14

    The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.

  13. Protective effects of maternal methyl donor supplementation on adult offspring of high fat diet-fed dams.

    PubMed

    Jiao, Fei; Yan, Xiaoshuang; Yu, Yuan; Zhu, Xiao; Ma, Ying; Yue, Zhen; Ou, Hailong; Yan, Zhonghai

    2016-08-01

    Obesity has become a global public health problem associated with metabolic dysfunction and chronic disorders. It has been shown that the risk of obesity and the DNA methylation profiles of the offspring can be affected by maternal nutrition, such as high-fat diet (HFD) consumption. The aim of this study was to investigate whether metabolic dysregulation and physiological abnormalities in offspring caused by maternal HFD can be alleviated by the treatment of methyl donors during pregnancy and lactation of dams. Female C57BL/6 mice were assigned to specific groups and given different nutrients (control diet, Control+Met, HFD and HFD+Met) throughout gestation and lactation. Offspring of each group were weaned onto a control diet at 3 weeks of age. Physiological (weight gain and adipose composition) and metabolic (plasma biochemical analyses) outcomes were assessed in male and female adult offspring. Expression and DNA methylation profiles of obesogenic-related genes including PPAR γ, fatty acid synthase, leptin and adiponectin were also detected in visceral fat of offspring. The results showed that dietary supplementation with methyl donors can prevent the adverse effects of maternal HFD on offspring. Changes in the expression and DNA methylation of obesogenic-related genes indicated that epigenetic regulation may contribute to the effects of maternal dietary factors on offspring outcomes.

  14. Prodrug approach to improve absorption of prednisolone

    PubMed Central

    Sheng, Ye; Yang, Xiaoyan; Pal, Dhananjay; Mitra, Ashim K.

    2015-01-01

    Amino acid and dipeptide prodrugs have been developed to examine their potential in enhancing aqueous solubility and permeability as well as to bypass P-glycoprotein (P-gp) mediated cellular efflux of prednisolone. Prodrugs have been synthesized and identified with LC/MS/MS and NMR. Prodrugs displayed significantly higher aqueous solubility relative to prednisolone. These compounds also exhibited higher stability under acidic conditions relative to basic medium. [14]-Erythromycin uptake remained unaltered in the presence of valine-valine-prednisolone (VVP) indicating lower affinity towards P-gp. Moreover, VVP generated significantly higher transepithelial permeability across MDCK-MDR1 cells compared to prednisolone. Importantly, [3H]-GlySar uptake diminished significantly in the presence of VVP indicating high affinity towards peptide transporters. Moreover, prednisolone was regenerated from VVP due to enzymatic hydrolysis in SIRC cell homogenate. Results obtained from these studies clearly suggest that peptide transporter targeted prodrugs is a viable strategy to improve aqueous solubility and overcome P-gp mediated cellular efflux of prednisolone. PMID:25888804

  15. Protective effect of keishi-bukuryo-gan and its constituent medicinal plants against nitric oxide donor-induced neuronal death in cultured cerebellar granule cells.

    PubMed

    Shimada, Y; Yokoyama, K; Goto, H; Sekiya, N; Mantani, N; Tahara, E; Hikiami, H; Terasawa, K

    2004-07-01

    Keishi-bukuryo-gan (Gui-Zhi-Fu-Ling-Wan) (KBG) is a traditional Chinese/Japanese medical (Kampo) formulation that has been administered to patients with "Oketsu" (blood stagnation) syndrome. In the process of neuronal cell death induced by brain ischemia, excessive generation of nitric oxide (NO) free radicals is implicated in the neurotoxicity. In the present study, we examined the protective effects of KBG and its constituent medicinal plants against NO donors, sodium nitroprusside (SNP) and 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (NOC18)-induced neuronal death in cultured rat cerebellar granule cells (CGCs). MTT assay showed cell viability to be significantly increased by the addition of KBG extract (KBGE) (100 microg/ml), Cinnamomi Cortex extract (CCE) (3, 10 and 30 microg/ml), Paeoniae Radix extract (PRE) (100 microg/ml) and Moutan Cortex extract (MCE) (10 and 30 microg/ml) compared with exposure to SNP (30 microM, 24 h) only. Also, cell viability was significantly increased by the addition of KBGE (100 and 300 microg/ml), CCE (30 and 100 microg/ml), PRE (100 and 300 microg/ml) and MCE (30 and 100 microg/ml) compared with exposure to NOC 18 (100 microM, 48 h) only. Persicae Semen extract and Hoelen extract did not protect against NO donor-induced neuronal death. These results suggest that KBG has protective effect against NO-mediated neuronal death in cultured CGCs and that it is derived from Cinnamomi Cortex, Paeoniae Radix and Moutan Cortex.

  16. Utilization of Enzyme-Immobilized Mesoporous Silica Nanocontainers (IBN-4) in Prodrug-Activated Cancer Theranostics

    PubMed Central

    Hung, Bau-Yen; Kuthati, Yaswanth; Kankala, Ranjith Kumar; Kankala, Shravankumar; Deng, Jin-Pei; Liu, Chen-Lun; Lee, Chia-Hung

    2015-01-01

    To develop a carrier for use in enzyme prodrug therapy, Horseradish peroxidase (HRP) was immobilized onto mesoporous silica nanoparticles (IBN-4: Institute of Bioengineering and Nanotechnology), where the nanoparticle surfaces were functionalized with 3-aminopropyltrimethoxysilane and further conjugated with glutaraldehyde. Consequently, the enzymes could be stabilized in nanochannels through the formation of covalent imine bonds. This strategy was used to protect HRP from immune exclusion, degradation and denaturation under biological conditions. Furthermore, immobilization of HRP in the nanochannels of IBN-4 nanomaterials exhibited good functional stability upon repetitive use and long-term storage (60 days) at 4 °C. The generation of functionalized and HRP-immobilized nanomaterials was further verified using various characterization techniques. The possibility of using HRP-encapsulated IBN-4 materials in prodrug cancer therapy was also demonstrated by evaluating their ability to convert a prodrug (indole-3-acetic acid (IAA)) into cytotoxic radicals, which triggered tumor cell apoptosis in human colon carcinoma (HT-29 cell line) cells. A lactate dehydrogenase (LDH) assay revealed that cells could be exposed to the IBN-4 nanocomposites without damaging their membranes, confirming apoptotic cell death. In summary, we demonstrated the potential of utilizing large porous mesoporous silica nanomaterials (IBN-4) as enzyme carriers for prodrug therapy. PMID:28347114

  17. A Novel Doxorubicin Prodrug with Controllable Photolysis Activation for Cancer Chemotherapy

    PubMed Central

    Zahavy, Eran; Wrasdilo, Wolf; Berns, Michael; Chan, Michael; Esener, Sadik

    2010-01-01

    ABSTRACT Purpose Doxorubicin (DOX) is a very effective anticancer agent. However, in its pure form, its application is limited by significant cardiotoxic side effects. The purpose of this study was to develop a controllably activatable chemotherapy prodrug of DOX created by blocking its free amine group with a biotinylated photocleavable blocking group (PCB). Methods An n-hydroxy succunamide protecting group on the PCB allowed selective binding at the DOX active amine group. The PCB included an ortho-nitrophenyl group for photo cleavability and a water-soluble glycol spacer arm ending in a biotin group for enhanced membrane interaction. Results This novel DOX-PCB prodrug had a 200-fold decrease in cytotoxicity compared to free DOX and could release active DOX upon exposure to UV light at 350 nm. Unlike DOX, DOX-PCB stayed in the cell cytoplasm, did not enter the nucleus, and did not stain the exposed DNA during mitosis. Human liver microsome incubation with DOX-PCB indicated stability against liver metabolic breakdown. Conclusions The development of the DOX-PCB prodrug demonstrates the possibility of using light as a method of prodrug activation in deep internal tissues without relying on inherent physical or biochemical differences between the tumor and healthy tissue for use as the trigger. PMID:20596761

  18. Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs.

    PubMed

    Immordino, Maria Laura; Brusa, Paola; Rocco, Flavio; Arpicco, Silvia; Ceruti, Maurizio; Cattel, Luigi

    2004-12-10

    Gemcitabine is a known anticancer agent rapidly deaminated to the inactive metabolite 2',2'-difluorodeoxyuridine; it must therefore be administered at very high dose. Many different approaches have been tried to improve the metabolic stability; we synthesized a series of increasingly lipophilic prodrugs of gemcitabine by linking the 4-amino group with valeroyl, heptanoyl, lauroyl and stearoyl linear acyl derivatives. We studied their stability at storage, in plasma and with the lysosomal intracellular enzyme cathepsins. We studied incorporation of these lipophilic prodrugs in liposomes, where their encapsulation efficiency (EE) closely depends on the length of the saturated 4-(N)-acyl chain, the phospholipids chosen and the presence of cholesterol. A maximum EE of 98% was determined for 4-(N)-stearoyl-gemcitabine incorporated in DSPC/DSPG 9:1. This formulation was correlated with the highest stability in vitro and in vivo. Cytotoxicity of gemcitabine prodrugs, free or encapsulated in liposomes, was between two- and sevenfold that of free gemcitabine. Encapsulation of long-chain lipophilic prodrugs of gemcitabine in liposomes protected the drug from degradation in plasma, assuring a long plasma half-time and intracellular release of the free drug.

  19. Prodrugs - an efficient way to breach delivery and targeting barriers.

    PubMed

    Huttunen, Kristiina M; Rautio, Jarkko

    2011-01-01

    The study of prodrugs that are chemically modified bioreversible derivatives of active drug compounds to alter their undesired properties has been expanded widely during the last decades. Despite the commercial success the prodrugs have afforded, the concept is still quite unknown among many scientist. Furthermore, many scientists regard prodrugs as a pure interest of academic research groups and not as a feasible solution to improve the delivery or targeting properties of new chemical entities, drug candidates failed in clinical trials, or drugs withdrawn from the market. Although there are still unmet needs that require addressing, prodrugs should be seen as fine-tuning tools for the successful drug research and development. This review represents the potential of prodrugs to improve the drug delivery by enhanced aqueous solubility or permeability as well as describes several targeted prodrug strategies.

  20. Prodrugs design based on inter- and intramolecular chemical processes.

    PubMed

    Karaman, Rafik

    2013-12-01

    This review provides the reader a concise overview of the majority of prodrug approaches with the emphasis on the modern approaches to prodrug design. The chemical approach catalyzed by metabolic enzymes which is considered as widely used among all other approaches to minimize the undesirable drug physicochemical properties is discussed. Part of this review will shed light on the use of molecular orbital methods such as DFT, semiempirical and ab initio for the design of novel prodrugs. This novel prodrug approach implies prodrug design based on enzyme models that were utilized for mimicking enzyme catalysis. The computational approach exploited for the prodrug design involves molecular orbital and molecular mechanics (DFT, ab initio, and MM2) calculations and correlations between experimental and calculated values of intramolecular processes that were experimentally studied to assign the factors determining the reaction rates in certain processes for better understanding on how enzymes might exert their extraordinary catalysis.

  1. Synthesis and characterization of novel dipeptide ester prodrugs of acyclovir

    NASA Astrophysics Data System (ADS)

    Nashed, Yasser E.; Mitra, Ashim K.

    2003-07-01

    Four dipeptide (Gly-Gly, Gly-Val, Val-Val, Val-Gly) ester prodrugs of 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir, ACV) were synthesized. LC/MS was used to characterize the new prodrugs. Both 1H NMR and 13C NMR spectra of the four prodrugs of ACV were measured and assigned based on spectral comparison with compounds of similar structures.

  2. Lipid prodrug nanocarriers in cancer therapy.

    PubMed

    Mura, Simona; Bui, Duc Trung; Couvreur, Patrick; Nicolas, Julien

    2015-06-28

    Application of nanotechnology in the medical field (i.e., nanomedicine) plays an important role in the development of novel drug delivery methods. Nanoscale drug delivery systems can indeed be customized with specific functionalities in order to improve the efficacy of the treatments. However, despite the progresses of the last decades, nanomedicines still face important obstacles related to: (i) the physico-chemical properties of the drug moieties which may reduce the total amount of loaded drug; (ii) the rapid and uncontrolled release (i.e., burst release) of the encapsulated drug after administration and (iii) the instability of the drug in biological media where a fast transformation into inactive metabolites can occur. As an alternative strategy to alleviate these drawbacks, the prodrug approach has found wide application. The covalent modification of a drug molecule into an inactive precursor from which the drug will be freed after administration offers several benefits such as: (i) a sustained drug release (mediated by chemical or enzymatic hydrolysis of the linkage between the drug-moiety and its promoiety); (ii) an increase of the drug chemical stability and solubility and, (iii) a reduced toxicity before the metabolization occurs. Lipids have been widely used as building blocks for the design of various prodrugs. Interestingly enough, these lipid-derivatized drugs can be delivered through a nanoparticulate form due to their ability to self-assemble and/or to be incorporated into lipid/polymer matrices. Among the several prodrugs developed so far, this review will focus on the main achievements in the field of lipid-based prodrug nanocarriers designed to improve the efficacy of anticancer drugs. Gemcitabine (Pubchem CID: 60750); 5-fluorouracil (Pubchem CID: 3385); Doxorubicin (Pubchem CID: 31703); Docetaxel (Pubchem CID: 148124); Methotrexate (Pubchem CID: 126941); Paclitaxel (Pubchem CID: 36314).

  3. Lectin-directed enzyme activated prodrug therapy (LEAPT): Synthesis and evaluation of rhamnose-capped prodrugs.

    PubMed

    Garnier, Philippe; Wang, Xiang-Tao; Robinson, Mark A; van Kasteren, Sander; Perkins, Alan C; Frier, Malcolm; Fairbanks, Antony J; Davis, Benjamin G

    2010-12-01

    The lectin-directed enzyme activated prodrug therapy (LEAPT) bipartite drug delivery system utilizes glycosylated enzyme, localized according to its sugar pattern, and capped prodrugs released by that enzyme. In this way, the sugar coat of a synthetic enzyme determines the site of release of a given drug. Here, prodrugs of doxorubicin and 5-fluorouracil capped by the nonmammalian l-rhamnosyl sugar unit have been efficiently synthesized and evaluated for use in the LEAPT system. Both are stable in blood, released by synthetically d-galactosylated rhamnosidase enzyme, and do not inhibit the uptake of the synthetic enzyme to its liver target. These results are consistent with their proposed mode of action and efficacy in models of liver cancer, and confirm modular flexibility in the drugs that may be used in LEAPT.

  4. A lipophilic nitric oxide donor and a lipophilic antioxidant compound protect rat heart against ischemia-reperfusion injury if given as hybrid molecule but not as a mixture.

    PubMed

    Rastaldo, Raffaella; Raffaella, Rastaldo; Cappello, Sandra; Sandra, Cappello; Di Stilo, Antonella; Antonella, Di Stilo; Folino, Anna; Anna, Folino; Losano, Gianni; Gianni, Losano; Pagliaro, Pasquale; Pasquale, Pagliaro

    2012-03-01

    Low concentrations of a hydrophilic nitric oxide donor (NOD) are reported to reduce myocardial reperfusion injury only when combined with a lipophilic antioxidant (AOX) to form a hybrid molecule (HYB). Here we tested whether liposoluble NOD requires to be combined with AOX to be protective. Isolated rat hearts underwent 30 minutes of ischemia and 120 minutes of reperfusion. To induce postconditioning, 1 μM solutions of the following liposoluble compounds were given during the first 20 minutes of reperfusion: NOD with weak (w-NOD) or strong NO-releasing potency (s-NOD); weak HYB built up with w-NOD and a per se ineffective AOX lead; strong HYB built up with s-NOD and the same AOX; mixtures of w-NOD plus AOX or s-NOD plus AOX. A significant reduction of infarct size with improved recovery of cardiac function was obtained only with weak HYB. We suggest that w-NOD requires the synergy with a per se ineffective AOX to protect. The synergy is possible only if the 2 moieties enter the cell simultaneously as a hybrid, but not as a mixture. It seems that strong HYB was ineffective because an excessive intracellular NO release produces a large amount of reactive species, as shown from the increased nitrotyrosine production.

  5. Electronic structural investigations of ruthenium compounds and anticancer prodrugs.

    PubMed

    Harris, Travis V; Szilagyi, Robert K; McFarlane Holman, Karen L

    2009-08-01

    Several Ru(III) compounds are propitious anticancer agents although the precise mechanisms of action remain unknown. With this paper we start to establish an experimental library of X-ray absorption spectroscopy (XAS) data for ten Ru compounds wherein the ligands [Cl(-), dimethyl sulfoxide, imidazole, and indazole] were varied systematically to provide electronic structural information for future use in correlating spectroscopic signatures with chemical properties. Despite the considerable difference in the coordination environments of the complexes studied, the overall differences in spectral features and electronic structures calculated using density functional theory are unexpectedly small. However, the differences in the electronic structure of the Ru(III) prodrugs KP1019 ([IndH][trans-RuCl(4)(Ind)(2)], Ind is indazole) and ICR ([ImH][trans-RuCl(4)(Im)(2)], Im is imidazole) observed in the XAS data show correlation with known chemical and biological activities in addition to the donor abilities of imidazole compared with indazole and reduction potentials of the complexes. These semiquantitative results lay the groundwork for future biochemical studies into the structure-function relationships of Ru-based anticancer drugs.

  6. [Clinical evaluation of living donor].

    PubMed

    Scolari, Maria Piera; Comai, G; La Manna, G; Liviano D'Arcangelo, G; Monti, M; Feliciangeli, G; Stefoni, S

    2009-01-01

    When possible, living donor transplantation represents the best therapeutic strategy for patients suffering from chronic renal failure. Studying the donor allows a complete and thorough clinical, laboratory and instrumental assessment that guarantees good organ function whilst protecting the health of the donor. The main parameters considered within this framework are age, renal function, nephrological complications, comorbidities (diabetes, hypertension, obesity, etc.), malignancies, and infection. Moreover, particular attention is paid to the sociopsychological aspects of the donation, particularly related to the donor, the recipient, and the entire family situation.

  7. An exogenous hydrogen sulphide donor, NaHS, inhibits the apoptosis signaling pathway to exert cardio-protective effects in a rat hemorrhagic shock model

    PubMed Central

    Xu, Yanjie; Dai, Xiongwei; Zhu, Danxia; Xu, Xiaoli; Gao, Cao; Wu, Changping

    2015-01-01

    Hydrogen sulfide (H2S) has been reported to be interwined in multiple systems, specifically in the cardiovascular system. However, the mechanisms underlying remain controversial. In the present study, we assessed the cardio-protective effects of H2S in the rat hemorrhagic shock model. Hemorrhagic shock was induced in adult male Sprague-Dawley rats by drawing blood from the femoral artery to maintain the mean arterial pressure at 35-40 mmHg for 1.5 h. The rats were assigned to four groups and the H2S donor, NaHS (28 μmol/kg, i.p.), was injected before the resuscitation in certain groups. After resuscitation the animals were observed and then killed to harvest the hearts. The morphological investigation and ultrastructural analyses were done and apoptotic cells were detected. The levels of relevant proteins were examined using Western blotting and immunohistochemical analyses. Resuscitated hemorrhagic shock induced heart injury and significantly increased the levels of serum myocardial enzymes, creatine kinase (CK) and lactate dehydrogenase (LDH) levels. Furthermore, it caused marked increase of apoptotic cells in heart tissue. Moreover, the expression of death receptor Fas and Fas-ligand, as well as the expression of apoptosis-relevant proteins active-caspase 3 and active-caspase 8 were markedly increased. Administration of NaHS significantly ameliorated hemorrhagic shock caused hemodynamic deterioration, decreased myocardial enzymes elevation, protected myocardial ultrastructure, and inhibited the expression of apoptosis-relevant proteins. It suggested that H2S might exert its cardio-protective roles via both the extrinsic Fas/FasL/caspase-8/caspase-3 pathway and the intrinsic mitochondria-involved pathways. PMID:26261501

  8. An exogenous hydrogen sulphide donor, NaHS, inhibits the apoptosis signaling pathway to exert cardio-protective effects in a rat hemorrhagic shock model.

    PubMed

    Xu, Yanjie; Dai, Xiongwei; Zhu, Danxia; Xu, Xiaoli; Gao, Cao; Wu, Changping

    2015-01-01

    Hydrogen sulfide (H2S) has been reported to be interwined in multiple systems, specifically in the cardiovascular system. However, the mechanisms underlying remain controversial. In the present study, we assessed the cardio-protective effects of H2S in the rat hemorrhagic shock model. Hemorrhagic shock was induced in adult male Sprague-Dawley rats by drawing blood from the femoral artery to maintain the mean arterial pressure at 35-40 mmHg for 1.5 h. The rats were assigned to four groups and the H2S donor, NaHS (28 μmol/kg, i.p.), was injected before the resuscitation in certain groups. After resuscitation the animals were observed and then killed to harvest the hearts. The morphological investigation and ultrastructural analyses were done and apoptotic cells were detected. The levels of relevant proteins were examined using Western blotting and immunohistochemical analyses. Resuscitated hemorrhagic shock induced heart injury and significantly increased the levels of serum myocardial enzymes, creatine kinase (CK) and lactate dehydrogenase (LDH) levels. Furthermore, it caused marked increase of apoptotic cells in heart tissue. Moreover, the expression of death receptor Fas and Fas-ligand, as well as the expression of apoptosis-relevant proteins active-caspase 3 and active-caspase 8 were markedly increased. Administration of NaHS significantly ameliorated hemorrhagic shock caused hemodynamic deterioration, decreased myocardial enzymes elevation, protected myocardial ultrastructure, and inhibited the expression of apoptosis-relevant proteins. It suggested that H2S might exert its cardio-protective roles via both the extrinsic Fas/FasL/caspase-8/caspase-3 pathway and the intrinsic mitochondria-involved pathways.

  9. Effect of ion pairing on in vitro transcorneal permeability of a Δ(9) -tetrahydrocannabinol prodrug: potential in glaucoma therapy.

    PubMed

    Hingorani, Tushar; Gul, Waseem; Elsohly, Mahmoud; Repka, Michael A; Majumdar, Soumyajit

    2012-02-01

    The aim of the present study was to evaluate and improve the in vitro transcorneal permeability characteristics of Δ(9) -tetrahydrocannabinol (THC) through prodrug derivatization and formulation approaches. In vitro corneal permeability of THC and its hemisuccinate (THC-HS) and hemiglutarate (THC-HG) ester prodrugs and WIN 55-212-2 (WIN), a synthetic cannabinoid, was determined using isolated rabbit cornea. The formulations studied included hydroxypropyl beta cyclodextrin (HPβCD) or randomly methylated beta cyclodextrin (RMβCD), as well as prodrug-ion-pair complexes with l-arginine or tromethamine. Corneal permeability of WIN was found to be two-fold higher than THC in the presence of HPβCD. THC-HS and THC-HG exhibited pH-dependent permeability. In the presence of HPβCD, at pH 5 (donor solution pH), both prodrugs exhibited six-fold higher permeability compared with THC. However, permeability of the prodrugs was about three-fold lower than that of THC at pH 7.4. RMβCD, at pH 7.4, led to a significant improvement in permeability. Formation of ion-pair complexes markedly improved the solubility and permeability of THC-HG (sevenfold and threefold greater permeability compared with THC and WIN, respectively) at pH 7.4. The in vitro results demonstrate that the use of an ion-pair complex of THC-HG could be an effective strategy for topical delivery of THC.

  10. Targeted prodrug approaches for hormone refractory prostate cancer.

    PubMed

    Aloysius, Herve; Hu, Longqin

    2015-05-01

    Due to the propensity of relapse and resistance with prolonged androgen deprivation therapy (ADT), there is a growing interest in developing non-hormonal therapeutic approaches as alternative treatment modalities for hormone refractory prostate cancer (HRPC). Although the standard treatment for HRPC consists of a combination of ADT with taxanes and anthracyclines, the clinical use of chemotherapeutics is limited by systemic toxicity stemming from nondiscriminatory drug exposure to normal tissues. In order to improve the tumor selectivity of chemotherapeutics, various targeted prodrug approaches have been explored. Antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT) strategies leverage tumor-specific antigens and transcription factors for the specific delivery of cytotoxic anticancer agents using various prodrug-activating enzymes. In prostate cancer, overexpression of tumor-specific proteases such as prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) is being exploited for selective activation of anticancer prodrugs designed to be activated through proteolysis by these prostate cancer-specific enzymes. PSMA- and PSA-activated prodrugs typically comprise an engineered high-specificity protease peptide substrate coupled to a potent cytotoxic agent via a linker for rapid release of cytotoxic species in the vicinity of prostate cancer cells following proteolytic cleavage. Over the past two decades, various such prodrugs have been developed and they were effective at inhibiting prostate tumor growth in rodent models; several of these prodrug approaches have been advanced to clinical trials and may be developed into effective therapies for HRPC.

  11. Design, Synthesis, and Evaluation of Prodrugs of Ertapenem

    PubMed Central

    2013-01-01

    Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption primarily because of very highly polarity. A prodrug approach is a bona fide strategy to improve oral absorption of compounds. Design and synthesis, in vitro and in vivo evaluation of diversified prodrugs of ertapenem, one of the only once daily dosed carbapenems is described. Many of the prodrugs prepared for evaluation are rapidly hydrolyzed in rat plasma. Only bis-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (medoxomil) ester prodrug was rapidly hydrolyzed in most of the plasmas including rat, human, dog, and monkey. Although the rate of conversion of ertapenem diethyl ester prodrug (6) was slow in in vitro plasma hydrolysis, it showed the best in vivo pharmacokinetic profile in dog by an intraduodenal dosing giving >31% total oral absorption. PMID:24900737

  12. Prodrug-based nanoparticulate drug delivery strategies for cancer therapy.

    PubMed

    Luo, Cong; Sun, Jin; Sun, Bingjun; He, Zhonggui

    2014-11-01

    Despite the rapid developments in nanotechnology and biomaterials, the efficient delivery of chemotherapeutic agents is still challenging. Prodrug-based nanoassemblies have many advantages as a potent platform for anticancer drug delivery, such as improved drug availability, high drug loading efficiency, resistance to recrystallization upon encapsulation, and spatially and temporally controllable drug release. In this review, we discuss prodrug-based nanocarriers for cancer therapy, including nanosystems based on polymer-drug conjugates, self-assembling small molecular weight prodrugs and prodrug-encapsulated nanoparticles (NPs). In addition, we discuss new trends in the field of prodrug-based nanoassemblies that enhance the delivery efficiency of anticancer drugs, with special emphasis on smart stimuli-triggered drug release, hybrid nanoassemblies, and combination drug therapy.

  13. Development of macromolecular prodrug for rheumatoid arthritis☆

    PubMed Central

    Yuan, Fang; Quan, Ling-dong; Cui, Liao; Goldring, Steven R.; Wang, Dong

    2012-01-01

    Rheumatoid arthritis (RA) is a chronic autoimmune disease that is considered to be one of the major public health problems worldwide. The development of therapies that target tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and co-stimulatory pathways that regulate the immune system have revolutionized the care of patients with RA. Despite these advances, many patients continue to experience symptomatic and functional impairment. To address this issue, more recent therapies that have been developed are designed to target intracellular signaling pathways involved in immunoregulation. Though this approach has been encouraging, there have been major challenges with respect to off-target organ side effects and systemic toxicities related to the widespread distribution of these signaling pathways in multiple cell types and tissues. These limitations have led to an increasing interest in the development of strategies for the macromolecularization of anti-rheumatic drugs, which could target them to the inflamed joints. This approach enhances the efficacy of the therapeutic agent with respect to synovial inflammation, while markedly reducing non-target organ adverse side effects. In this manuscript, we provide a comprehensive overview of the rational design and optimization of macromolecular prodrugs for treatment of RA. The superior and the sustained efficacy of the prodrug may be partially attributed to their Extravasation through Leaky Vasculature and subsequent Inflammatory cell-mediated Sequestration (ELVIS) in the arthritic joints. This biologic process provides a plausible mechanism, by which macromolecular prodrugs preferentially target arthritic joints and illustrates the potential benefits of applying this therapeutic strategy to the treatment of other inflammatory diseases. PMID:22433784

  14. Prediction of Protection against Asian Enterovirus 71 Outbreak Strains by Cross-neutralizing Capacity of Serum from Dutch Donors, The Netherlands

    PubMed Central

    Koen, Gerrit; van Eijk, Hetty; Koekkoek, Sylvie M.; de Jong, Menno D.; Wolthers, Katja C.

    2016-01-01

    Outbreaks of human enterovirus 71 (EV-71) in Asia are related to high illness and death rates among children. To gain insight into the potential threat for the population of Europe, we determined the neutralizing activity in intravenous immunoglobulin (IVIg) batches and individual serum samples from donors in the Netherlands against EV-71 strains isolated in Europe and in Asia. All IVIg batches and 41%, 79%, and 65% of serum samples from children ≤5 years of age, women of childbearing age, and HIV-positive men, respectively, showed high neutralizing activity against a Dutch C1 strain, confirming widespread circulation of EV-71 in the Netherlands. Asian B3–4 and C4 strains were efficiently cross-neutralized, predicting possible protection against extensive circulation and associated outbreaks of those types in Europe. However, C2 and C5 strains that had few mutations in the capsid region consistently escaped neutralization, emphasizing the importance of monitoring antigenic diversity among circulating EV-71 strains. PMID:27533024

  15. Design, synthesis, and preliminary pharmacological evaluation of new imidazolinones as L-DOPA prodrugs.

    PubMed

    Giorgioni, Gianfabio; Claudi, Francesco; Ruggieri, Sabrina; Ricciutelli, Massimo; Palmieri, Giovanni F; Di Stefano, Antonio; Sozio, Piera; Cerasa, Laura S; Chiavaroli, Annalisa; Ferrante, Claudio; Orlando, Giustino; Glennon, Richard A

    2010-03-01

    L-DOPA, the immediate biological precursor of dopamine, is still considered the drug of choice in the treatment of Parkinson's disease. However, therapy with L-DOPA is associated with a number of acute problems. With the aim to increase the bioavailability after oral administration, we designed a multi-protected L-DOPA prodrugs able to release the drug by both spontaneous chemical or enzyme catalyzed hydrolysis. The new compounds have been synthesized and preliminarily evaluated for their water solubility, log P, chemical stability, and enzymatic stability. The results indicate that the incorporation of the amino acidic moiety of L-DOPA into an imidazoline-4-one ring provides prodrugs sufficiently stable to potentially cross unchanged the acidic environment of the stomach, and to be absorbed from the intestine. They also might be able to release L-DOPA in human plasma after enzymatic hydrolysis. The ability of prodrugs 6a-b to increase basal levels of striatal DA, and influence brain neurochemistry associated with dopaminergic activity following oral administration, as well as the radical-scavenging activity against DPPH for compounds 6a-b and 15a are also reported.

  16. 10-Boronic acid substituted camptothecin as prodrug of SN-38.

    PubMed

    Wang, Lei; Xie, Shao; Ma, Longjun; Chen, Yi; Lu, Wei

    2016-06-30

    Malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antitumor therapy. In this study, the 7-ethyl-10-boronic acid camptothecin (B1) was synthesized for the first time as prodrug of SN-38, by linking a cleavable aryl carbon-boron bond to the SN-38. Prodrug B1 selectively activated by H2O2, converted rapidly to the active form SN-38 under favorable oxidative conditions in cancer cells with elevated levels of H2O2. The cell survival assay showed that prodrug B1 was equally or more effective in inhibiting the growth of six different cancer cells, as compared to SN-38. Unexpectedly, prodrug B1 displayed even more potent Topo I inhibitory activity than SN-38, suggesting that it was not only a prodrug of SN-38 but also a typical Topo I inhibitor. Prodrug B1 also demonstrated a significant antitumor activity at 2.0 mg/kg in a xenograft model using human brain star glioblastoma cell lines U87MG.

  17. Quinone Induced Activation of Keap1/Nrf2 Signaling by Aspirin Prodrugs Masquerading as Nitric Oxide

    PubMed Central

    Dunlap, Tareisha; Piyankarage, Sujeewa C.; Wijewickrama, Gihani T.; Abdul-Hay, Samer; Vanni, Michael; Litosh, Vladislav; Luo, Jia; Thatcher, Gregory R. J.

    2013-01-01

    The promising therapeutic potential of the NO-donating hybrid aspirin prodrugs (NO-ASA), includes induction of chemopreventive mechanisms, and has been reported in almost 100 publications. One example, NCX-4040 (pNO-ASA), is bioactivated by esterase to a quinone methide (QM) electrophile. In cell cultures, pNO-ASA and QM-donating X-ASA prodrugs that cannot release NO rapidly depleted intracellular GSH and caused DNA damage; however, induction of Nrf2 signaling elicited cellular defense mechanisms including upregulation of NAD(P)H:quinone oxidoreductase-1 (NQO1) and glutamate-cysteine ligase (GCL). In HepG2 cells, the “NO-specific” 4,5-diaminofluorescein reporter, DAF-DA, responded to NO-ASA and X-ASA, with QM-induced oxidative stress masquerading as NO. LC-MS/MS analysis demonstrated efficient alkylation of Cys residues of proteins including glutathione-S-transferase-P1 (GST-P1) and Kelch-like ECH-associated protein 1 (Keap1). Evidence was obtained for alkylation of Keap1 Cys residues associated with Nrf2 translocation to the nucleus, nuclear translocation of Nrf2, activation of antioxidant response element (ARE), and upregulation of cytoprotective target genes. At least in cell culture, pNO-ASA acts as a QM-donor, bioactivated by cellular esterase activity to release salicylates, NO3−, and an electrophilic QM. Finally, two novel aspirin prodrugs were synthesized, both potent activators of ARE, designed to release only the QM and salicylates on bioactivation. Current interest in electrophilic drugs acting via Nrf2 signaling suggests that QM-donating hybrid drugs can be designed as informative chemical probes in drug discovery. PMID:23035985

  18. Discovery of olmesartan hexetil: a new potential prodrug of olmesartan.

    PubMed

    El-Gamal, Mohammed I; Anbar, Hanan S; Chung, Hye Jin; Kim, Hyun-Il; Cho, Young-Jin; Lee, Bong Sang; Lee, Sun Ahe; Moon, Ji Yun; Lee, Dong Jin; Kwon, Dow; Choi, Won-Jai; Jeon, Hong-Ryeol; Oh, Chang-Hyun

    2013-03-01

    Synthesis of a new ester prodrug of olmesartan, olmesartan hexetil (1), is described. It is in vitro stabilities and in vivo pharmacokinetics (PK) were evaluated. It showed high stability in simulated gastric juice, and was rapidly hydrolyzed to olmesartan in rat liver microsomes and rat plasma in vitro. C(max) and AUC(last) for olmesartan were significantly increased in case of hexetil prodrug, compared with olmesartan medoxomil. Olmesartan hexetil is proposed to be an efficient prodrug of olmesartan with markedly increased oral bioavailability.

  19. First enzymatically activated Taxotere prodrugs designed for ADEPT and PMT.

    PubMed

    Bouvier, Emmanuel; Thirot, Sylvie; Schmidt, Frédéric; Monneret, Claude

    2004-03-01

    Described here are the syntheses and preliminary biological evaluations of the first two enzymatically activated prodrugs of docetaxel (Taxotere) reported to date. These prodrugs were designed as potential candidates for selective chemotherapy in ADEPT or PMT. They are constituted of a glucuronic acid moiety, a double spacer and the cytotoxic drug, differing only by the spacer substitution. The prodrugs were stable in a buffer, and the in vitro studies showed good detoxification and hydrolysis kinetics. As docetaxel was efficiently released in both cases, these compounds are very valuable candidates for further biological evaluations.

  20. Donor Tag Game

    MedlinePlus

    ... Games > Donor Tag Game Printable Version Donor Tag Game This feature requires version 6 or later of ... LGBTQ+ Donors Blood Donor Community Real Stories SleevesUp Games Facebook Avatars and Badges Banners eCards Enter your ...

  1. Synthesis and biological studies of different duocarmycin based glycosidic prodrugs for their use in the antibody-directed enzyme prodrug therapy.

    PubMed

    Tietze, Lutz F; Schuster, Heiko J; Krewer, Birgit; Schuberth, Ingrid

    2009-01-22

    The synthesis and biological evaluation of novel prodrugs for use in the antibody directed enzyme prodrug therapy (ADEPT) of cancer based on the cytotoxic antibiotic duocarmycin SA (1) are described. In this approach, we investigated the influence of the sugar moiety of the glycosidic prodrug on the QIC(50) values as well as on the stability and the water solubility. The best result was found for prodrug 22 containing an alpha-mannoside moiety with a QIC(50) value of 4500.

  2. Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia.

    PubMed

    Guise, Christopher P; Mowday, Alexandra M; Ashoorzadeh, Amir; Yuan, Ran; Lin, Wan-Hua; Wu, Dong-Hai; Smaill, Jeff B; Patterson, Adam V; Ding, Ke

    2014-02-01

    Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.

  3. Development of a novel sulfonate ester-based prodrug strategy.

    PubMed

    Hanaya, Kengo; Yoshioka, Shohei; Ariyasu, Shinya; Aoki, Shin; Shoji, Mitsuru; Sugai, Takeshi

    2016-01-15

    A self-immolative γ-aminopropylsulfonate linker was investigated for use in the development of prodrugs that are reactive to various chemical or biological stimuli. To demonstrate their utility, a leucine-conjugated prodrug of 5-chloroquinolin-8-ol (5-Cl-8-HQ), which is a potent inhibitor against aminopeptidase from Aeromonas proteolytica (AAP), was synthesized. The sulfonate prodrug was considerably stable under physiological conditions, with only enzyme-mediated hydrolysis of leucine triggering the subsequent intramolecular cyclization to simultaneously release 5-Cl-8-HQ and form γ-sultam. It was also confirmed that this γ-aminopropylsulfonate linker was applicable for prodrugs of not only 8-HQ derivatives but also other drugs bearing a phenolic hydroxy group.

  4. The Prodrug Approach: A Successful Tool for Improving Drug Solubility.

    PubMed

    Jornada, Daniela Hartmann; dos Santos Fernandes, Guilherme Felipe; Chiba, Diego Eidy; de Melo, Thais Regina Ferreira; dos Santos, Jean Leandro; Chung, Man Chin

    2015-12-29

    Prodrug design is a widely known molecular modification strategy that aims to optimize the physicochemical and pharmacological properties of drugs to improve their solubility and pharmacokinetic features and decrease their toxicity. A lack of solubility is one of the main obstacles to drug development. This review aims to describe recent advances in the improvement of solubility via the prodrug approach. The main chemical carriers and examples of successful strategies will be discussed, highlighting the advances of this field in the last ten years.

  5. Stimuli-responsive PEGylated prodrugs for targeted doxorubicin delivery.

    PubMed

    Xu, Minghui; Qian, Junmin; Liu, Xuefeng; Liu, Ting; Wang, Hongjie

    2015-05-01

    In recent years, stimuli-sensitive prodrugs have been extensively studied for the rapid "burst" release of antitumor drugs to enhance chemotherapeutic efficiency. In this study, a novel stimuli-sensitive prodrug containing galactosamine as a targeting moiety, poly(ethylene glycol)-doxorubicin (PEG-DOX) conjugate, was developed for targeting HepG2 human liver cancer cells. To obtain the PEG-DOX conjugate, both galactosamine-decorated poly(ethylene glycol) aldehyde (Gal-PEG-CHO) and methoxy poly(ethylene glycol) aldehyde (mPEG-CHO) were firstly synthesized and functionalized with dithiodipropionate dihydrazide (TPH) through direct reductive amination via Schiff's base formation, and then DOX molecules were chemically conjugated to the hydrazide end groups of TPH-functionalized Gal-/m-PEG chains via pH-sensitive hydrazone linkages. The chemical structures of TPH-functionalized PEG and PEG-DOX prodrug were confirmed by (1)H NMR analysis. The PEG-DOX conjugate could self-assemble into spherical nanomicelles with a mean diameter of 140 nm, as indicated by transmission electron microscopy and dynamic light scattering. The drug loading content and loading efficiency in the prodrug nanomicelles were as high as 20 wt.% and 75 wt.%, respectively. In vitro drug release studies showed that DOX was released rapidly from the prodrug nanomicelles at the intracellular levels of pH and reducing agent. Cellular uptake and MTT experiments demonstrated that the galactosamine-decorated prodrug nanomicelles were more efficiently internalized into HepG2 cells via a receptor-mediated endocytosis process and exhibited a higher toxicity, compared with pristine prodrug nanomicelles. These results suggest that the novel Gal-PEG-DOX prodrug nanomicelles have tremendous potential for targeted liver cancer therapy.

  6. [Application of phosphates and phosphonates prodrugs in drug research and development].

    PubMed

    Ji, Xun; Wang, Jiang; Zhang, Lei; Zhao, Lin-Xiang; Jiang, Hua-Liang; Liu, Hong

    2013-05-01

    Based on the character of the molecular structure, the prodrugs of phosphates and phosphonates were divided into two categories. The first is the drug which contained the phosphate group, introducing protected groups to increase lipophilicity and improve bioavailability. The other one is the drug which had no phosphate group, introducing the phosphate group into molecules to enhance the solubility, regulate the distribution coefficient and enhance the drug-like property. This review focuses on the application of phosphates and phosphonates in drug research and development based on improvement of physico-chemical property, drug safety and the pharmacokinetics.

  7. Large amino acid transporter 1 (LAT1) prodrugs of valproic acid: new prodrug design ideas for central nervous system delivery.

    PubMed

    Peura, Lauri; Malmioja, Kalle; Laine, Krista; Leppänen, Jukka; Gynther, Mikko; Isotalo, Antti; Rautio, Jarkko

    2011-10-03

    Central nervous system (CNS) drug delivery is a major challenge in drug development because the blood-brain barrier (BBB) efficiently restricts the entry of drug molecules into the CNS at sufficient amounts. The brain uptake of poorly penetrating drugs could be improved by utilizing the transporters at the BBB with a prodrug approach. In this study, we designed four phenylalanine derivatives of valproic acid and studied their ability to utilize a large amino acid transporter 1 (LAT1) in CNS delivery with an aim to show that the meta-substituted phenylalanine prodrugs bind to LAT1 with a higher affinity compared with the affinity of the para-substituted derivatives. All of the prodrugs crossed the BBB carrier mediatedly via LAT1 in in situ rat brain perfusion. For the first time, we introduced a novel meta-substituted phenylalanine analogue promoiety which improved the LAT1 affinity 10-fold and more importantly the rat brain uptake of the prodrug 2-fold compared with those of the para-substituted derivatives. Therefore, we have characterized a new prodrug design idea for CNS drug delivery utilizing a transporter-mediated prodrug approach.

  8. HUMAN SKIN PERMEATION OF 3-O-ALKYL CARBAMATE PRODRUGS OF NALTREXONE

    PubMed Central

    Vaddi, Haranath K.; Banks, Stan L.; Chen, Jianhong; Hammell, Dana C.; Crooks, Peter A.; Stinchcomb, Audra L.

    2009-01-01

    N-Monoalkyl and N,N-dialkyl carbamate prodrugs of naltrexone (NTX), an opioid antagonist, were synthesized and their in vitro permeation across human skin was determined. Relevant physicochemical properties were also determined. Most prodrugs exhibited lower melting points, lower aqueous solubilities, and higher oil solubilities than NTX. The flux values from N-monoalkyl carbamate prodrugs were significantly higher than those from NTX and N,N-dialkyl carbamates. The melting points of N-monoalkyl carbamate prodrugs were quite low compared to the N,N-dialkyl carbamate prodrugs and NTX. Heats of fusion for the N,N-dialkyl carbamate prodrugs were higher than that for NTX. N-Monoalkyl carbamate prodrugs had higher stratum corneum/vehicle partition coefficients than their N,N-dialkyl counterparts. Higher percent prodrug bioconversion to NTX in skin appeared to be related to increased skin flux. N,N-Dialkyl carbamate prodrugs were more stable in buffer and in plasma than N-monoalkyl carbamate prodrugs. In conclusion, N-monoalkyl carbamate prodrugs of NTX improved the systemic delivery of NTX across human skin in vitro. N,N-Dialkyl substitution in the prodrug moiety decreased skin permeation and plasma hydrolysis to the parent drug. The cross-sectional area of the carbamate head group was the major determinant of flux of the N-monoalkyl and N,N-dialkyl carbamate prodrugs of NTX. PMID:18972573

  9. Prodrugs Bioactivated to Quinones Target NF-κB and Multiple Protein Networks: Identification of the Quinonome.

    PubMed

    Pierce, Emily N; Piyankarage, Sujeewa C; Dunlap, Tareisha; Litosh, Vladislav; Siklos, Marton I; Wang, Yue-Ting; Thatcher, Gregory R J

    2016-07-18

    Electrophilic reactive intermediates resulting from drug metabolism have been associated with toxicity and off-target effects and in some drug discovery programs trigger NO-GO decisions. Many botanicals and dietary supplements are replete with such reactive electrophiles, notably Michael acceptors, which have been demonstrated to elicit chemopreventive mechanisms; and Michael acceptors are gaining regulatory approval as contemporary cancer therapeutics. Identifying protein targets of these electrophiles is central to understanding potential therapeutic benefit and toxicity risk. NO-donating NSAID prodrugs (NO-NSAIDs) have been the focus of extensive clinical and preclinical studies in inflammation and cancer chemoprevention and therapy: a subset exemplified by pNO-ASA, induces chemopreventive mechanisms following bioactivation to an electrophilic quinone methide (QM) Michael acceptor. Having previously shown that these NO-independent, QM-donors activated Nrf2 via covalent modification of Keap-1, we demonstrate that components of canonical NF-κB signaling are also targets, leading to the inhibition of NF-κB signaling. Combining bio-orthogonal probes of QM-donor ASA prodrugs with mass spectrometric proteomics and pathway analysis, we proceeded to characterize the quinonome: the protein cellular targets of QM-modification by pNO-ASA and its ASA pro-drug congeners. Further comparison was made using a biorthogonal probe of the "bare-bones", Michael acceptor, and clinical anti-inflammatory agent, dimethyl fumarate, which we have shown to inhibit NF-κB signaling. Identified quinonome pathways include post-translational protein folding, cell-death regulation, protein transport, and glycolysis; and identified proteins included multiple heat shock elements, the latter functionally confirmed by demonstrating activation of heat shock response.

  10. Targeted anticancer prodrug with mesoporous silica nanoparticles as vehicles

    NASA Astrophysics Data System (ADS)

    Fan, Jianquan; Fang, Gang; Wang, Xiaodan; Zeng, Fang; Xiang, Yufei; Wu, Shuizhu

    2011-11-01

    A targeted anticancer prodrug system was fabricated with 180 nm mesoporous silica nanoparticles (MSNs) as carriers. The anticancer drug doxorubicin (DOX) was conjugated to the particles through an acid-sensitive carboxylic hydrazone linker which is cleavable under acidic conditions. Moreover, folic acid (FA) was covalently conjugated to the particle surface as the targeting ligand for folate receptors (FRs) overexpressed in some cancer cells. The in vitro release profiles of DOX from the MSN-based prodrug systems showed a strong dependence on the environmental pH values. The fluorescent dye FITC was incorporated in the MSNs so as to trace the cellular uptake on a fluorescence microscope. Cellular uptakes by HeLa, A549 and L929 cell lines were tested for FA-conjugated MSNs and plain MSNs respectively, and a much more efficient uptake by FR-positive cancer cells (HeLa) can be achieved by conjugation of folic acid onto the particles because of the folate-receptor-mediated endocytosis. The cytotoxicities for the FA-conjugated MSN prodrug, the plain MSN prodrug and free DOX against three cell lines were determined, and the result indicates that the FA-conjugated MSN prodrug exhibits higher cytotoxicity to FR-positive cells, and reduced cytotoxicity to FR-negative cells. Thus, with 180 nm MSNs as the carriers for the prodrug system, good drug loading, selective targeting and sustained release of drug molecules within targeted cancer cells can be realized. This study may provide useful insights for designing and improving the applicability of MSNs in targeted anticancer prodrug systems.

  11. Improved peptide prodrugs of 5-ALA for PDT: rationalization of cellular accumulation and protoporphyrin IX production by direct determination of cellular prodrug uptake and prodrug metabolization.

    PubMed

    Giuntini, Francesca; Bourré, Ludovic; MacRobert, Alexander J; Wilson, Michael; Eggleston, Ian M

    2009-07-09

    Twenty-seven dipeptide derivatives of general structure Ac-Xaa-ALA-OR were synthesized as potential prodrugs for 5-aminolaevulinic acid-based photodynamic therapy (ALA-PDT). Xaa is an alpha-amino acid, chosen to provide a prodrug with appropriately tailored lipophilicity and water solubility. Although no simple correlation is observed between downstream production of protoporphyrin IX (PpIX) in PAM212 keratinocytes and HPLC-derived descriptors of compound lipophilicity, quantification of prodrug uptake reveals that most of the dipeptides are actually more efficiently accumulated than ALA in PAM212 and also A549 and Caco-2 cell lines. Subsequent ALA release is the limiting factor, which emphasizes the importance of decoupling prodrug uptake and intracellular metabolization when assessing the efficacy of ALA derivatives for PDT. In agreement with PpIX fluorescence studies, at a concentration of 0.1 mM, l-Phe derivatives 4m and 4o, and l-Leu, l-Met, and l-Glu derivatives 4f, 4k, and 4u, exhibit significantly enhanced photoxicity in PAM212 cells compared to ALA.

  12. Asymmetric Synthesis of a CBI-Based Cyclic N-Acyl O-Amino Phenol Duocarmycin Prodrug

    PubMed Central

    2015-01-01

    A short, asymmetric synthesis of a cyclic N-acyl O-amino phenol duocarmycin prodrug subject to reductive activation based on the simplified 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) DNA alkylation subunit is described. A key element of the approach entailed treatment of iodo-epoxide 7, prepared by N-alkylation of 6 with (S)-glycidal 3-nosylate, with EtMgBr at room temperature to directly provide the optically pure alcohol 8 in 78% yield (99% ee) derived from an effective metal–halogen exchange and subsequent regioselective intramolecular 6-endo-tet cyclization. Following O-debenzylation, introduction of a protected N-methylhydroxamic acid, direct trannannular spirocyclization, and subsequent stereoelectronically controlled acid-catalyzed cleavage of the resulting cyclopropane (HCl), further improvements in a unique intramolecular cyclization with N–O bond formation originally introduced for formation of the reductively labile prodrug functionality are detailed. PMID:25247380

  13. Effect of the butyrate prodrug pivaloyloxymethyl butyrate (AN9) on a mouse model for spinal muscular atrophy

    PubMed Central

    Edwards, Jonathan D.; Butchbach, Matthew E. R.

    2016-01-01

    Spinal muscular atrophy (SMA) is an early-onset motor neuron disease that leads to loss of muscle function. Butyrate (BA)-based compounds markedly improve the survival and motor phenotype of SMA mice. In this study, we examine the protective effects of the BA prodrug pivaloyloxymethyl butyrate (AN9) on the survival of SMNΔ7 SMA mice. Oral administration of AN9 beginning at PND04 almost doubled the average lifespan of SMNΔ7 SMA mice. AN9 treatment also increased the growth rate of SMNΔ7 SMA mice when compared to vehicle-treated SMNΔ7 SMA mice. In conclusion, BA prodrugs like AN9 have ameliorative effects on SMNΔ7 SMA mice. PMID:27911337

  14. Structure-activity relationships for dipeptide prodrugs of acyclovir: implications for prodrug design.

    PubMed

    Santos, Cledir R; Capela, Rita; Pereira, Cláudia S G P; Valente, Emília; Gouveia, Luís; Pannecouque, Christophe; De Clercq, Erik; Moreira, Rui; Gomes, Paula

    2009-06-01

    A series of water-soluble dipeptide ester prodrugs of the antiviral acyclovir (ACV) were evaluated for their chemical stability, cytotoxicity, and antiviral activity against several strains of Herpes Simplex-1 and -2, vaccinia, vesicular stomatitis, cytomegalovirus and varicella zoster viruses. ACV dipeptide esters were very active against herpetic viruses, independently of the rate at which they liberate the parent drug. Their minimum cytotoxic concentrations were above 100 microM and the resulting MCC/EC(50) values were lower than those of ACV. When comparing the reactivity of Phe-Gly esters and amides (ACV, zidovudine, paracetamol, captopril and primaquine) in pH 7.4 buffer it was found that the rate of drug release increases with drug's leaving group ability. Release of the parent drug from Phe-Gly in human plasma is markedly faster than in pH 7.4 buffer, thus suggesting that the dipeptide-based prodrug approach can be successfully applied to bioactive agents containing thiol, phenol and amine functional groups.

  15. Recent Trends in Targeted Anticancer Prodrug and Conjugate Design

    PubMed Central

    Singh, Yashveer; Palombo, Matthew; Sinko, Patrick J.

    2009-01-01

    Anticancer drugs are often nonselective antiproliferative agents (cytotoxins) that preferentially kill dividing cells by attacking their DNA at some level. The lack of selectivity results in significant toxicity to noncancerous proliferating cells. These toxicities along with drug resistance exhibited by the solid tumors are major therapy limiting factors that results into poor prognosis for patients. Prodrug and conjugate design involves the synthesis of inactive drug derivatives that are converted to an active form inside the body and preferably at the site of action. Classical prodrug and conjugate design has focused on the development of prodrugs that can overcome physicochemical (e.g., solubility, chemical instability) or biopharmaceutical problems (e.g., bioavailability, toxicity) associated with common anticancer drugs. The recent targeted prodrug and conjugate design, on the other hand, hinges on the selective delivery of anticancer agents to tumor tissues thereby avoiding their cytotoxic effects on noncancerous cells. Targeting strategies have attempted to take advantage of low extracellular pH, elevated enzymes in tumor tissues, the hypoxic environment inside the tumor core, and tumor-specific antigens expressed on tumor cell surfaces. The present review highlights recent trends in prodrug and conjugate rationale and design for cancer treatment. The various approaches that are currently being explored are critically analyzed and a comparative account of the advantages and disadvantages associated with each approach is presented. PMID:18691040

  16. Simvastatin prodrug micelles target fracture and improve healing.

    PubMed

    Jia, Zhenshan; Zhang, Yijia; Chen, Yen Hsun; Dusad, Anand; Yuan, Hongjiang; Ren, Ke; Li, Fei; Fehringer, Edward V; Purdue, P Edward; Goldring, Steven R; Daluiski, Aaron; Wang, Dong

    2015-02-28

    Simvastatin (SIM), a widely used anti-lipidemic drug, has been identified as a bone anabolic agent. Its poor water solubility and the lack of distribution to the skeleton, however, have limited its application in the treatment of bone metabolic diseases. In this study, an amphiphilic macromolecular prodrug of SIM was designed and synthesized to overcome these limitations. The polyethylene glycol (PEG)-based prodrug can spontaneously self-assemble to form micelles. The use of SIM trimer as the prodrug's hydrophobic segment allows easy encapsulation of additional free SIM. The in vitro studies showed that SIM/SIM-mPEG micelles were internalized by MC3T3 cells via lysosomal trafficking and consistently induced expression of both BMP2 and DKK1 mRNA, suggesting that the prodrug micelle retains the biological functions of SIM. After systemic administration, optical imaging suggests that the micelles would passively target to bone fracture sites associated with hematoma and inflammation. Furthermore, flow cytometry study revealed that SIM/SIM-mPEG micelles had preferred cellular uptake by inflammatory and resident cells within the fracture callus tissue. The treatment study using a mouse osteotomy model validated the micelles' therapeutic efficacy in promoting bone fracture healing as demonstrated by micro-CT and histological analyses. Collectively, these data suggest that the macromolecular prodrug-based micelle formulation of SIM may have great potential for clinical management of impaired fracture healing.

  17. Prodrugs of aza nucleosides based on proton transfer reaction

    NASA Astrophysics Data System (ADS)

    Karaman, Rafik

    2010-12-01

    DFT calculation results for intramolecular proton transfer reactions in Kirby's enzyme models 1- 7 reveal that the reaction rate is quite responsive to geometric disposition, especially to distance between the two reactive centers, r GM, and the angle of attack, α (the hydrogen bonding angle). Hence, the study on the systems reported herein could provide a good basis for designing aza nucleoside prodrug systems that are less hydrophilic than their parental drugs and can be used, in different dosage forms, to release the parent drug in a controlled manner. For example, based on the calculated log EM, the cleavage process for prodrug 1ProD is predicted to be about 1010 times faster than that for prodrug 7ProD and about 104 times faster than prodrug 3ProD: rate 1ProD > rate 3ProD > rate 7ProD . Hence, the rate by which the prodrug releases the aza nucleoside drug can be determined according to the structural features of the linker (Kirby's enzyme model).

  18. Initial development of a cytotoxic amino-seco-CBI warhead for delivery by prodrug systems.

    PubMed

    Twum, Elvis A; Nathubhai, Amit; Wood, Pauline J; Lloyd, Matthew D; Thompson, Andrew S; Threadgill, Michael D

    2015-07-01

    Cyclopropabenzaindoles (CBIs) are exquisitely potent cytotoxins which bind and alkylate in the minor groove of DNA. They are not selective for cancer cells, so prodrugs are required. CBIs can be formed at physiological pH by Winstein cyclisation of 1-chloromethyl-3-substituted-5-hydroxy-2,3-dihydrobenzo[e]indoles (5-OH-seco-CBIs). Corresponding 5-NH2-seco-CBIs should also undergo Winstein cyclisation similarly. A key triply orthogonally protected intermediate on the route to 5-NH2-seco-CBIs has been synthesised, via selective monotrifluoroacetylation of naphthalene-1,3-diamine, Boc protection, electrophilic iodination, selective allylation at the trifluoroacetamide and 5-exo radical ring-closure with TEMPO. This intermediate has potential for introduction of peptide prodrug masking units (deactivating the Winstein cyclisation and cytotoxicity), addition of diverse indole-amide side-chains (enhancing non-covalent binding prior to alkylation) and use of different leaving groups (replacing the usual chlorine, allowing tuning of the rate of Winstein cyclisation). This key intermediate was elaborated into a simple model 5-NH2-seco-CBI with a dimethylaminoethoxyindole side-chain. Conversion to a bio-reactive entity and the bioactivity of this system were confirmed through DNA-melting studies (ΔTm=13°C) and cytotoxicity against LNCaP human prostate cancer cells (IC50=18nM).

  19. Optimization of alkylating agent prodrugs derived from phenol and aniline mustards: a new clinical candidate prodrug (ZD2767) for antibody-directed enzyme prodrug therapy (ADEPT).

    PubMed

    Springer, C J; Dowell, R; Burke, P J; Hadley, E; Davis, D H; Blakey, D C; Melton, R G; Niculescu-Duvaz, I

    1995-12-22

    Sixteen novel potential prodrugs derived from phenol or aniline mustards and their 16 corresponding drugs with ring substitution and/or different alkylating functionalities were designed. The [[[4-]bis(2-bromoethyl)-(1a), [[[4-[bis(2-iodoethyl)-(1b), and [[[4-[(2-chloroethyl)-[2-(mesyloxy)ethyl]amino]phenyl]oxy] carbonyl]-L-glutamic acids (1c), their [[[2- and 3-substituted-4-[bis(2-chloroethyl)amino]phenyl]oxy]carbonyl]-L- glutamic acids (1e-1), and the [[3-substituted-4-[bis(2-chloroethyl)amino]phenyl]carbamoyl]-L- glutamic acids (1o-r) were synthesized. They are bifunctional alkylating agents in which the activating effect of the phenolic hydroxyl or amino function is masked through an oxycarbonyl or a carbamoyl bond to a glutamic acid. These prodrugs were designed to be activated to their corresponding phenol and aniline nitrogen mustard drugs at a tumor site by prior administration of a monoclonal antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in antibody-directed enzyme prodrug therapy (ADEPT). The synthesis of the analogous novel parent drugs (2a-r) is also described. The viability of a colorectal cell line (LoVo) was monitored with the potential prodrugs and the parent drugs. The differential in the cytotoxicity between the potential prodrugs and their corresponding active drugs ranged between 12 and > 195 fold. Compounds 1b-d,f,o exhibited substantial prodrug activity, since a cytotoxicity differential of > 100 was achieved compared to 2b-d,f,o respectively. The ability of the potential prodrugs to act as substrates for CPG2 was determined (kinetic parameters KM and kcat), and the chemical stability was measured for all the compounds. The unsubstituted phenols with different alkylating functionalities (1a-c) proved to have the highest ratio of the substrates kcat:KM. From these studies [[[4-[bis(2-iodoethyl)amino]phenyl]oxy]carbonyl]-L-glutamic acid (1b) emerges as a new ADEPT clinical trial candidate due to its physicochemical and

  20. Long-Acting Diclofenac Ester Prodrugs for Joint Injection: Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension.

    PubMed

    Mertz, Nina; Larsen, Susan Weng; Kristensen, Jesper; Østergaard, Jesper; Larsen, Claus

    2016-10-01

    A prodrug approach for local and sustained diclofenac action after injection into joints based on ester prodrugs having a pH-dependent solubility is presented. Inherent ester prodrug properties influencing the duration of action include their pH-dependent solubility and charge state, as well as susceptibility to undergo esterase facilitated hydrolysis. In this study, physicochemical properties and pH rate profiles of 3 diclofenac ester prodrugs differing with respect to the spacer carbon chain length between the drug and the imidazole-based promoiety were determined and a rate equation for prodrug degradation in aqueous solution in the pH range 1-10 was derived. In the pH range 6-10, the prodrugs were subject to parallel degradation to yield diclofenac and an indolinone derivative. The prodrug degradation was found to be about 6-fold faster in 80% (vol/vol) human plasma as compared to 80% (vol/vol) human synovial fluid with 2-(1-methyl-1H-imidazol-2-yl)ethyl 2-(2-(2,6 dichlorophenyl)amino)phenylacetate being the poorest substrate toward enzymatic cleavage. The conversion and release of parent diclofenac from prodrug suspensions in vitro were studied using the rotating dialysis model. The results suggest that it is possible to alter and control dissolution and reconversion behavior of the diclofenac prodrugs, thus making the prodrug approach feasible for local and sustained diclofenac action after joint injection.

  1. Prodrug design to improve pharmacokinetic and drug delivery properties: challenges to the discovery scientists.

    PubMed

    Jana, S; Mandlekar, S; Marathe, P

    2010-01-01

    The prodrug design is a versatile, powerful method that can be applied to a wide range of parent drug molecules, administration routes, and formulations. Clinically, the majority of prodrugs are used with the aim of enhancing drug permeation by increasing lipophilicity, or by improving aqueous solubility. Prodrug design may improve the bioavailability of parent molecule, and thus can be integrated into the iterative process of lead optimization, rather than employing it as a post-hoc approach. The purpose of this review is to provide an update of advances and progress in the knowledge of current strategic approaches of prodrug design, along with their real-world utility in drug discovery and development. The review covers the type of prodrugs and functional groups that are amenable to prodrug design. Various prodrug approaches for improving oral drug delivery are discussed, with numerous examples of marketed prodrugs, including improved aqueous solubility, improved lipophilicity, transporter-mediated absorption, and prodrug design to achieve site-specific delivery. Tools employed for prodrug screening, and specific challenges in prodrug research and development are also elaborated. This article is intended to encourage discovery scientists to be creative and consider a rationally designed prodrug approach during the lead optimization phase of drug discovery programs, when the structure activity relationship (SAR) for the drug target is incompatible with pharmacokinetic or biopharmaceutical objectives.

  2. Protective effects of alpha phenyl-tert-butyl nitrone and ascorbic acid in human adipose derived mesenchymal stem cells from differently aged donors

    PubMed Central

    Hohaus, Christian; Jörg Meisel, Hans; Krystel, llona; Stolzing, Alexandra

    2017-01-01

    Adipose-derived mesenchymal stem cells (ADSCs) are multipotent stem cells that promote therapeutic effects and are frequently used in autologous applications. Little is known about how ADSCs respond to genotoxic stress and whether or not donor age affects DNA damage and repair. In this study, we used the comet assay to assess DNA damage and repair in human ADSCs derived from young (20-40 years), middle-aged (41-60 years), and older (61+ years) donors following treatment with H2O2 or UV light. Tail lengths in H2O2-treated ADSCs were substantially higher than the tail lengths in UV-treated ADSCs. After 30 minutes of treatment with H2O2, ADSCs preconditioned with alpha phenyl-tert-butyl nitrone (PBN) or ascorbic acid (AA) showed a significant reduction in % tail DNA. The majority of ADSCs treated with PBN or AA displayed low olive tail movements at various timepoints. In general and indicative of DNA repair, % tail length and % tail DNA peaked at 30 minutes and then decreased to near-control levels at the 2 hour and 4 hour timepoints. Differently aged ADSCs displayed comparable levels of DNA damage in the majority of these experiments, suggesting that the age of the donor does not affect the DNA damage response in cultured ADSCs. PMID:27638293

  3. New prodrugs based on phospholipid-nucleoside conjugates

    SciTech Connect

    MacCoss, M.

    1982-02-03

    A method is described for the preparation of defined, isomerically pure phospholipid-nucleoside conjugates as a prodrug in which the drug (araC) is attached to the phospholipid by a monophosphate linkage. Key intermediates in the process involve selective blocking and deblocking of the nucleoside derivative. These particular monophosphate-linked derivatives represent a new class of prodrug, which are useful by themselves or in combination with diphosphate linked derivatives. Several new compositions involving diphosphate linked derivatives are described in which the products are isomerically pure and having defined fatty acid chain lengths.

  4. Antibody-directed enzyme prodrug therapy: a promising approach for a selective treatment of cancer based on prodrugs and monoclonal antibodies.

    PubMed

    Tietze, Lutz F; Krewer, Birgit

    2009-09-01

    The antibody-directed enzyme prodrug therapy allows a selective liberation of cytotoxic agents from non-toxic prodrugs in cancerous tissue by targeted antibody-enzyme conjugates. We have developed a series of novel glycosidic prodrugs based on the natural antibiotic CC-1065 and the duocarmycins, which are up to 4800 times less toxic than the drugs liberated from these prodrugs in the presence of the activating enzyme (e.g., beta-D-galactosidase). Furthermore, the drugs show very high cytotoxicities with IC(50) values of as low as 4.5 pm. In this report, we summarize our recent results on the development and biological evaluation of these novel third-generation prodrugs with higher water solubility, higher difference in cytotoxicity between the prodrugs and the corresponding drugs and improved cytotoxicity of the drugs as compared with previous compounds.

  5. Glutathione-S-transferase selective release of metformin from its sulfonamide prodrug.

    PubMed

    Rautio, Jarkko; Vernerová, Monika; Aufderhaar, Imke; Huttunen, Kristiina M

    2014-11-01

    In this study, three sulfonamide prodrugs of metformin were designed and synthesized. The bioconversion of the sulfonamide prodrugs by glutathione-S-transferase (GST) was evaluated in rat and human liver S9 fractions as well as with recombinant human GST forms. One of the prodrugs (3) was bioactivated by GST and released metformin in a quantitative manner, whereas the two others were enzymatically stable. Prodrug 3 had a much higher logD value relative to metformin and it was reasonably stable in both acidic buffer and rat small intestine homogenate, which indicates that this prodrug has the potential to increase the oral absorption of metformin.

  6. Synthesis and biological evaluation of prodrugs based on the natural antibiotic duocarmycin for use in ADEPT and PMT.

    PubMed

    Tietze, Lutz F; Schmuck, Kianga; Schuster, Heiko J; Müller, Michael; Schuberth, Ingrid

    2011-02-07

    Chemotherapy of malign tumors is usually associated with serious side effects as common anticancer drugs lack selectivity. An approach to deal with this problem is the antibody-directed enzyme prodrug therapy (ADEPT) and the prodrug monotherapy (PMT). Herein, the synthesis and biological evaluation of new glycosidic prodrugs suitable for both concepts are described. All prodrugs but one are stable in human serum and show QIC(50) values (IC(50) of prodrug/IC(50) of prodrug in the presence of the appropriate glycohydrolase) of up to 6500. This is the best value found so far for compounds interacting with DNA.

  7. Cancer chemotherapy: a SN-38 (7-ethyl-10-hydroxycamptothecin) glucuronide prodrug for treatment by a PMT (Prodrug MonoTherapy) strategy.

    PubMed

    Angenault, Stéphane; Thirot, Sylvie; Schmidt, Frédéric; Monneret, Claude; Pfeiffer, Bruno; Renard, Pierre

    2003-03-10

    A glucuronide-based prodrug of SN-38 (7-ethyl-10-hydroxycamptothecin) has been synthesized for use in a Prodrug MonoTherapy Strategy (PMT). Since this prodrug is significantly less cytotoxic than SN-38 itself and efficiently releases the drug in vitro in the presence of beta-D-glucuronidase, it can be considered as an appropriate candidate for cancer treatment by a PMT strategy.

  8. The novel mitochondria-targeted hydrogen sulfide (H2S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro.

    PubMed

    Gerő, Domokos; Torregrossa, Roberta; Perry, Alexis; Waters, Alicia; Le-Trionnaire, Sophie; Whatmore, Jacqueline L; Wood, Mark; Whiteman, Matthew

    2016-11-01

    The development of diabetic vascular complications is initiated, at least in part, by mitochondrial reactive oxygen species (ROS) production in endothelial cells. Hyperglycemia induces superoxide production in the mitochondria and initiates changes in the mitochondrial membrane potential that leads to mitochondrial dysfunction. Hydrogen sulfide (H2S) supplementation has been shown to reduce the mitochondrial oxidant production and shows efficacy against diabetic vascular damage in vivo. However, the half-life of H2S is very short and it is not specific for the mitochondria. We have therefore evaluated two novel mitochondria-targeted anethole dithiolethione and hydroxythiobenzamide H2S donors (AP39 and AP123 respectively) at preventing hyperglycemia-induced oxidative stress and metabolic changes in microvascular endothelial cells in vitro. Hyperglycemia (HG) induced significant increase in the activity of the citric acid cycle and led to elevated mitochondrial membrane potential. Mitochondrial oxidant production was increased and the mitochondrial electron transport decreased in hyperglycemic cells. AP39 and AP123 (30-300nM) decreased HG-induced hyperpolarisation of the mitochondrial membrane and inhibited the mitochondrial oxidant production. Both H2S donors (30-300nM) increased the electron transport at respiratory complex III and improved the cellular metabolism. Targeting H2S to mitochondria retained the cytoprotective effect of H2S against glucose-induced damage in endothelial cells suggesting that the molecular target of H2S action is within the mitochondria. Mitochondrial targeting of H2S also induced >1000-fold increase in the potency of H2S against hyperglycemia-induced injury. The high potency and long-lasting effect elicited by these H2S donors strongly suggests that these compounds could be useful against diabetic vascular complications.

  9. Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine.

    PubMed

    Weiss, Jason T; Dawson, John C; Fraser, Craig; Rybski, Witold; Torres-Sánchez, Carmen; Bradley, Mark; Patton, E Elizabeth; Carragher, Neil O; Unciti-Broceta, Asier

    2014-06-26

    Bioorthogonal chemistry has become one of the main driving forces in current chemical biology, inspiring the search for novel biocompatible chemospecific reactions for the past decade. Alongside the well-established labeling strategies that originated the bioorthogonal paradigm, we have recently proposed the use of heterogeneous palladium chemistry and bioorthogonal Pd(0)-labile prodrugs to develop spatially targeted therapies. Herein, we report the generation of biologically inert precursors of cytotoxic gemcitabine by introducing Pd(0)-cleavable groups in positions that are mechanistically relevant for gemcitabine's pharmacological activity. Cell viability studies in pancreatic cancer cells showed that carbamate functionalization of the 4-amino group of gemcitabine significantly reduced (>23-fold) the prodrugs' cytotoxicity. The N-propargyloxycarbonyl (N-Poc) promoiety displayed the highest sensitivity to heterogeneous palladium catalysis under biocompatible conditions, with a reaction half-life of less than 6 h. Zebrafish studies with allyl, propargyl, and benzyl carbamate-protected rhodamines confirmed N-Poc as the most suitable masking group for implementing in vivo bioorthogonal organometallic chemistry.

  10. Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury

    PubMed Central

    Lee, Dongwon; Park, Seunggyu; Bae, Soochan; Jeong, Dahee; Park, Minhyung; Kang, Changsun; Yoo, Wooyoung; Samad, Mohammed A.; Ke, Qingen; Khang, Gilson; Kang, Peter M.

    2015-01-01

    Overproduction of hydrogen peroxide (H2O2) causes oxidative stress and is the main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury. Suppression of oxidative stress is therefore critical in the treatment of I/R injury. Here, we report H2O2-activatable antioxidant prodrug (BRAP) that is capable of specifically targeting the site of oxidative stress and exerting anti-inflammatory and anti-apoptotic activities. BRAP with a self-immolative boronic ester protecting group was designed to scavenge H2O2 and release HBA (p-hydroxybenzyl alcohol) with antioxidant and anti-inflammatory activities. BRAP exerted potent antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)- and H2O2-stimulated cells by suppressing the generation of ROS and pro-inflammatory cytokines. In mouse models of hepatic I/R and cardiac I/R, BRAP exerted potent antioxidant, anti-inflammatory and anti-apoptotic activities due to the synergistic effects of H2O2-scavenging boronic esters and therapeutic HBA. In addition, administration of high doses of BRAP daily for 7 days showed no renal or hepatic function abnormalities. Therefore BRAP has tremendous therapeutic potential as H2O2-activatable antioxidant prodrug for the treatment of I/R injuries. PMID:26563741

  11. Aspartic acid based nucleoside phosphoramidate prodrugs as potent inhibitors of hepatitis C virus replication.

    PubMed

    Maiti, Munmun; Maiti, Mohitosh; Rozenski, Jef; De Jonghe, Steven; Herdewijn, Piet

    2015-05-14

    In view of a persistent threat to mankind, the development of nucleotide-based prodrugs against hepatitis C virus (HCV) is considered as a constant effort in many medicinal chemistry groups. In an attempt to identify novel nucleoside phosphoramidate analogues for improving the anti-HCV activity, we have explored, for the first time, aspartic acid (Asp) and iminodiacetic acid (IDA) esters as amidate counterparts by considering three 2'-C-methyl containing nucleosides, 2'-C-Me-cytidine, 2'-C-Me-uridine and 2'-C-Me-2'-fluoro-uridine. Synthesis of these analogues required protection for the vicinal diol functionality of the sugar moiety and the amino group of the cytidine nucleoside to regioselectively perform phosphorylation reaction at the 5'-hydroxyl group. Anti-HCV data demonstrate that the Asp-based phosphoramidates are ∼550 fold more potent than the parent nucleosides. The inhibitory activity of the Asp-ProTides was higher than the Ala-ProTides, suggesting that Asp would be a potential amino acid candidate to be considered for developing novel antiviral prodrugs.

  12. Propyphenazone-Based Analogues as Prodrugs and Selective Cyclooxygenase-2 Inhibitors

    PubMed Central

    2014-01-01

    Improving the gastrointestinal safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) is an important goal. Herein, we report two strategies, using the nonacidic propyphenazone structure, with potential to overcome the side effects of NSAIDs. Propyphenazone was employed to temporarily mask the free acid group of the widely used NSAIDs ibuprofen, diclofenac, and ketoprofen to develop three mutual prodrugs hypothesized to have minimal GI irritation. The three prodrugs exhibit in vivo anti-inflammatory and analgesic activities with improved potency over each parent drug when compared to a nonhydrolyzable control betahistine–propyphenazone (BET–MP). Additionally, ANT–MP formed by the irreversible coupling of propyphenazone and 4-aminoantipyrine, displayed exceptional COXII selectivity (COXII IC50 of 0.97 ± 0.04 μM, compared to no observed inhibition of COXI at 160 μM). Inhibition of COXII suppresses inflammatory diseases without affecting COXI-mediated GI tract events. ANT–MP exhibited maximal analgesic effect when tested in vivo in an abdominal writhing assay (100% protection) and its anti-inflammatory activity showed a peak at 2 h in a carrageenan-induced paw edema model. Its unique selectivity toward the COXII enzyme was investigated using molecular modeling techniques. PMID:25221653

  13. Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Prodrugs as Drug Candidates for the Treatment of Ischemic Disorders: Insights into NO-Releasing Prodrug Biotransformation and Hemoglobin-NO Biochemistry.

    PubMed

    Xu, Guoyan G; Deshpande, Tanvi M; Ghatge, Mohini S; Mehta, Akul Y; Omar, Abdel Sattar M; Ahmed, Mostafa H; Venitz, Jurgen; Abdulmalik, Osheiza; Zhang, Yan; Safo, Martin K

    2015-12-15

    We have developed novel nitric oxide (NO)-releasing prodrugs of efaproxiral (RSR13) for their potential therapeutic applications in a variety of diseases with underlying ischemia. RSR13 is an allosteric effector of hemoglobin (Hb) that decreases the protein's affinity for oxygen, thereby increasing tissue oxygenation. NO, because of its vasodilatory property, in the form of ester prodrugs has been found to be useful in managing several cardiovascular diseases by increasing blood flow and oxygenation in ischemic tissues. We synthesized three NO-donor ester derivatives of RSR13 (DD-1, DD-2, and DD-3) by attaching the NO-releasing moieties nitrooxyethyl, nitrooxypropyl, and 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate, respectively, to the carboxylate of RSR13. In vitro studies demonstrated that the compounds released NO in a time-dependent manner upon being incubated with l-cysteine (1.8-9.3%) or human serum (2.3-52.5%) and also reduced the affinity of Hb for oxygen in whole blood (ΔP50 of 4.9-21.7 mmHg vs ΔP50 of 25.4-32.1 mmHg for RSR13). Crystallographic studies showed RSR13, the hydrolysis product of the reaction between DD-1 and deoxygenated Hb, bound to the central water cavity of Hb. Also, the hydrolysis product, NO, was observed exclusively bound to the two α hemes, the first such HbNO structure to be reported, capturing the previously proposed physiological bis-ligated nitrosylHb species. Finally, nitrate was observed bound to βHis97. Ultraperformance liquid chromatography-mass spectrometry analysis of the compounds incubated with matrices used for the various studies demonstrated the presence of the predicted reaction products. Our findings, beyond the potential therapeutic application, provide valuable insights into the biotransformation of NO-releasing prodrugs and their mechanism of action and into hemoglobin-NO biochemistry at the molecular level.

  14. Simvastatin Prodrug Micelles Target Fracture and Improve Healing

    PubMed Central

    Dusad, Anand; Yuan, Hongjiang; Ren, Ke; Li, Fei; Fehringer, Edward V.; Purdue, P. Edward; Goldring, Steven R.; Daluiski, Aaron; Wang, Dong

    2014-01-01

    Simvastatin (SIM), a widely used anti-lipidaemic drug, has been identified as a bone anabolic agent. Its poor water solubility and the lack of distribution to the skeleton, however, have limited its application in the treatment of bone metabolic diseases. In this study, an amphiphilic macromolecular prodrug of SIM was designed and synthesized to overcome these limitations. The polyethylene glycol (PEG)-based prodrug can spontaneously self-assemble to form micelles. The use of SIM trimer as the prodrug’s hydrophobic segment allows easy encapsulation of additional free SIM. The in vitro studies showed that SIM/SIM-mPEG micelles were internalized by MC3T3 cells via lysosomal trafficking and consistently induced expression of both BMP2 and DKK1 mRNA, suggesting that the prodrug micelle retains the biological functions of SIM. After systemic administration, optical imaging suggests that the micelles would passively target to bone fracture sites associated with hematoma and inflammation. Furthermore, flow cytometry study revealed that SIM/SIM-mPEG micelles had preferred cellular uptake by inflammatory and resident cells within the fracture callus tissue. The treatment study using a mouse osteotomy model validated the micelles’ therapeutic efficacy in promoting bone fracture healing as demonstrated by micro-CT and histological analyses. Collectively, these data suggest that the macromolecular prodrug-based micelle formulation of SIM may have great potential for clinical management of impaired fracture healing. PMID:25542644

  15. Successful kinase bypass with new acyclovir phosphoramidate prodrugs.

    PubMed

    McGuigan, Christopher; Derudas, Marco; Bugert, Joachim J; Andrei, Graciela; Snoeck, Robert; Balzarini, Jan

    2008-08-01

    Novel phosphoramidates of acyclovir have been prepared and evaluated in vitro against acyclovir-sensitive and -resistant herpes simplex virus (HSV) types 1 and 2 and varicella-zoster virus (VZV). Unlike the parent nucleoside these novel phosphate prodrugs retain antiviral potency versus the ACV-resistant virus strain, suggesting an efficient bypass of the viral thymidine kinase.

  16. Computationally-designed phenylephrine prodrugs - a model for enhancing bioavailability

    NASA Astrophysics Data System (ADS)

    Karaman, Rafik; Karaman, Donia; Zeiadeh, Isra'

    2013-11-01

    DFT calculations at B3LYP 6-31G (d,p) for intramolecular proton transfer in a number of Kirby's enzyme models demonstrated that the driving force for the proton transfer efficiency is the distance between the two reactive centres (rGM) and the attack angle (α); and the rate of the reaction is linearly correlated with rGM2 and sin (180°- α). Based on these results three phenylephrine prodrugs were designed to provide phenylephrine with higher bioavailability than their parent drug. Using the experimental t1/2 (the time needed for the conversion of 50% of the reactants to products) and EM (effective molarity) values for these processes the t1/2 values for the conversion of the three prodrugs to the parent drug, phenylephrine were calculated. The calculated t1/2 values for ProD 1 and ProD 2 were very high (145 days and several years, respectively) whereas that of ProD 3 was found to be about 35 hours. Therefore, the intra-conversion rates of the phenylephrine prodrugs to phenylephrine can be programmed according to the nature of the prodrug linker.

  17. Novel antiglaucoma prodrugs and codrugs of ethacrynic acid.

    PubMed

    Cynkowska, Grazyna; Cynkowski, Tadeusz; Al-Ghananeem, Abeer M; Al-Ghananeem, Abeer A; Guo, Hong; Ashton, Paul; Crooks, Peter A

    2005-08-01

    The purpose of this study was to synthesize a novel prodrug of ethacrynic acid (ECA) with short chain polyethylene glycols (PEGs) and codrugs of ECA with the beta-adrenergic blocking agent atenolol (ATL) or timolol (TML) to overcome the adverse effects of ECA and to enhance its physicochemical properties.

  18. Quinone-induced activation of Keap1/Nrf2 signaling by aspirin prodrugs masquerading as nitric oxide.

    PubMed

    Dunlap, Tareisha; Piyankarage, Sujeewa C; Wijewickrama, Gihani T; Abdul-Hay, Samer; Vanni, Michael; Litosh, Vladislav; Luo, Jia; Thatcher, Gregory R J

    2012-12-17

    The promising therapeutic potential of the NO-donating hybrid aspirin prodrugs (NO-ASA) includes induction of chemopreventive mechanisms and has been reported in almost 100 publications. One example, NCX-4040 (pNO-ASA), is bioactivated by esterase to a quinone methide (QM) electrophile. In cell cultures, pNO-ASA and QM-donating X-ASA prodrugs that cannot release NO rapidly depleted intracellular GSH and caused DNA damage; however, induction of Nrf2 signaling elicited cellular defense mechanisms including upregulation of NAD(P)H:quinone oxidoreductase-1 (NQO1) and glutamate-cysteine ligase (GCL). In HepG2 cells, the "NO-specific" 4,5-diaminofluorescein reporter, DAF-DA, responded to NO-ASA and X-ASA, with QM-induced oxidative stress masquerading as NO. LC-MS/MS analysis demonstrated efficient alkylation of Cys residues of proteins including glutathione-S-transferase-P1 (GST-P1) and Kelch-like ECH-associated protein 1 (Keap1). Evidence was obtained for alkylation of Keap1 Cys residues associated with Nrf2 translocation to the nucleus, nuclear translocation of Nrf2, activation of antioxidant response element (ARE), and upregulation of cytoprotective target genes. At least in cell culture, pNO-ASA acts as a QM donor, bioactivated by cellular esterase activity to release salicylates, NO(3)(-), and an electrophilic QM. Finally, two novel aspirin prodrugs were synthesized, both potent activators of ARE, designed to release only the QM and salicylates on bioactivation. Current interest in electrophilic drugs acting via Nrf2 signaling suggests that QM-donating hybrid drugs can be designed as informative chemical probes in drug discovery.

  19. Transporter targeted gatifloxacin prodrugs: synthesis, permeability, and topical ocular delivery.

    PubMed

    Vooturi, Sunil K; Kadam, Rajendra S; Kompella, Uday B

    2012-11-05

    In this work, we aim to design and synthesize prodrugs of gatifloxacin targeting organic cation transporter (OCT), monocarboxylate transporter (MCT), and ATB (0, +) transporters and to identify a prodrug with enhanced delivery to the back of the eye. Dimethylamino-propyl, carboxy-propyl, and amino-propyl(2-methyl) derivatives of gatifloxacin (GFX), DMAP-GFX, CP-GFX, and APM-GFX, were designed and synthesized to target OCT, MCT, and ATB (0, +) transporters, respectively. An LC-MS method was developed to analyze drug and prodrug levels in various studies. Solubility and log D (pH 7.4) were measured for prodrugs and the parent drug. The permeability of the prodrugs was determined in the cornea, conjunctiva, and sclera-choroid-retinal pigment epitheluim (SCRPE) and compared with gatifloxacin using an Ussing chamber assembly. Permeability mechanisms were elucidated by determining the transport in the presence of transporter specific inhibitors. 1-Methyl-4-phenylpyridinium iodide (MPP+), nicotinic acid sodium salt, and α-methyl-DL-tryptophan were used to inhibit OCT, MCT, and ATB (0, +) transporters, respectively. A prodrug selected based on in vitro studies was administered as an eye drop to pigmented rabbits, and the delivery to various eye tissues including vitreous humor was compared with gatifloxacin dosing. DMAP-GFX exhibited 12.8-fold greater solubility than GFX. All prodrugs were more lipophilic, with the measured log D (pH 7.4) values ranging from 0.05 to 1.04, when compared to GFX (log D: -1.15). DMAP-GFX showed 1.4-, 1.8-, and 1.9-fold improvement in permeability across the cornea, conjunctiva, and SCRPE when compared to GFX. Moreover, it exhibited reduced permeability in the presence of MPP+ (competitive inhibitor of OCT), indicating OCT-mediated transport. CP-GFX showed 1.2-, 2.3-, and 2.5-fold improvement in permeability across the cornea, conjunctiva, and SCRPE, respectively. In the presence of nicotinic acid (competitive inhibitor of MCT), the

  20. The first generation of β-galactosidase-responsive prodrugs designed for the selective treatment of solid tumors in prodrug monotherapy.

    PubMed

    Legigan, Thibaut; Clarhaut, Jonathan; Tranoy-Opalinski, Isabelle; Monvoisin, Arnaud; Renoux, Brigitte; Thomas, Mikaël; Le Pape, Alain; Lerondel, Stéphanie; Papot, Sébastien

    2012-11-12

    Massive attack: Galactoside prodrugs have been designed that can be selectively activated by lysosomal β-galactosidase located inside cancer cells expressing a specific tumor-associated receptor. This efficient enzymatic process triggers a potent cytotoxic effect, releasing the potent antimitotic agent MMAE and allowing the destruction of both receptor-positive and surrounding receptor-negative tumor cells.

  1. Theranostic reduction-sensitive gemcitabine prodrug micelles for near-infrared imaging and pancreatic cancer therapy

    NASA Astrophysics Data System (ADS)

    Han, Haijie; Wang, Haibo; Chen, Yangjun; Li, Zuhong; Wang, Yin; Jin, Qiao; Ji, Jian

    2015-12-01

    A biodegradable and reduction-cleavable gemcitabine (GEM) polymeric prodrug with in vivo near-infrared (NIR) imaging ability was reported. This theranostic GEM prodrug PEG-b-[PLA-co-PMAC-graft-(IR820-co-GEM)] was synthesized by ring-opening polymerization and ``click'' reaction. The as-prepared reduction-sensitive prodrug could self-assemble into prodrug micelles in aqueous solution confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release studies showed that these prodrug micelles were able to release GEM in an intracellular-mimicking reductive environment. These prodrug micelles could be effectively internalized by BxPC-3 pancreatic cancer cells, which were observed by confocal laser scanning microscopy (CLSM). Meanwhile, a methyl thiazolyl tetrazolium (MTT) assay demonstrated that this prodrug exhibited high cytotoxicity against BxPC-3 cells. The in vivo whole-animal near-infrared (NIR) imaging results showed that these prodrug micelles could be effectively accumulated in tumor tissue and had a longer blood circulation time than IR820-COOH. The endogenous reduction-sensitive gemcitabine prodrug micelles with the in vivo NIR imaging ability might have great potential in image-guided pancreatic cancer therapy.A biodegradable and reduction-cleavable gemcitabine (GEM) polymeric prodrug with in vivo near-infrared (NIR) imaging ability was reported. This theranostic GEM prodrug PEG-b-[PLA-co-PMAC-graft-(IR820-co-GEM)] was synthesized by ring-opening polymerization and ``click'' reaction. The as-prepared reduction-sensitive prodrug could self-assemble into prodrug micelles in aqueous solution confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release studies showed that these prodrug micelles were able to release GEM in an intracellular-mimicking reductive environment. These prodrug micelles could be effectively internalized by BxPC-3 pancreatic cancer cells, which

  2. Activation of multiple chemotherapeutic prodrugs by the natural enzymolome of tumour-localised probiotic bacteria.

    PubMed

    Lehouritis, Panos; Stanton, Michael; McCarthy, Florence O; Jeavons, Matthieu; Tangney, Mark

    2016-01-28

    Some chemotherapeutic drugs (prodrugs) require activation by an enzyme for efficacy. We and others have demonstrated the ability of probiotic bacteria to grow specifically within solid tumours following systemic administration, and we hypothesised that the natural enzymatic activity of these tumour-localised bacteria may be suitable for activation of certain such chemotherapeutic drugs. Several wild-type probiotic bacteria; Escherichia coli Nissle, Bifidobacterium breve, Lactococcus lactis and Lactobacillus species, were screened against a panel of popular prodrugs. All strains were capable of activating at least one prodrug. E. coli Nissle 1917 was selected for further studies because of its ability to activate numerous prodrugs and its resistance to prodrug toxicity. HPLC data confirmed biochemical transformation of prodrugs to their toxic counterparts. Further analysis demonstrated that different enzymes can complement prodrug activation, while simultaneous activation of multiple prodrugs (CB1954, 5-FC, AQ4N and Fludarabine phosphate) by E. coli was confirmed, resulting in significant efficacy improvement. Experiments in mice harbouring murine tumours validated in vitro findings, with significant reduction in tumour growth and increase in survival of mice treated with probiotic bacteria and a combination of prodrugs. These findings demonstrate the ability of probiotic bacteria, without the requirement for genetic modification, to enable high-level activation of multiple prodrugs specifically at the site of action.

  3. JS-K, a Nitric Oxide Prodrug, Has Enhanced Cytotoxicity in Colon Cancer Cells with Knockdown of Thioredoxin Reductase 1

    PubMed Central

    Edes, Kornelia; Cassidy, Pamela; Shami, Paul J.; Moos, Philip J.

    2010-01-01

    Background The selenoenzyme thioredoxin reductase 1 has a complex role relating to cell growth. It is induced as a component of the cellular response to potentially mutagenic oxidants, but also appears to provide growth advantages to transformed cells by inhibiting apoptosis. In addition, selenocysteine-deficient or alkylated forms of thioredoxin reductase 1 have also demonstrated oxidative, pro-apoptotic activity. Therefore, a greater understanding of the role of thioredoxin reductase in redox initiated apoptotic processes is warranted. Methodology The role of thioredoxin reductase 1 in RKO cells was evaluated by attenuating endogenous thioredoxin reductase 1 expression with siRNA and then either inducing a selenium-deficient thioredoxin reductase or treatment with distinct redox challenges including, hydrogen peroxide, an oxidized lipid, 4-hydroxy-2-nonenol, and a nitric oxide donating prodrug. Thioredoxin redox status, cellular viability, and effector caspase activity were measured. Conclusions/Significance In cells with attenuated endogenous thioredoxin reductase 1, a stably integrated selenocysteine-deficient form of the enzyme was induced but did not alter either the thioredoxin redox status or the cellular growth kinetics. The oxidized lipid and the nitric oxide donor demonstrated enhanced cytotoxicity when thioredoxin reductase 1 was knocked-down; however, the effect was more pronounced with the nitric oxide prodrug. These results are consistent with the hypothesis that attenuation of the thioredoxin-system can promote apoptosis in a nitric oxide-dependent manner. PMID:20098717

  4. Volunteer donor apheresis.

    PubMed

    Waxman, Dan A

    2002-02-01

    Volunteer donor apheresis has evolved from early plasmapheresis procedures that collected single components into technically advanced multicomponent procedures that can produce combinations of red blood cells, platelets, and plasma units. Blood collection and utilization is increasing annually in the United States. The number of apheresis procedures is also increasing such that single donor platelet transfusions now exceed platelet concentrates from random donors. Donor qualifications for apheresis vary from those of whole blood. Depending on the procedure, the donor weight, donation interval, and platelet count must be taken into consideration. Adverse effects of apheresis are well known and fortunately occur in only a very small percentage of donors. The recruitment of volunteer donors is one of the most challenging aspects of a successful apheresis program. As multicomponent apheresis becomes more commonplace, it is important for collection centers to analyze the best methods to recruit and collect donors.

  5. [Assessment and selection of kidney living donors].

    PubMed

    Gentil Govantes, Miguel Ángel; Pereira Palomo, Porfirio

    2010-01-01

    Donor protection should always be taken account during the selection and assessment of a living donor. On these terms, the evaluation of a potential donor must include these issues: 1) The donor act is altruistic, consciousness and out of coercion; 2) Life expectancy and quality of life of the recipient will improve after the living donor kidney transplantation; 3) The donor has normal renal function and the potential risk of developing nephropathy in the long term follow up is scarce (familiar nephropathies and other processes that may increase the potential risk for renal disease in the future, like severe hypertension, diabetes, etc must be ruled out). The glomerular filtrate should meet criteria for the normal function corresponding to age furthermore the absence of proteinuria and urine smear is normal; 4) The screening in the donor should contemplate those clinical situations or diseases non related to the kidney function but might elevate the surgical and/or anesthesia risk besides disease transmission to the recipient (as neoplasia or infections); 5) The surgical act is possible without technical difficulties and always performed after a negative result of the crossmatch between donor and recipient. The living donor evaluation process will follow a different schedule based on each particular case and the center facilities. Any case, the mentioned process is divided in two parts: The first one contains an initial screening (using non invasive and low cost tests) that allows discarding contraindications for donation (in both donor and recipient). In a second phase the assessment of the donor varies with donor characteristics. However, a test for renal function is mandatory besides imaging techniques (like angioTC), screening for transmissible diseases and a detailed evaluation for psychosocial aspects preferably made by professional. Moreover Spanish policy on living donation requires a report with information about the consent for donation developed by an

  6. MDCK cell permeability characteristics of a sulfenamide prodrug: strategic implications in considering sulfenamide prodrugs for oral delivery of NH-acids.

    PubMed

    Guarino, Victor R; Nti-Addae, Kwame; Stella, Valentino J

    2011-01-01

    The objective of this Letter is both to report the permeability results of a linezolid-based sulfenamide prodrug in an MDCK cell model (enterocyte surrogate system) and to discuss the strategic implications of these results for considering sulfenamide prodrugs to enhance the oral delivery of weakly acidic NH-acids (e.g., amides, ureas, etc.). The two main findings from this study are that the sulfenamide prodrug does not appear to survive intracellular transport due to conversion to linezolid and that there appears to be an apically-oriented surface conversion pathway that can additionally serve to convert the sulfenamide prodrug to linezolid upon approach of the apical membrane. It is hoped that these findings, along with the discussion of the strategic implications, will facilitate a greater awareness of the potential strengths and weaknesses inherent in the sulfenamide prodrug approach for enhancing the oral delivery of weakly acidic NH-acid drugs.

  7. A short course of infusion of a hydrogen sulfide-donor attenuates endotoxemia induced organ injury via stimulation of anti-inflammatory pathways, with no additional protection from prolonged infusion.

    PubMed

    Aslami, Hamid; Beurskens, Charlotte J P; de Beer, Friso M; Kuipers, Maria T; Roelofs, Joris J T H; Hegeman, Maria A; Van der Sluijs, Koen F; Schultz, Marcus J; Juffermans, Nicole P

    2013-02-01

    Organ failure is associated with increased mortality and morbidity in patients with systemic inflammatory response syndrome. Previously, we showed that a short course of infusion of a hydrogen sulfide (H(2)S) donor reduced metabolism with concurrent reduction of lung injury. Here, we hypothesize that prolonged H(2)S infusion is more protective than a short course in endotoxemia with organ failure. Also, as H(2)S has both pro- and anti-inflammatory effects, we explored the effect of H(2)S on interleukin production. Endotoxemia was induced by an intravenous bolus injection of LPS (7.5mg/kg) in mechanically ventilated rats. H(2)S donor NaHS (2mg/kg) or vehicle (saline) was infused and organ injury was determined after either 4 or 8h. A short course of H(2)S infusion was associated with reduction of lung and kidney injury. Prolonged infusion did not enhance protection. Systemically, infusion of H(2)S increased both the pro-inflammatory response during endotoxemia, as demonstrated by increased TNF-α levels, as well as the anti-inflammatory response, as demonstrated by increased IL-10 levels. In LPS-stimulated whole blood of healthy volunteers, co-incubation with H(2)S had solely anti-inflammatory effects, resulting in decreased TNF-α levels and increased IL-10 levels. Co-incubation with a neutralizing IL-10 antibody partly abrogated the decrease in TNF-α levels. In conclusion, a short course of H(2)S infusion reduced organ injury during endotoxemia, at least in part via upregulation of IL-10.

  8. Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells

    PubMed Central

    Su, Hao; Zhang, Pengcheng; Cheetham, Andrew G; Koo, Jin Mo; Lin, Ran; Masood, Asad; Schiapparelli, Paula; Quiñones-Hinojosa, Alfredo; Cui, Honggang

    2016-01-01

    Chemical modification of small molecule hydrophobic drugs is a clinically proven strategy to devise prodrugs with enhanced treatment efficacy. While this prodrug strategy improves the parent drug's water solubility and pharmacokinetic profile, it typically compromises the drug's potency against cancer cells due to the retarded drug release rate and reduced cellular uptake efficiency. Here we report on the supramolecular design of self-assembling prodrugs (SAPD) with much improved water solubility while maintaining high potency against cancer cells. We found that camptothecin (CPT) prodrugs created by conjugating two CPT molecules onto a hydrophilic segment can associate into filamentous nanostructures in water. Our results suggest that these SAPD exhibit much greater efficacy against primary brain cancer cells relative to that of irinotecan, a clinically used CPT prodrug. We believe these findings open a new avenue for rational design of supramolecular prodrugs for cancer treatment. PMID:27217839

  9. Brain uptake of a Zidovudine prodrug after nasal administration of solid lipid microparticles.

    PubMed

    Dalpiaz, Alessandro; Ferraro, Luca; Perrone, Daniela; Leo, Eliana; Iannuccelli, Valentina; Pavan, Barbara; Paganetto, Guglielmo; Beggiato, Sarah; Scalia, Santo

    2014-05-05

    Our previous results demonstrated that a prodrug obtained by the conjugation of the antiretroviral drug zidovudine (AZT) with ursodeoxycholic acid (UDCA) represents a potential carrier for AZT in the central nervous system, thus possibly increasing AZT efficiency as an anti-HIV drug. Based on these results and in order to enhance AZT brain targeting, the present study focuses on solid lipid microparticles (SLMs) as a carrier system for the nasal administration of UDCA-AZT prodrug. SLMs were produced by the hot emulsion technique, using tristearin and stearic acid as lipidic carriers, whose mean diameters were 16 and 7 μm, respectively. SLMs were of spherical shape, and their prodrug loading was 0.57 ± 0.03% (w/w, tristearin based) and 1.84 ± 0.02% (w/w, stearic acid based). The tristearin SLMs were able to control the prodrug release, whereas the stearic acid SLMs induced a significant increase of the dissolution rate of the free prodrug. The free prodrug was rapidly hydrolyzed in rat liver homogenates with a half-life of 2.7 ± 0.14 min (process completed within 30 min). The tristearin SLMs markedly enhanced the stability of the prodrug (75% of the prodrug still present after 30 min), whereas the stabilization effect of the stearic acid SLMs was lower (14% of the prodrug still present after 30 min). No AZT and UDCA-AZT were detected in the rat cerebrospinal fluid (CSF) after an intravenous prodrug administration (200 μg). Conversely, the nasal administration of stearic acid based SLMs induced the uptake of the prodrug in the CSF, demonstrating the existence of a direct nose-CNS pathway. In the presence of chitosan, the CSF prodrug uptake increased six times, up to 1.5 μg/mL within 150 min after nasal administration. The loaded SLMs appear therefore as a promising nasal formulation for selective zidovudine brain uptake.

  10. New Taxol (paclitaxel) prodrugs designed for ADEPT and PMT strategies in cancer chemotherapy.

    PubMed

    Alaoui, Abdessamad El; Saha, Nabendu; Schmidt, Frédéric; Monneret, Claude; Florent, Jean-Claude

    2006-07-15

    Two new glucuronide paclitaxel prodrugs have been synthesized. Linked to the 2'-OH of the drug by a carbonate function, they include a self-immolative spacer bearing an arylnitro or arylamino group between the drug and the glucuronic acid residue. Both prodrugs were well detoxified and easily cleaved in the presence of beta-D-glucuronidase with fast removal of the spacer, releasing paclitaxel. The arylamino spacer-containing prodrug, more stable than the corresponding nitro analogue, was selected for further studies.

  11. Prodrugs of phosphonates and phosphates: crossing the membrane barrier.

    PubMed

    Wiemer, Andrew J; Wiemer, David F

    2015-01-01

    A substantial portion of metabolism involves transformation of phosphate esters, including pathways leading to nucleotides and oligonucleotides, carbohydrates, isoprenoids and steroids, and phosphorylated proteins. Because the natural substrates bear one or more negative charges, drugs that target these enzymes generally must be charged as well, but small charged molecules can have difficulty traversing the cell membrane by means other than endocytosis. The resulting dichotomy has stimulated a great deal of effort to develop effective prodrugs, compounds that carry little or no charge to enable them to transit biological membranes, but able to release the parent drug once inside the target cell. This chapter presents recent studies on advances in prodrug forms, along with representative examples of their application to marketed and developmental drugs.

  12. A screen for and validation of prodrug antimicrobials.

    PubMed

    Fleck, Laura E; North, E Jeffrey; Lee, Richard E; Mulcahy, Lawrence R; Casadei, Gabriele; Lewis, Kim

    2014-01-01

    The rise of resistant pathogens and chronic infections tolerant to antibiotics presents an unmet need for novel antimicrobial compounds. Identifying broad-spectrum leads is challenging due to the effective penetration barrier of Gram-negative bacteria, formed by an outer membrane restricting amphipathic compounds, and multidrug resistance (MDR) pumps. In chronic infections, pathogens are shielded from the immune system by biofilms or host cells, and dormant persisters tolerant to antibiotics are responsible for recalcitrance to chemotherapy with conventional antibiotics. We reasoned that the dual need for broad-spectrum and sterilizing compounds could be met by developing prodrugs that are activated by bacterium-specific enzymes and that these generally reactive compounds could kill persisters and accumulate over time due to irreversible binding to targets. We report the development of a screen for prodrugs, based on identifying compounds that nonspecifically inhibit reduction of the viability dye alamarBlue, and then eliminate generally toxic compounds by testing for cytotoxicity. A large pilot of 55,000 compounds against Escherichia coli produced 20 hits, 3 of which were further examined. One compound, ADC111, is an analog of a known nitrofuran prodrug nitrofurantoin, and its activity depends on the presence of activating enzymes nitroreductases. ADC112 is an analog of another known antimicrobial tilbroquinol with unknown mechanism of action, and ADC113 does not belong to an approved class. All three compounds had a good spectrum and showed good to excellent activity against persister cells in biofilm and stationary cultures. These results suggest that screening for overlooked prodrugs may present a viable platform for antimicrobial discovery.

  13. The Design, Synthesis and Screening of Potential Pyridinium Oxime Prodrugs.

    DTIC Science & Technology

    1985-07-31

    but this dihydropyridine oxime probably does not contribute to the reactivation of brain AChE. It is noteworthy that pro-2-PAM given prophylactically 10...Brain Barrier by Its Dihydropyridine Derivative. Science, 190, 155. 21. Bodor, N., Shek, E. and Higuchi, T. (1976) Improved Delivery Through...Biological Membranes 1. Synthesis and Properties of 1-Methyl-1,6 Dihydropyridine -2-Carbaldoxime, A Pro-Drug of N-Methyl Pyridinium-2- -Carbaldoxime Chloride

  14. Nanoparticles Containing High Loads of Paclitaxel Silicate Prodrugs: Formulation, Drug Release, and Anti-cancer Efficacy

    PubMed Central

    Han, Jing; Michel, Andrew R.; Lee, Han Seung; Kalscheuer, Stephen; Wohl, Adam; Hoye, Thomas R.; McCormick, Alon V.; Panyam, Jayanth; Macosko, Christopher W.

    2016-01-01

    We have investigated particle size, interior structure, drug release kinetics, and anticancer efficacy of PEG-b-PLGA-based nanoparticles loaded with a series of paclitaxel (PTX) silicate prodrugs [PTX-Si(OR)3]. Silicate derivatization enabled us to adjust the hydrophobicity and hydrolytic lability of the prodrugs by the choice of the alkyl group (R) in the silicate derivatives. The greater hydrophobicity of these prodrugs allows for the preparation of nanoparticles that are stable in aqueous dispersion even when loaded with up to ca. 75 wt% of the prodrug. The hydrolytic lability of silicates allows for facile conversion of prodrugs back to the parent drug, PTX. A suite of eight PTX-silicate prodrugs was investigated; nanoparticles were made by flash nanoprecipitation (FNP) using a confined impingement jet mixer with a dilution step (CIJ-D). The resulting nanoparticles were 80–150 nm in size with a loading level of 47–74 weight percent (wt%) of a PTX-silicate, which corresponds to 36–59 effective wt % of free PTX. Cryogenic transmission electron microscopy images show that particles are typically spherical with a core-shell structure. Prodrug/drug release profiles were measured. Release tended to be slower for prodrugs having greater hydrophobicity and slower hydrolysis rate. Nanoparticles loaded with PTX-silicate prodrugs that hydrolyze most rapidly showed in vitro cytotoxicity similar to that of the parent PTX. Nanoparticles loaded with more labile silicates also tended to show greater in vivo efficacy. PMID:26505116

  15. A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability.

    PubMed

    Murakami, Teruo

    2016-09-01

    Orally administered drugs are categorized into 4 classes depending on the solubility and permeability in a Biopharmaceutics Classification System. Prodrug derivatization is one of feasible approaches in modifying the physicochemical properties such as low solubility and low permeability without changing the in vivo pharmacological action of the parent drug. In this article, prodrug-targeted solute carrier (SLC) transporters were searched randomly by PubMed. Collected SLC transporters are amino acid transporter 1, bile acid transporter, carnitine transporter 2, glucose transporter 1, peptide transporter 1, vitamin C transporter 1, and multivitamin transporter. The usefulness of transporter-targeted prodrugs was evaluated in terms of membrane permeability, stability under acidic condition, and conversion to the parent drug. Among prodrugs collected, peptide transporter-targeted prodrugs exhibited the highest number, and some prodrugs such as valaciclovir and valganciclovir are clinically available. ATP-binding cassette efflux transporter, P-glycoprotein (P-gp), reduces the intestinal absorption of lipophilic P-gp substrate drugs, and SLC transporter-targeted prodrugs of P-gp substrate drugs circumvented the P-gp-mediated efflux transport. Thus, SLC transporter-targeted prodrug derivatization seems to be feasible approach to increase the oral bioavailability by overcoming various unwanted physicochemical properties of orally administered drugs, although the effect of food on prodrug absorption should be taken into consideration.

  16. Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir

    PubMed Central

    Patel, Mitesh; Mandava, Nanda; Gokulgandhi, Mitan; Pal, Dhananjay; Mitra, Ashim K.

    2014-01-01

    Poor systemic concentrations of lopinavir (LPV) following oral administration occur due to high cellular efflux by P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) and extensive metabolism by CYP3A4 enzymes. In this study, amino acid prodrugs of LPV were designed and investigated for their potential to circumvent efflux processes and first pass effects. Three amino acid prodrugs were synthesized by conjugating isoleucine, tryptophan and methionine to LPV. Prodrug formation was confirmed by the LCMS/MS and NMR technique. Interaction of LPV prodrugs with efflux proteins were carried out in P-gp (MDCK-MDR1) and MRP2 (MDCK-MRP2) transfected cells. Aqueous solubility studies demonstrated that prodrugs generate higher solubility relative to LPV. Prodrugs displayed higher stability under acidic conditions and degraded significantly with rise in pH. Uptake and transport data suggested that prodrugs carry significantly lower affinity towards P-gp and MRP2 relative to LPV. Moreover, prodrugs exhibited higher liver microsomal stability relative to LPV. Hence, amino acid prodrug modification might be a viable approach for enhancing LPV absorption across intestinal epithelial and brain endothelial cells which expresses high levels of P-gp and MRP2. PMID:24727459

  17. Nanoparticles Containing High Loads of Paclitaxel-Silicate Prodrugs: Formulation, Drug Release, and Anticancer Efficacy.

    PubMed

    Han, Jing; Michel, Andrew R; Lee, Han Seung; Kalscheuer, Stephen; Wohl, Adam; Hoye, Thomas R; McCormick, Alon V; Panyam, Jayanth; Macosko, Christopher W

    2015-12-07

    We have investigated particle size, interior structure, drug release kinetics, and anticancer efficacy of PEG-b-PLGA-based nanoparticles loaded with a series of paclitaxel (PTX)-silicate prodrugs [PTX-Si(OR)3]. Silicate derivatization enabled us to adjust the hydrophobicity and hydrolytic lability of the prodrugs by the choice of the alkyl group (R) in the silicate derivatives. The greater hydrophobicity of these prodrugs allows for the preparation of nanoparticles that are stable in aqueous dispersion even when loaded with up to ca. 75 wt % of the prodrug. The hydrolytic lability of silicates allows for facile conversion of prodrugs back to the parent drug, PTX. A suite of eight PTX-silicate prodrugs was investigated; nanoparticles were made by flash nanoprecipitation (FNP) using a confined impingement jet mixer with a dilution step (CIJ-D). The resulting nanoparticles were 80-150 nm in size with a loading level of 47-74 wt % (wt %) of a PTX-silicate, which corresponds to 36-59 effective wt % of free PTX. Cryogenic transmission electron microscopy images show that particles are typically spherical with a core-shell structure. Prodrug/drug release profiles were measured. Release tended to be slower for prodrugs having greater hydrophobicity and slower hydrolysis rate. Nanoparticles loaded with PTX-silicate prodrugs that hydrolyze most rapidly showed in vitro cytotoxicity similar to that of the parent PTX. Nanoparticles loaded with more labile silicates also tended to show greater in vivo efficacy.

  18. Prodrug approaches for enhancing the bioavailability of drugs with low solubility.

    PubMed

    Müller, Christa E

    2009-11-01

    Low water solubility and low bioavailability are frequent problems in drug development, particularly in the area of central nervous system (CNS) drugs. This short review describes selected prodrug approaches which have been developed to enhance the bioavailability of drugs, especially that of poorly soluble drugs. Some of the most successful drugs on the market are prodrugs. With a better understanding of active-transport processes at cell membranes in the gut as well as at the blood-brain barrier, the importance of prodrug approaches will further increase in the future. Prodrug approaches will already be considered in the early phase of drug discovery.

  19. In vitro and in vivo evaluation of a sulfenamide prodrug of basic metformin.

    PubMed

    Huttunen, Kristiina M; Leppänen, Jukka; Vepsäläinen, Jouko; Sirviö, Jouni; Laine, Krista; Rautio, Jarkko

    2012-08-01

    In the present study, a previously described sulfenamide prodrug of a basic antidiabetic drug, metformin, was evaluated further. This sulfenamide prodrug was designed to improve the permeability and consequently the oral absorption and bioavailability (F) of the highly water-soluble metformin. Bioactivation of the prodrug was mediated by reduced glutathione, but it has been reported that sulfenamide prodrugs can also be bioactivated by other endogenous thiols like cysteine, and free thiol-containing proteins. Consistent with earlier findings for a sulfenamide prodrug of a weakly acid drug, linezolid, the permeability studies indicated that the metformin prodrug was also prematurely bioactivated on the apical surface of the Caco-2 cell monolayer. Nevertheless, the bioavailability of metformin was increased by approximately 25% after oral administration of the prodrug in rats, most probably because of better oral absorption. This indicates that the sulfenamide prodrug approach may be used to improve the moderate oral bioavailability of metformin, which may help to decrease the uncomfortable gastrointestinal adverse effects associated with metformin therapy as the daily doses of metformin can be reduced. Furthermore, the present study confirms that the applicability of the sulfenamide prodrug approach can be successfully extended from weak NH acids to very basic guanide-type drugs.

  20. Theranostic reduction-sensitive gemcitabine prodrug micelles for near-infrared imaging and pancreatic cancer therapy.

    PubMed

    Han, Haijie; Wang, Haibo; Chen, Yangjun; Li, Zuhong; Wang, Yin; Jin, Qiao; Ji, Jian

    2016-01-07

    A biodegradable and reduction-cleavable gemcitabine (GEM) polymeric prodrug with in vivo near-infrared (NIR) imaging ability was reported. This theranostic GEM prodrug PEG-b-[PLA-co-PMAC-graft-(IR820-co-GEM)] was synthesized by ring-opening polymerization and "click" reaction. The as-prepared reduction-sensitive prodrug could self-assemble into prodrug micelles in aqueous solution confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release studies showed that these prodrug micelles were able to release GEM in an intracellular-mimicking reductive environment. These prodrug micelles could be effectively internalized by BxPC-3 pancreatic cancer cells, which were observed by confocal laser scanning microscopy (CLSM). Meanwhile, a methyl thiazolyl tetrazolium (MTT) assay demonstrated that this prodrug exhibited high cytotoxicity against BxPC-3 cells. The in vivo whole-animal near-infrared (NIR) imaging results showed that these prodrug micelles could be effectively accumulated in tumor tissue and had a longer blood circulation time than IR820-COOH. The endogenous reduction-sensitive gemcitabine prodrug micelles with the in vivo NIR imaging ability might have great potential in image-guided pancreatic cancer therapy.

  1. Strategies in the designing of prodrugs, taking into account the antiviral and anticancer compounds.

    PubMed

    Lesniewska-Kowiel, Monika A; Muszalska, Izabela

    2017-03-31

    Prodrugs are a wide group of substances of low or no pharmacological activity. The search for prodrugs is aimed at obtaining drugs characterized by better pharmacokinetic properties, pharmaceutical availability and selective activity of the active substance. Prodrug strategies involve chemical modifications and syntheses of new structures as well as the establishment of systems that deliver active substances for therapeutic aims that is prodrug-based treatments. The paper describes decisive factors in prodrug designing, such as enzymes participating in their activation, concepts of chemical modifications in the group of antiviral drugs and new anticancer treatments based on prodrugs (ADEPT, GDEPT, LEAPT). Prodrugs are seen as a possibility to design medicines which are selective for their therapeutic aim, for example a tumorous cell or a microorganism. Such an approach is possible thanks to the knowledge on: pathogenesis of diseases at molecular level, metabolism of healthy and affected cells as well as metabolism of microorganisms (bacteria, fungi, protozoa, etc.). Many drugs which have been used for years are still studied in relation to their metabolism and their molecular mechanism of operation, providing new knowledge on active substances. Many of them meet the criteria of being a prodrug. The paper indicates methods of discovering new structures or modifications of known structures and their synthesis as well as new therapeutic strategies using prodrugs, which are expected to be successful and to broaden the knowledge on what is happening to the drug in the body, in addition to providing a molecular explanation of xenobiotics activity.

  2. Stereoisomeric Prodrugs to Improve Corneal Absorption of Prednisolone: Synthesis and In Vitro Evaluation.

    PubMed

    Sheng, Ye; Yang, Xiaoyan; Wang, Zhiying; Mitra, Ashim K

    2016-06-01

    A series of stereoisomeric prodrugs have been designed to examine efficacy in generating higher corneal absorption relative to prednisolone. Prodrugs have been studied and identified with LC/MS/MS and NMR analyses. Prodrugs have been characterized for aqueous solubility, buffer stability, and cytotoxicity. Cellular uptake and permeability studies have been conducted across MDCK-MDR1 cells to determine prodrug affinity towards P-glycoprotein (P-gp) and peptide transporters. Enzyme-mediated degradation of prodrugs has been determined using Statens Seruminstitut rabbit cornea (SIRC) cell homogenates. Prodrugs exhibited higher aqueous solubility relative to prednisolone. Prodrugs circumvented P-gp-mediated cellular efflux and were recognized by peptide transporters. Prodrugs (DP, DDP) produced with D-isomers (D-valine) were significantly stable against both chemical and enzymatic hydrolyses. The order of degradation rate constants observed in chemical and enzymatic hydrolyses were in the same order, i.e., L-valine-L-valine-prednisolone (LLP) > L-valine-D-valine-prednisolone (LDP) > D-valine-L-valine-prednisolone (DLP) > D-valine-D-valine-prednisolone (DDP). Results obtained from this study clearly suggest that stereoisomeric prodrug approach is an effective strategy to overcome P-gp-mediated efflux and improve transcorneal permeability of prednisolone following topical administration.

  3. Recent advances in drugs and prodrugs design of chitosan.

    PubMed

    Vinsova, J; Vavrikova, E

    2008-01-01

    The aim of this review is to outline the recent advances in chitosan molecular modeling, especially its usage as a prodrug or drug in a field of antibacterial, anticarcinogenic and antioxidant activity. Polymeric materials like peptides, polysaccharides and other natural products have recently attracted attention as biodegradabile drug carriers. They can optimize clinical drug application, minimize the undesirable drug properties and improve drug efficiency. They are used for the slow release of effective components as depot forms, to improve membrane permeability, solubility and site-specific targeting. Chitosan is such a prospective cationic polysaccharide which has shown number of functions in many fields, including bio medicinal, pharmaceutical, preservative, microbial and others. This article discusses the structure characteristics of chitosan, a number of factors such as degree of polymerization, level of deacetylation, types of quarternisation, installation of various hydrophilic substituents, metal complexation, and combination with other active agents. Biodegradable, non-toxic and non-allergenic nature of chitosan encourages its potential use as a carrier for drug delivery systems in all above mentioned targets. The use of chitosan prodrug conjugates is aimed at the site-specific transport to the target cells use, for example, a spacer tetrapeptide Gly-Phe-Leu-Gly, promotion of drug incorporation into cells via endocytosis, hybridization or synergism of two types of drugs or a drug with a bioactive carrier. The design of chitosan macromolecule prodrugs is also discussed.

  4. Synthesis and characterization of mPEG-PLA prodrug micelles.

    PubMed

    Hans, Meredith; Shimoni, Karin; Danino, Dganit; Siegel, Steven J; Lowman, Anthony

    2005-01-01

    Polymeric prodrugs of mPEG-PLA-haloperidol (methoxypoly(ethylene glycol)-b-poly(lactic acid)) can self-assemble into nanoscale micelle-like structures in aqueous solutions. mPEG-PLA-haloperidol was prepared and characterized using 1H and 13C NMR. The conjugation efficiency was found to be 64.8 +/- 21%. Micelles that form spontaneously upon solubilization of the mPEG-PLA and the polymeric prodrugs in water were characterized using a variety of techniques. The mPEG-PLA and prodrug micelles were found to have diameters of 28.73 +/- 1.45 and 49.67 +/- 4.29 nm, respectively, using dynamic light scattering (DLS). The micelle size and polydispersity were also evaluated with cryogenic transmission electron microscopy (cryo-TEM) and were consistent with the DLS results. Cryo-TEM and proton NMR confirmed that the micelles were spherical in shape. DLS was also used to determine the aggregation numbers of the micelles. The aggregation numbers ranged from 351 to 603. The change in aggregation number was dependent on the total drug incorporation into the micelle core. Critical micelle concentrations were determined for the various micelle/drug formulations and found to range from 3 to 14 microg/mL. Finally, drug was incorporated into the micelle core using the conjugate, free drug with a saturated aqueous phase during production, or a combination of both techniques. Drug incorporation could be increased from 3% to 20% (w/w) using the different formulations.

  5. Plasma-mediated release of morphine from synthesized prodrugs.

    PubMed

    Thomas, Thommey P; Huang, Baohua; Desai, Ankur; Zong, Hong; Cheng, Xue-Min; Kotlyar, Alina; Leroueil, Pascale R; Dunham, Thomas; van der Spek, Abraham; Ward, Brent B; Baker, James R

    2010-11-01

    Two morphine prodrugs ('PDA' and 'PDB') were synthesized and the kinetics of esterase-mediated morphine release from these prodrugs were determined when incubated with plasma from different animal species. Morphine was rapidly released from PDA by all species plasma with the maximum reached within 5-10min; the released morphine was biologically active as determined by an in vitro cAMP assay. The morphine was released from PDB at a slower and species-dependent rate (mouse>rat>guinea pig>human). Morphine's release from PDB appeared to be mediated by carboxyl esterases as the release was inhibited by the carboxyl esterase inhibitor benzil. PDA nor PDB induce cytotoxicity in the neuronal cell lines SK-NSH and SH-SY5Y. The carboxyl and amino functional moieties present on the linker portions of PDA and PDB, respectively, may facilitate their conjugation to nanoparticles to tailor morphine pharmacokinetics and specific targeting. These studies suggest the potential clinical utility of these prodrugs for morphine release at desired rates by administration of their mixture at selected ratios.

  6. Macromolecular Pt(IV) Prodrugs from Poly(organo)phosphazenes

    PubMed Central

    Banfić, Jelena; Theiner, Sarah; Körner, Wilfried; Brüggemann, Oliver; Berger, Walter; Keppler, Bernhard K.; Heffeter, Petra; Teasdale, Ian

    2016-01-01

    The preparation of novel macromolecular prodrugs via the conjugation of two platinum(IV) complexes to suitably functionalized poly(organo)phosphazenes is presented. The inorganic/organic polymers provide carriers with controlled dimensions due to the use of living cationic polymerization and allow the preparation of conjugates with excellent aqueous solubility but long-term hydrolytic degradability. The macromolecular Pt(IV) prodrugs are designed to undergo intracellular reduction and simultaneous release from the macromolecular carrier to present the active Pt(II) drug derivatives. In vitro investigations show a significantly enhanced intracellular uptake of Pt for the macromolecular prodrugs when compared to small molecule Pt complexes, which is also reflected in an increase in cytotoxicity. Interestingly, drug-resistant sublines also show a significantly smaller resistance against the conjugates compared to clinically established platinum drugs, indicating that an alternative uptake route of the Pt(IV) conjugates might also be able to overcome acquired resistance against Pt(II) drugs. In vivo studies of a selected conjugate show improved tumor shrinkage compared to the respective Pt(IV) complex. PMID:27169668

  7. New green synthesis and formulations of acyclovir prodrugs.

    PubMed

    de Regil-Hernández, Rubén; Martínez-Lagos, Fernando; Rodríguez-Bayón, Amalia; Sinisterra, José-Vicente

    2011-01-01

    Different green synthesis of alkyl esters of acyclovir (acyclovir prodrugs) is described. Hexanoic, decanoic, dodecanoic and tetradecanoic acyclovir esters were synthesized reacting acyclovir and the respective acid anhydride in dimethyl sulfoxide (DMSO), in solvents from renewable sources and without solvent (T=30 °C). Yields in prodrugs after 10 min of reaction were >95% using DMSO as solvent. The purification methodology was very simple, shorter and greener than previously described. The biosolvent, N,N-dimethylamide of decanoic acid, let us to obtain >95% yield at 24 h. This oily biosolvent is not dermotoxic and the reaction crude can directly be used in topic formulations. Syntheses without solvent proceeded successfully for acyclovir esters. Indeed, dodecanoate and tetradecanoate yielding >98% conversion of reactants in 30 min. In spite of requiring mild temperature (65 °C), substrate molar ratios were lowered to 1 : 1, thus conducing to a more efficient use of raw materials. The synthetic procedures were scaled up to a 300 g batch (yield 98-99% isolated ester). These esters can be used as acyclovir prodrugs in topic formulations. The esters release from an oil/water micro-emulsion and a hydrogel formulation were tested with good results.

  8. Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency

    PubMed Central

    Ehinger, Johannes K.; Piel, Sarah; Ford, Rhonan; Karlsson, Michael; Sjövall, Fredrik; Frostner, Eleonor Åsander; Morota, Saori; Taylor, Robert W.; Turnbull, Doug M.; Cornell, Clive; Moss, Steven J.; Metzsch, Carsten; Hansson, Magnus J.; Fliri, Hans; Elmér, Eskil

    2016-01-01

    Mitochondrial complex I (CI) deficiency is the most prevalent defect in the respiratory chain in paediatric mitochondrial disease. This heterogeneous group of diseases includes serious or fatal neurological presentations such as Leigh syndrome and there are very limited evidence-based treatment options available. Here we describe that cell membrane-permeable prodrugs of the complex II substrate succinate increase ATP-linked mitochondrial respiration in CI-deficient human blood cells, fibroblasts and heart fibres. Lactate accumulation in platelets due to rotenone-induced CI inhibition is reversed and rotenone-induced increase in lactate:pyruvate ratio in white blood cells is alleviated. Metabolomic analyses demonstrate delivery and metabolism of [13C]succinate. In Leigh syndrome patient fibroblasts, with a recessive NDUFS2 mutation, respiration and spare respiratory capacity are increased by prodrug administration. We conclude that prodrug-delivered succinate bypasses CI and supports electron transport, membrane potential and ATP production. This strategy offers a potential future therapy for metabolic decompensation due to mitochondrial CI dysfunction. PMID:27502960

  9. AP39, a Mitochondria-Targeted Hydrogen Sulfide Donor, Supports Cellular Bioenergetics and Protects against Alzheimer's Disease by Preserving Mitochondrial Function in APP/PS1 Mice and Neurons

    PubMed Central

    Zhao, Feng-li; Fang, Fang; Qiao, Pei-feng; Yan, Ning; Gao, Dan; Yan, Yong

    2016-01-01

    Increasing evidence suggests that mitochondrial functions are altered in AD and play an important role in AD pathogenesis. It has been established that H2S homeostasis is balanced in AD. The emerging mitochondrial roles of H2S include antioxidation, antiapoptosis, and the modulation of cellular bioenergetics. Here, using primary neurons from the well-characterized APP/PS1 transgenic mouse model, we studied the effects of AP39 (a newly synthesized mitochondrially targeted H2S donor) on mitochondrial function. AP39 increased intracellular H2S levels, mainly in mitochondrial regions. AP39 exerted dose-dependent effects on mitochondrial activity in APP/PS1 neurons, including increased cellular bioenergy metabolism and cell viability at low concentrations (25–100 nM) and decreased energy production and cell viability at a high concentration (250 nM). Furthermore, AP39 (100 nM) increased ATP levels, protected mitochondrial DNA, and decreased ROS generation. AP39 regulated mitochondrial dynamics, shifting from fission toward fusion. After 6 weeks, AP39 administration to APP/PS1 mice significantly ameliorated their spatial memory deficits in the Morris water maze and NORT and reduced Aβ deposition in their brains. Additionally, AP39 inhibited brain atrophy in APP/PS1 mice. Based on these results, AP39 was proposed as a promising drug candidate for AD treatment, and its anti-AD mechanism may involve protection against mitochondrial damage. PMID:27057285

  10. AP39, a Mitochondria-Targeted Hydrogen Sulfide Donor, Supports Cellular Bioenergetics and Protects against Alzheimer's Disease by Preserving Mitochondrial Function in APP/PS1 Mice and Neurons.

    PubMed

    Zhao, Feng-Li; Fang, Fang; Qiao, Pei-feng; Yan, Ning; Gao, Dan; Yan, Yong

    2016-01-01

    Increasing evidence suggests that mitochondrial functions are altered in AD and play an important role in AD pathogenesis. It has been established that H2S homeostasis is balanced in AD. The emerging mitochondrial roles of H2S include antioxidation, antiapoptosis, and the modulation of cellular bioenergetics. Here, using primary neurons from the well-characterized APP/PS1 transgenic mouse model, we studied the effects of AP39 (a newly synthesized mitochondrially targeted H2S donor) on mitochondrial function. AP39 increased intracellular H2S levels, mainly in mitochondrial regions. AP39 exerted dose-dependent effects on mitochondrial activity in APP/PS1 neurons, including increased cellular bioenergy metabolism and cell viability at low concentrations (25-100 nM) and decreased energy production and cell viability at a high concentration (250 nM). Furthermore, AP39 (100 nM) increased ATP levels, protected mitochondrial DNA, and decreased ROS generation. AP39 regulated mitochondrial dynamics, shifting from fission toward fusion. After 6 weeks, AP39 administration to APP/PS1 mice significantly ameliorated their spatial memory deficits in the Morris water maze and NORT and reduced Aβ deposition in their brains. Additionally, AP39 inhibited brain atrophy in APP/PS1 mice. Based on these results, AP39 was proposed as a promising drug candidate for AD treatment, and its anti-AD mechanism may involve protection against mitochondrial damage.

  11. Chemical and enzymatic stability of amino acid prodrugs containing methoxy, ethoxy and propylene glycol linkers.

    PubMed

    Gupta, Deepak; Gupta, Sheeba Varghese; Lee, Kyung-Dall; Amidon, Gordon L

    2009-01-01

    We evaluated the chemical and enzymatic stabilities of prodrugs containing methoxy, ethoxy and propylene glycol linkers in order to find a suitable linker for prodrugs of carboxylic acids with amino acids. l-Valine and l-phenylalanine prodrugs of model compounds (benzoic acid and phenyl acetic acid) containing methoxy, ethoxy and propylene glycol linkers were synthesized. The hydrolysis rate profile of each compound was studied at physiologically relevant pHs (1.2, 4, 6 and 7.4). Enzymatic hydrolysis of propylene glycol containing compounds was studied using Caco-2 homogenate as well as purified enzyme valacyclovirase. It was observed that the stability of the prodrugs increases with the linker length (propyl > ethyl > methyl). The model prodrugs were stable at acidic pH as compared to basic pH. It was observed that the prodrug with the aliphatic amino acid promoiety was more stable compared to its aromatic counterpart. The comparison between benzyl and the phenyl model compounds revealed that the amino acid side chain is significant in determining the stability of the prodrug whereas the benzyl or phenyl carboxylic acid had little or no effect on the stability. The enzymatic activation studies of propylene glycol linker prodrug in the presence of valacyclovirase and cell homogenate showed faster generation of the parent drug at pH 7.4. The half-life of prodrugs at pH 7.4 was more than 12 h, whereas in the presence of cell homogenate the half-lives were less than 1 h. Hydrolysis by Caco-2 homogenate generated the parent compound in two steps, where the prodrug was first converted to the intermediate, propylene glycol benzoate, which was then converted to the parent compound (benzoic acid). Enzymatic hydrolysis of propylene glycol containing prodrugs by valacyclovirase showed hydrolysis of the amino acid ester part to generate the propylene glycol ester of model compound (propylene glycol benzoate) as the major product. The amino acid prodrugs containing methoxy

  12. Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen–Antioxidant Mutual Prodrugs

    PubMed Central

    Ashraf, Zaman; Alamgeer; Rasool, Raqiqatur; Hassan, Mubashir; Ahsan, Haseeb; Afzal, Samina; Afzal, Khurram; Cho, Hongsik; Kim, Song Ja

    2016-01-01

    Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a–c were obtained by reacting its –COOH group with chloroacetyl derivatives 3a–c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a–c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001) is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001). The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a–c interacts with the residues present in active binding sites of target protein. The stability of drug–target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug. PMID:28009827

  13. Synthesis of a novel legumain-cleavable colchicine prodrug with cell-specific toxicity.

    PubMed

    Smith, Robert Løvsletten; Åstrand, Ove Alexander Høgmoen; Nguyen, Luan Minh; Elvestrand, Tina; Hagelin, Gunnar; Solberg, Rigmor; Johansen, Harald Thidemann; Rongved, Pål

    2014-07-01

    Conventional chemotherapy has undesirable toxic side-effects to healthy tissues due to low cell selectivity of cytotoxic drugs. One approach to increase the specificity of a cytotoxic drug is to make a less toxic prodrug which becomes activated at the tumour site. The cysteine protease legumain have remarkable restricted substrate specificity and is the only known mammalian asparaginyl (Asn) endopeptidase. Over-expression of legumain is reported in cancers and unstable atherosclerotic plaques, and utilizing legumain is a promising approach to activate prodrugs. In this study we have synthesized the legumain-cleavable peptide sequence N-Boc-Ala-Ala-Asn-Val-OH. The peptide was subsequently conjugated to deacetyl colchicine during three steps to produce Suc-Ala-Ala-Asn-Val-colchicine (prodrug) with >90% chemical purity. Several cell lines with different expressions and activities of legumain were used to evaluate the general toxicity, specificity and efficacy of the microtubule inhibitor colchicine, valyl colchicine and the legumain-cleavable colchicine prodrug. The prodrug was more toxic to the colorectal cancer HCT116 cells (expressing both the 36kDa active and 56kDa proform of legumain) than SW620 cells (only expressing the 56kDa prolegumain) indicating a relationship between toxicity of the prodrug and activity of legumain in the cells. Also, in monoclonal legumain over-expressing HEK293 cells the prodrug toxicity was higher compared to native HEK293 cells. Furthermore, co-administration of the prodrug either with the potent legumain inhibitor cystatin E/M or the endocytosis inhibitor Dyngo-4a inhibited cell death, indicating that the prodrug toxicity was dependent on both asparaginyl endopeptidase activity and endocytosis. This colchicine prodrug adds to a legumain-activated prodrug strategy approach and could possibly be of use both in targeted anticancer and anti-inflammatory therapy.

  14. Pharmacological Properties of a New Antimalarial Bisthiazolium Salt, T3, and a Corresponding Prodrug, TE3

    PubMed Central

    Nicolas, Olivier; Margout, Delphine; Taudon, Nicolas; Wein, Sharon; Calas, Michèle; Vial, Henri J.; Bressolle, Françoise M. M.

    2005-01-01

    A new approach to malarial chemotherapy based on quaternary ammonium that targets membrane biogenesis during intraerythrocytic Plasmodium falciparum development has recently been developed. To increase the bioavailability, nonionic chemically modified prodrugs were synthesized. In this paper, the pharmacological properties of a bisthiazolium salt (T3) and its bioprecursor (TE3) were studied. Their antimalarial activities were determined in vitro against the growth of P. falciparum and in vivo against the growth of P. vinckei in mice. Pharmacokinetic evaluations were performed after T3 (1.3 and 3 mg/kg of body weight administered intravenously; 6.4 mg/kg administered intraperitoneally) and TE3 (1.5 and 3 mg/kg administered intravenously; 12 mg/kg administered orally) administrations to rats. After intraperitoneal administration, very low doses offer protection in a murine model of malaria (50% efficient dose [ED50] of 0.2 to 0.25 mg/kg). After oral administration, the ED50 values were 13 and 5 mg/kg for T3 and TE3, respectively. Both compounds exerted antimalarial activity in the low nanomolar range. After TE3 administration, rapid prodrug-drug conversion occurred; the mean values of the pharmacokinetic parameters for T3 were as follows: total clearance, 1 liter/h/kg; steady-state volume of distribution, 14.8 liters/kg; and elimination half-life, 12 h. After intravenous administration, T3 plasma concentrations increased in proportion to the dose. The absolute bioavailability was 72% after intraperitoneal administration (T3); it was 15% after oral administration (TE3). T3 plasma concentrations (8 nM) 24 h following oral administration of TE3 were higher than the 50% inhibitory concentrations for the most chloroquine-resistant strains of P. falciparum (6.3 nM). PMID:16127032

  15. Expanding the live kidney donor pool: ethical considerations regarding altruistic donors, paired and pooled programs.

    PubMed

    Patel, Shaneel Rajendra; Chadha, Priyanka; Papalois, Vassilios

    2011-06-01

    In renal transplant, there is a well-known deficiency in organ supply relative to demand. Live donation provides superior results when compared with deceased donation including a better rate of graft success and fewer immunologic complications. This deficiency in organs leads to significant morbidity and mortality rates. Alternative avenues have been extensively explored that may expand the live donor pool. They include altruistic donation as well as paired and pooled exchange programs. Altruistic donation is a truly selfless act from a donor unknown to the recipient. Kidney paired donation involves 2 incompatible donor-recipient pairs swapping donors to produce compatibility. Pooled donation involves at least 2 pairs, and can take the form of domino chains in which altruistic input sets up a chain of transplants, in which each recipient's incompatible donor makes a donation for the next recipient. Despite application of these various methods, there lie extensive ethical issues surrounding them. Misconceptions frequently occur; for instance, the perceived benefit that donating an organ to a loved one is greater for a related donor than for an altruistic one. Additionally, it is frequently believed that immunologic incompatibility offers coerced donors liberation from surgery, and that overcoming these barriers by introducing exchange programs provides vulnerable donors less protection. This article explores these and other complex ethical issues surrounding the various methods of expanding the donor pool. The authors offer opinions that challenge the ethical issues and attempt to overcome those views that hinder progress in the field.

  16. Comparison between 3-Nitrooxyphenyl acetylsalicylate (NO-ASA) and O2-(acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA) as safe anti-inflammatory, analgesic, antipyretic, antioxidant prodrugs.

    PubMed

    Chattopadhyay, Mitali; Velazquez, Carlos A; Pruski, April; Nia, Kamran V; Abdellatif, Khaled R; Keefer, Larry K; Kashfi, Khosrow

    2010-11-01

    Chronic inflammation is an underlying etiological factor in carcinogenesis; nonsteroidal anti-inflammatory drugs (NSAIDs) and their chemically modified NO-releasing prodrugs (NO-NSAIDs) are promising chemopreventive agents. The aim of this study was to conduct a head-to-head comparison between two NO-ASAs possessing different NO donor groups, an organic nitrate [3-nitrooxyphenyl acetylsalicylate (NO-ASA; NCX-4016)] and an N-diazeniumdiolate [NONO-ASA, O(2)- (acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA; CVM-01)], as antiulcerogenic, analgesic, anti-inflammatory, and antipyretic agents. All drugs were administered orally at equimolar doses. For antiulcerogenic study, 6 h after administration, the number and size of hemorrhagic lesions in stomachs from euthanized animals were counted. Tissue samples were frozen for prostaglandin E(2) (PGE(2)), superoxide dismutase (SOD), and malondialdehyde determination. For anti-inflammatory study, 1 h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 6 h. For antipyretic study, 1 h after dosing, fever was induced by intraperitoneal LPS, and body core temperatures measured for 5 h. For analgesic study, time-dependent analgesic effect of prodrugs was evaluated by carrageenan-induced hyperalgesia. Drugs were administered 30 min after carrageenan. NO-ASA and NONO-ASA were equipotent as analgesic and anti-inflammatory agents but were better than aspirin. Despite a drastic reduction of PGE(2) in stomach tissue, both prodrugs were devoid of gastric side effects. Lipid peroxidation induced by aspirin was higher than that observed by prodrugs. SOD activity induced by both prodrugs was similar, but approximately 2-fold higher than that induced by aspirin. CVM-01 is as effective as NCX-4016 in anti-inflammatory, analgesic, and antipyretic assays in vivo, and it showed an equivalent safety profile in the stomach. These results underscore the use of N

  17. O-Glycosyl Donors

    NASA Astrophysics Data System (ADS)

    López, J. Cristóbal

    O-Glycosyl donors, despite being one of the last successful donors to appear, have developed themselves into a burgeoning class of glycosyl donors. They can be classified in two main types: O-alkyl and O-aryl (or hetaryl) glycosyl donors. They share, however, many characteristics, they can be (1) synthesized from aldoses, either by modified Fisher glycosidation (O-alkyl) or by nucleophilic aromatic substitution (O-aryl or O-hetaryl), (2) stable to diverse chemical manipulations, (3) directly used for saccharide coupling, and (4) chemoselectively activated. Among these, n-pentenyl glycosides stand apart. They were the first O-alkyl glycosyl donors to be described and have paved the way to many conceptual developments in oligosaccharide synthesis. The development of the chemoselectivity-based "armed-disarmed" approach for saccharide coupling, including its stereoelectronic or torsional variants, now extended to other kinds of glycosyl donors, was first recognized in n-pentenyl glycosides. The chemical manipulation of the anomeric substituent in the glycosyl donor to induce reactivity differences between related species (sidetracking) was also introduced in n-pentenyl glycosides. An evolution of this concept, the "latent-active" strategy for glycosyl couplings, first described in thioglycosyl donors (vide infra), has been elegantly applied to O-glycosyl donors. Thus, allyl and vinyl glycosides, 2-(benzyloxycarbonyl)benzyl (BCB) glycosides and 2'-carboxybenzyl (CB) glycosides are useful "latent-active" glycosyl pairs. Finally, unprotected 3-methoxy-2-pyridyl (MOP) glycosides have been used in glycosylation processes with moderate success.

  18. Sulfur dioxide prodrugs: triggered release of SO2via a click reaction.

    PubMed

    Wang, Wenyi; Ji, Xingyue; Du, Zhenming; Wang, Binghe

    2017-01-24

    Sulfur dioxide (SO2) is being recognized as a possible endogenous gasotransmitter with importance on par with that of NO, CO, and H2S. Herein we describe a series of SO2 prodrugs that are activated for SO2 release via a bioorthogonal click reaction. The release rate can be tuned by adjusting the substituents on the prodrug.

  19. Synthesis and evaluation of atorvastatin esters as prodrugs metabolically activated by human carboxylesterases.

    PubMed

    Mizoi, Kenta; Takahashi, Masato; Haba, Masami; Hosokawa, Masakiyo

    2016-02-01

    We synthesized 11 kinds of prodrug with an esterified carboxylic acid moiety of atorvastatin in moderate to high yields. We discovered that they underwent metabolic activation specifically by the human carboxylesterase 1 (CES1) isozyme. The results suggested that these ester compounds of atorvastatin have the potential to act as prodrugs in vivo.

  20. Acid-responsive PEGylated doxorubicin prodrug nanoparticles for neuropilin-1 receptor-mediated targeted drug delivery.

    PubMed

    Song, Huijuan; Zhang, Ju; Wang, Weiwei; Huang, Pingsheng; Zhang, Yumin; Liu, Jianfeng; Li, Chen; Kong, Deling

    2015-12-01

    Self-assembled prodrug nanoparticles have demonstrated great promise in cancer chemotherapy. In the present study, we developed a new kind of prodrug nanoparticles for targeted drug delivery. PEGylated doxorubicin conjugate with an acid-cleavable cis-aconityl spacer was prepared. Then it was functionalized with a tumor-penetrating peptide, Cys-Arg-Gly-Asp-Lys (CRGDK), providing the prodrug nanoparticles with the specific binding ability to neurophilin-1 receptor. In acid mediums, doxorubicin could be released from the prodrug nanoparticles with an accumulative release around 60% through the acid-triggered hydrolysis of cis-aconityl bond and nanoparticle disassembly. Whereas, drug release was slow under a neutral pH and the accumulative drug release was less than 16%. In the cell culture tests, our prodrug nanoparticles showed enhanced endocytosis and cytotoxicity in cancer cells including HepG2, MCF-7 and MDA-MB-231 cells, but lower cytotoxicity in human cardiomyocyte H2C9. In the animal experiments, the prodrug nanoparticles were intravenously injected into Balb/c nude mice bearing MDA-MB-231 tumors. Enhanced drug penetration and accumulation in tumors, accompanying with a rapid early tumor-binding behavior, was observed after intravenous injection of the peptide modified prodrug nanoparticles. These data suggests that the acid-sensitive and tumor-targeting PEGylated doxorubicin prodrug nanoparticle may be an efficient drug delivery system for cancer chemotherapy.

  1. Characterization of in vitro biotransformation of new, orally active, direct thrombin inhibitor ximelagatran, an amidoxime and ester prodrug.

    PubMed

    Clement, Bernd; Lopian, Katrin

    2003-05-01

    N-Hydroxylated amidines (amidoximes) can be used as prodrugs of amidines. The prodrug principle was developed in our laboratory for pentamidine and had been applied to several other drug candidates. One of these compounds is melagatran, a novel, synthetic, low molecular weight, direct thrombin inhibitor. To increase the poor oral bioavailability due to its strong basic amidine functionality selected to fit the arginine side pocket of thrombin, the less basic N-hydroxylated amidine was used in addition to an ethyl ester-protecting residue. The objective of this investigation was to study the reduction and the hydrolytic metabolism of ximelagatran via two mono-prodrugs (N-hydroxy-melagatran and ethyl-melagatran) to melagatran by in vitro experiments. New high-performance liquid chromatography methods were developed to analyze all four compounds. The biotransformation of ximelagatran to melagatran involving the reduction of the amidoxime function and the ester cleavage could be demonstrated in vitro by microsomes and mitochondria from liver and kidney of pig and human, and the kinetic parameters were determined. So far, one enzyme system capable of reducing N-hydroxylated structures has been identified in pig liver microsomes, consisting of cytochrome b(5), NADH-cytochrome b(5) reductase, and a P450 isoenzyme of the subfamily 2D. This enzyme system also reduces ximelagatran and N-hydroxy-melagatran. The participation of recombinant human CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, and 3A4 with cytochrome b(5) and b(5) reductase in the reduction can be excluded. In summary, ximelagatran and N-hydroxy-melagatran are easily reduced by several enzyme systems located in microsomes and mitochondria of different organs.

  2. Prodrugs as self-assembled hydrogels: a new paradigm for biomaterials.

    PubMed

    Vemula, Praveen Kumar; Wiradharma, Nikken; Ankrum, James A; Miranda, Oscar R; John, George; Karp, Jeffrey M

    2013-12-01

    Prodrug-based self-assembled hydrogels represent a new class of active biomaterials that can be harnessed for medical applications, in particular the design of stimuli responsive drug delivery devices. In this approach, a promoiety is chemically conjugated to a known-drug to generate an amphiphilic prodrug that is capable of forming self-assembled hydrogels. Prodrug-based self-assembled hydrogels are advantageous as they alter the solubility of the drug, enhance drug loading, and eliminate the use of harmful excipients. In addition, self-assembled prodrug hydrogels can be designed to undergo controlled drug release or tailored degradation in response to biological cues. Herein we review the development of prodrug-based self-assembled hydrogels as an emerging class of biomaterials that overcome several common limitations encountered in conventional drug delivery.

  3. A Novel, Unusually Efficacious Duocarmycin Carbamate Prodrug That Releases No Residual Byproduct

    PubMed Central

    Wolfe, Amanda L.; Duncan, Katharine K.; Parelkar, Nikhil K.; Weir, Scott J.; Vielhauer, George A.; Boger, Dale L.

    2012-01-01

    A unique heterocyclic carbamate prodrug of seco-CBI-indole2 that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug. An in vivo evaluation of the prodrug found that its efficacy exceeded that of the parent drug, that its therapeutic window of efficacy versus toxicity is much larger than the parent drug, and that its slow free drug release permitted the safe and efficacious use of doses 150-fold higher than the parent compound. PMID:22650244

  4. Efficacious Cyclic N-Acyl O-Amino Phenol Duocarmycin Prodrugs

    PubMed Central

    Wolfe, Amanda L.; Duncan, Katharine K.; Parelkar, Nikhil K.; Brown, Douglas; Vielhauer, George A.; Boger, Dale L.

    2013-01-01

    Two novel cyclic N-acyl O-amino phenol prodrugs are reported as new members of a unique class of reductively cleaved prodrugs of the duocarmycin family of natural products. These prodrugs were explored with the expectation that they may be cleaved selectively within hypoxic tumor environments that have intrinsically higher concentrations of reducing nucleophiles and were designed to liberate the free drug without the release of an extraneous group. In vivo evaluation of the prodrug 6 showed that it exhibits extraordinary efficacy (T/C > 1500, L1210; 6/10 one year survivors) substantially exceeding that of the free drug, that its therapeutic window of activity is much larger permitting a dosing ≥ 40-fold higher than the free drug, and yet that it displays a potency in vivo that approaches the free drug (within 3-fold). Clearly, the prodrug 6 benefits from either its controlled slow release of the free drug or its preferential intracellular reductive cleavage. PMID:23627265

  5. Improvement of Topical Palmitoylethanolamide Anti-Inflammatory Activity by Pegylated Prodrugs.

    PubMed

    Tronino, Diana; Russo, Roberto; Ostacolo, Carmine; Mazzolari, Angelica; De Caro, Carmen; Avagliano, Carmen; Laneri, Sonia; La Rana, Giovanna; Sacchi, Antonia; Della Valle, Francesco; Vistoli, Giulio; Calignano, Antonio

    2015-09-08

    A small library of polyethylene glycol esters of palmitoylethanolamide (PEA) was synthesized with the aim of improving the pharmacokinetic profile of the parent drug after topical administration. Synthesized prodrugs were studied for their skin accumulation, pharmacological activities, in vitro chemical stability, and in silico enzymatic hydrolysis. Prodrugs proved to be able to delay and prolong the pharmacological activity of PEA by modification of its skin accumulation profile. Pharmacokinetic improvements were particularly evident when specific structural requirements, such as flexibility and reduced molecular weight, were respected. Some of the synthesized prodrugs prolonged the pharmacological effects 5 days following topical administration, while a formulation composed by PEA and two pegylated prodrugs showed both rapid onset and long-lasting activity, suggesting the potential use of polyethylene glycol prodrugs of PEA as a suitable candidate for the treatment of skin inflammatory diseases.

  6. Donor Telomere Length SAA

    Cancer.gov

    A new NCI study has found that, among patients with severe aplastic anemia who received a hematopoietic cell transplant from an unrelated donor, those whose donor white blood cells had longer telomeres had higher survival rates five-years after transplant

  7. Rich Donors, Poor Countries

    ERIC Educational Resources Information Center

    Thomas, M. A.

    2012-01-01

    The shifting ideological winds of foreign aid donors have driven their policy towards governments in poor countries. Donors supported state-led development policies in poor countries from the 1940s to the 1970s; market and private-sector driven reforms during the 1980s and 1990s; and returned their attention to the state with an emphasis on…

  8. When disaster strikes: death of a living organ donor.

    PubMed

    Ratner, L E; Sandoval, P R

    2010-12-01

    Donor safety is of paramount importance in living donor transplantation. Yet, living donor deaths occur. We believe that problems exist in our system of live donor transplantation that can be summarized in a series of simple statements: (1) Donor mortality can never be completely eliminated; (2) Live donor risk has not been mitigated so that it is as low as possible; (3) After a donor death, systematic reviews are not routinely performed to identify correctable causes; (4) The lessons learned from any donor death are not adequately communicated to other programs and (5) The administrative mechanisms and resources are not universally available at all transplant centers to implement lessons learned. To rectify these problems, we propose the following: (1) A national living donor death task force be established with the purpose of performing systematic reviews of any donor death. (2) Findings of these reviews be disseminated to all institutions performing live donor transplants on a secure, password-protected website. (3) A no-fault donor death indemnity fund be established to provide a financial imperative for institutions to cooperate with this external peer-review. These measures will serve the best interests of the involved institutions, the transplant community, and most importantly, the patients and their families.

  9. Substrate-Competitive Activity-Based Profiling of Ester Prodrug Activating Enzymes.

    PubMed

    Xu, Hao; Majmudar, Jaimeen D; Davda, Dahvid; Ghanakota, Phani; Kim, Ki H; Carlson, Heather A; Showalter, Hollis D; Martin, Brent R; Amidon, Gordon L

    2015-09-08

    Understanding the mechanistic basis of prodrug delivery and activation is critical for establishing species-specific prodrug sensitivities necessary for evaluating preclinical animal models and potential drug-drug interactions. Despite significant adoption of prodrug methodologies for enhanced pharmacokinetics, functional annotation of prodrug activating enzymes is laborious and often unaddressed. Activity-based protein profiling (ABPP) describes an emerging chemoproteomic approach to assay active site occupancy within a mechanistically similar enzyme class in native proteomes. The serine hydrolase enzyme family is broadly reactive with reporter-linked fluorophosphonates, which have shown to provide a mechanism-based covalent labeling strategy to assay the activation state and active site occupancy of cellular serine amidases, esterases, and thioesterases. Here we describe a modified ABPP approach using direct substrate competition to identify activating enzymes for an ethyl ester prodrug, the influenza neuraminidase inhibitor oseltamivir. Substrate-competitive ABPP analysis identified carboxylesterase 1 (CES1) as an oseltamivir-activating enzyme in intestinal cell homogenates. Saturating concentrations of oseltamivir lead to a four-fold reduction in the observed rate constant for CES1 inactivation by fluorophosphonates. WWL50, a reported carbamate inhibitor of mouse CES1, blocked oseltamivir hydrolysis activity in human cell homogenates, confirming CES1 is the primary prodrug activating enzyme for oseltamivir in human liver and intestinal cell lines. The related carbamate inhibitor WWL79 inhibited mouse but not human CES1, providing a series of probes for analyzing prodrug activation mechanisms in different preclinical models. Overall, we present a substrate-competitive activity-based profiling approach for broadly surveying candidate prodrug hydrolyzing enzymes and outline the kinetic parameters for activating enzyme discovery, ester prodrug design, and

  10. A Food Effect Study of an Oral Thrombin Inhibitor and Prodrug Approach To Mitigate It.

    PubMed

    Lee, Jihye; Kim, Bongchan; Kim, Tae Hun; Lee, Sun Hwa; Park, Hee Dong; Chung, Kyungha; Lee, Sung-Hack; Paek, Seungyup; Kim, Eunice EunKyeong; Yoon, SukKyoon; Kim, Aeri

    2016-04-04

    LB30870, a new direct thrombin inhibitor, showed 80% reduction in oral bioavailability in fed state. The present study aims to propose trypsin binding as a mechanism for such negative food effect and demonstrate a prodrug approach to mitigate food effect. Effect of food composition on fed state oral bioavailability of LB30870 was studied in dogs. Various prodrugs were synthesized, and their solubility, permeability, and trypsin binding affinity were measured. LB30870 and prodrugs were subject to cocrystallization with trypsin, and the X-ray structures of cocrystals were determined. Food effect was studied in dogs for selected prodrugs. Protein or lipid meal appeared to affect oral bioavailability of LB30870 in dogs more than carbohydrate meal. Blocking both carboxyl and amidine groups of LB30870 resulted in trypsin Ki values orders of magnitude higher than that of LB30870. Prodrugs belonged to either Biopharmaceutical Classification System I, II, or III. X-ray crystallography revealed that prodrugs did not bind to trypsin, but instead their hydrolysis product at the amidine blocking group formed cocrystal with trypsin. A prodrug with significantly less food effect than LB30870 was identified. Binding of prodrugs to food components such as dietary fiber appeared to counteract the positive effect brought with the prodrug approach. Further formulation research is warranted to enhance the oral bioavailability of prodrugs. In conclusion, this study is the first to demonstrate that the negative food effect of LB30870 can be attributed to trypsin binding. Trypsin binding study is proposed as a screening tool during lead optimization to minimize food effect.

  11. Supramolecular curcumin-barium prodrugs for formulating with ceramic particles.

    PubMed

    Kamalasanan, Kaladhar; Anupriya; Deepa, M K; Sharma, Chandra P

    2014-10-01

    A simple and stable curcumin-ceramic combined formulation was developed with an aim to improve curcumin stability and release profile in the presence of reactive ceramic particles for potential dental and orthopedic applications. For that, curcumin was complexed with barium (Ba(2+)) to prepare curcumin-barium (BaCur) complex. Upon removal of the unbound curcumin and Ba(2+) by dialysis, a water-soluble BaCur complex was obtained. The complex was showing [M+1](+) peak at 10,000-20,000 with multiple fractionation peaks of MALDI-TOF-MS studies, showed that the complex was a supramolecular multimer. The (1)H NMR and FTIR studies revealed that, divalent Ba(2+) interacted predominantly through di-phenolic groups of curcumin to form an end-to-end complex resulted in supramolecular multimer. The overall crystallinity of the BaCur was lower than curcumin as per XRD analysis. The complexation of Ba(2+) to curcumin did not degrade curcumin as per HPLC studies. The fluorescence spectrum was blue shifted upon Ba(2+) complexation with curcumin. Monodisperse nanoparticles with size less than 200dnm was formed, out of the supramolecular complex upon dialysis, as per DLS, and upon loading into pluronic micelles the size was remaining in similar order of magnitude as per DLS and AFM studies. Stability of the curcumin was improved greater than 50% after complexation with Ba(2+) as per UV/Vis spectroscopy. Loading of the supramloecular nanoparticles into pluronic micelles had further improved the stability of curcumin to approx. 70% in water. These BaCur supramolecule nanoparticles can be considered as a new class of prodrugs with improved solubility and stability. Subsequently, ceramic nanoparticles with varying chemical composition were prepared for changing the material surface reactivity in terms of the increase in, degradability, surface pH and protein adsorption. Further, these ceramic particles were combined with curcumin prodrug formulations and optimized the curcumin release

  12. Relapse after non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: early transplantation, use of an unrelated donor, and chronic graft-versus-host disease are protective.

    PubMed

    Enright, H; Davies, S M; DeFor, T; Shu, X; Weisdorf, D; Miller, W; Ramsay, N K; Arthur, D; Verfaillie, C; Miller, J; Kersey, J; McGlave, P

    1996-07-15

    We analyzed the incidence of posttransplant chronic myelogenous leukemia (CML) relapse in 283 consecutive related-donor (n = 177) and unrelated-donor (n = 106) allogeneic transplant recipients. Twenty-two of 165 related-donor recipients with stable or advanced disease at the time of transplant had hematologic relapse of CML following transplant (5-year Kaplan-Meier estimate of relapse, 20%; 95% confidence interval [CI], 11 to 30%). One of 12 patients transplanted in second stable phase following blast crisis also relapsed. Fifteen related-donor transplant recipients relapsed within 5 years of transplant; however, seven relapsed between 5 and 9 years after transplant. Factors independently associated with an increased risk of posttransplant relapse for related-donor recipients included prolonged interval between diagnosis and transplant (relative risk, [RR], 3.81; P = .009) and bone marrow basophilia (RR, 5.62; P = .01). Related-donor recipients with posttransplant chronic graft-versus-host disease (CGVHD) had a decreased risk of relapse (RR, 0.24; P = .005). Only two of 106 unrelated-donor transplant recipients relapsed following transplant (5-year Kaplan-Meier estimate of relapse, 3%; 95% CI, 0% to 7%). When both related- and unrelated-donor recipients were considered, the use of an unrelated donor was independently associated with a decreased risk of relapse (RR, 0.24; P = .07). Twelve of 16 relapsing patients who received further therapy (nine of 13 who underwent second transplant and three of three who received donor leukocyte infusions) remain alive. This analysis shows that relapse, sometimes occurring long after transplant, is an important adverse outcome in allogeneic transplantation for CML. Early transplant, posttransplant CGVHD, and use of an unrelated donor are associated with a reduced incidence of relapse, perhaps due to allogeneic disparities enhancing the graft-versus-leukemia effect.

  13. [Motivations of oocytes donors].

    PubMed

    Cauvin, P

    2009-01-01

    Oocyte donation is a complex situation that requires the applicant couple to deal with the presence of the donor in the history of the child conception. Accepting the eggs is not the same thing than accepting the donor. Her place in the child's life depends on how his parents will accept her phantasmal reality beyond her real person. Paying attention to the story told by the donors on their motivations may help parents internalize this conception to three. We show from two clinical observations, that the generosity of donors is connected to personal issues that do not relate to unborn child or its parents. If there are two mothers in oocyte donation, they are not really in competition because there are also two children: the child conceived through donation is that of the project of the couple, the child to which the donor thinks, is and will remain in phantasmal domain, i.e. linked to the personal history of the donor. We also show that the psychological interview fully responds to the donor expectations when it seeks to highlight her motives.

  14. Blood donor well-being: a primary responsibility of blood collection agencies.

    PubMed

    Reiss, Robert F

    2011-01-01

    Current FDA regulations and AABB standards do not adequately protect the well-being of blood donors. Several practices have adverse consequences for donors, including: elevated incidence of donation related reactions and injuries, iron deficiency anemia in premenopausal women, and inadequate counseling of donors to obtain medical follow-up for health risks identified during pre-donation health screening. These practices can be improved without impacting negatively on the national blood supply. In addition to revising current blood collection operations, blood centers should explore the feasibility of establishing expanded donor health screening programs and determining their effectiveness in improving donor health, donor recruitment, and donor retention.

  15. Mesenchymal stromal cells retrovirally transduced with prodrug-converting genes are suitable vehicles for cancer gene therapy.

    PubMed

    Ďuriniková, E; Kučerová, L; Matúšková, M

    2014-01-01

    Mesenchymal stem/stromal cells (MSC) possess a set of several fairly unique properties which make them ideally suitable both for cellular therapies and regenerative medicine. These include: relative ease of isolation, the ability to differentiate along mesenchymal and non-mesenchymal lineages in vitro and the ability to be extensively expanded in culture without a loss of differentiative capacity. MSC are not only hypoimmunogenic, but they mediate immunosuppression upon transplantation, and possess pronounced anti-inflammatory properties. They are able to home to damaged tissues, tumors, and metastases following systemic administration. The ability of homing holds big promise for tumor-targeted delivery of therapeutic agents. Viruses are naturally evolved vehicles efficiently transferring their genes into host cells. This ability made them suitable for engineering vector systems for the delivery of genes of interest. MSC can be retrovirally transduced with genes encoding prodrug-converting genes (suicide genes), which are not toxic per se, but catalyze the formation of highly toxic metabolites following the application of a nontoxic prodrug. The homing ability of MSC holds advantages compared to virus vehicles which display many shortcomings in effective delivery of the therapeutic agents. Gene therapies mediated by viruses are limited by their restricted ability to track cancer cells infiltrating into the surrounding tissue, and by their low migratory capacity towards tumor. Thus combination of cellular therapy and gene delivery is an attractive option - it protects the vector from immune surveillance, and supports targeted delivery of a therapeutic gene/protein to the tumor site.

  16. Macrophage mediated PCI enhanced gene-directed enzyme prodrug therapy

    NASA Astrophysics Data System (ADS)

    Christie, Catherine E.; Zamora, Genesis; Kwon, Young J.; Berg, Kristian; Madsen, Steen J.; Hirschberg, Henry

    2015-03-01

    Photochemical internalization (PCI) is a photodynamic therapy-based approach for improving the delivery of macromolecules and genes into the cell cytosol. Prodrug activating gene therapy (suicide gene therapy) employing the transduction of the E. coli cytosine deaminase (CD) gene into tumor cells, is a promising method. Expression of this gene within the target cell produces an enzyme that converts the nontoxic prodrug, 5-FC, to the toxic metabolite, 5-fluorouracil (5-FU). 5-FC may be particularly suitable for brain tumors, because it can readily cross the bloodbrain barrier (BBB). In addition the bystander effect, where activated drug is exported from the transfected cancer cells into the tumor microenvironment, plays an important role by inhibiting growth of adjacent tumor cells. Tumor-associated macrophages (TAMs) are frequently found in and around glioblastomas. Monocytes or macrophages (Ma) loaded with drugs, nanoparticles or photosensitizers could therefore be used to target tumors by local synthesis of chemo attractive factors. The basic concept is to combine PCI, to enhance the ex vivo transfection of a suicide gene into Ma, employing specially designed core/shell NP as gene carrier.

  17. Preparation of alginate beads containing a prodrug of diethylenetriaminepentaacetic acid

    PubMed Central

    Yang, Yu-Tsai; Di Pasqua, Anthony J.; He, Weiling; Tsai, Tsuimin; Sueda, Katsuhiko; Zhang, Yong; Jay, Michael

    2012-01-01

    A penta-ethyl ester prodrug of the radionuclide decorporation agent diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was encapsulated in alginate beads by the ionotropic gelation method. An optimal formulation was found by varying initial concentrations of DTPA pentaethyl ester, alginate polymer, Tween 80 surfactant and calcium chloride. All prepared alginate beads were ~1.6 mm in diameter, and the optimal formulation had loading and encapsulation efficiencies of 91.0 ± 1.1 and 72.6 ± 2.2%, respectively, and only 3.2 ± 0.8% water absorption after storage at room temperature in ~80% relative humidity. Moreover, Fourier transform infrared spectroscopy showed that DTPA penta-ethyl ester did not react with excipients during formation of the DTPA penta-ethyl ester-containing alginate beads. Release of prodrug from alginate beads was via anomalous transport, and its stability enhanced by encapsulation. Collectively, these data suggest that this solid dosage form may be suitable for oral administration after radionuclide contamination. PMID:23399237

  18. Molecular Pathways: Hypoxia-activated prodrugs in cancer therapy.

    PubMed

    Baran, Natalia; Konopleva, Marina

    2017-01-30

    Hypoxia is a known feature of aggressive solid tumors as well as a critical hallmark of the niche in aggressive hematologic malignances. Hypoxia is associated with insufficient response to standard therapy, resulting in disease progression and curtailed patients' survival through maintenance of noncycling cancer stem-like cells. A better understanding of the mechanisms and signaling pathways induced by hypoxia is essential to overcoming these effects. Recent findings demonstrate that bone marrow in the setting of hematologic malignancies is highly hypoxic and that progression of the disease is associated with expansion of hypoxic niches and stabilization of the oncogenic hypoxia-inducible factor-1alpha (HIF-1α). Solid tumors have also been shown to harbor hypoxic areas, maintaining survival of cancer cells via the HIF-1α pathway. Developing new strategies for targeting hypoxia has become a crucial approach in modern cancer therapy. The number of preclinical and clinical trials targeting low-oxygen tumor compartments or the hypoxic bone marrow niche via hypoxia-activated prodrugs is increasing. This review discusses the development of the hypoxia-activated prodrugs and their applicability in treating both hematologic malignancies and solid tumors.

  19. Design, synthesis and in vitro evaluation of novel water-soluble prodrugs of buparvaquone.

    PubMed

    Mäntylä, Antti; Rautio, Jarkko; Nevalainen, Tapio; Keski-Rahkonen, Pekka; Vepsälainen, Jouko; Järvinen, Tomi

    2004-10-01

    Novel water-soluble phosphate prodrugs (2b-5b) of buparvaquone-oxime (1a) and buparvaquone-O-methyloxime (1b) were synthesized and evaluated in vitro as potential oral prodrugs against leishmaniasis. Buparvaquone-oxime (1a), and most probably also buparvaquone-O-methyloxime (1b), released the parent buparvaquone via a cytochrome P450-catalysed reaction. The prodrugs 2b-5b showed significantly higher aqueous solubilities (>4 mg/ml) than buparvaquone (< or = 0.03 microg/ml) over a pH range of 3.0-7.4. The prodrugs 2b, 3b and 5b rapidly released (t1/2 = 7 min) the corresponding oximes of buparvaquone (1a and 1b), and prodrug 4b at a moderate rate (t1/2 = 22.5 min) in alkaline phosphatase solution in vitro. Prodrug 3b was the most chemically stable in the aqueous solutions over a pH range of 3.0-7.4 (t1/2 > 8 days). Although buparvaquone-oxime (1a) has been shown to undergo a cytochrome P450-catalysed oxidation in liver microsomes to the parent buparvaquone and behave as a novel bioreversible prodrug, its usefulness is limited in oral drug delivery due to its poor aqueous solubility, like buparvaquone itself. Further phosphorylation of an oxime form of buparvaquone significantly increased water solubility, and this novel approach is therefore useful to improve physicochemical properties of drugs containing a ketone functional group.

  20. Synthesis, metabolism and cellular permeability of enzymatically stable dipeptide prodrugs of acyclovir.

    PubMed

    Talluri, Ravi S; Samanta, Swapan K; Gaudana, Ripal; Mitra, Ashim K

    2008-09-01

    The objective of this study was to synthesize and evaluate novel enzymatically stable dipeptide prodrugs for improved absorption of acyclovir. l-Valine-l-valine-acyclovir (LLACV), l-valine-d-valine-acyclovir (LDACV), d-valine-l-valine-acyclovir (DLACV) and d-valine-d-valine-acyclovir (DDACV) were successfully synthesized. The uptake and transport studies were conducted on a Caco-2 cell line. Buffer stability and metabolism of the prodrugs in Caco-2, rat intestine and liver homogenates were studied. Structure and purity of the all compounds were confirmed with LC-MS/MS and NMR spectroscopy. Uptake and transport of [(3)H] glycylsarcosine was inhibited by all prodrugs except DDACV. DLACV and DDACV exhibited no measurable degradation in Caco-2 homogenate. Except DDACV other three prodrugs were hydrolyzed in rat intestine and liver homogenates. The order of permeability across Caco-2 was LDACV>LLACV>DDACV>DLACV. A linear correlation between the amount of prodrug transported and over all permeability of acyclovir was established. This study shows that the incorporation of one d-valine in a dipeptide did not abolish its affinity towards peptide transporters (PEPT). Moreover, it enhanced enzymatic stability of prodrug to a certain extent depending on the position in a dipeptide conjugate. This strategy improved both the cellular permeability and the amount of intact prodrug transported which would enable targeting the nutrient transporters at blood ocular barrier (BOB).

  1. "Click" reaction in conjunction with diazeniumdiolate chemistry: developing high-load nitric oxide donors.

    PubMed

    Oladeinde, Oyebola A; Hong, Sam Y; Holland, Ryan J; Maciag, Anna E; Keefer, Larry K; Saavedra, Joseph E; Nandurdikar, Rahul S

    2010-10-01

    The use of Cu(I)-catalyzed "click" reactions of alkyne-substituted diazeniumdiolate prodrugs with bis- and tetrakis-azido compounds is described. The "click" reaction for the bis-azide using CuSO(4)/Na-ascorbate predominantly gave the expected bis-triazole. However, CuI/diisopropylethylamine predominantly gave uncommon triazolo-triazole products as a result of oxidative coupling. Neither set of "click" conditions showed evidence of compromising the integrity of the diazeniumdiolate groups. The chemistry developed has applications in the synthesis of polyvalent and dendritic nitric oxide donors.

  2. Synthesis and pharmacological evaluation of nucleoside prodrugs designed to target siderophore biosynthesis in Mycobacterium tuberculosis.

    PubMed

    Dawadi, Surendra; Kawamura, Shuhei; Rubenstein, Anja; Remmel, Rory; Aldrich, Courtney C

    2016-03-15

    The nucleoside antibiotic, 5'-O-[N-(salicyl)sulfamoyl]adenosine (1), possesses potent whole-cell activity against Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). This compound is also active in vivo, but suffers from poor drug disposition properties that result in poor bioavailability and rapid clearance. The synthesis and evaluation of a systematic series of lipophilic ester prodrugs containing linear and α-branched alkanoyl groups from two to twelve carbons at the 3'-position of a 2'-fluorinated analog of 1 is reported with the goal to improve oral bioavailability. The prodrugs were stable in simulated gastric fluid (pH 1.2) and under physiological conditions (pH 7.4). The prodrugs were also remarkably stable in mouse, rat, and human serum (relative serum stability: human∼rat≫mouse) displaying a parabolic trend in the SAR with hydrolysis rates increasing with chain length up to eight carbons (t1/2=1.6 h for octanoyl prodrug 7 in mouse serum) and then decreasing again with higher chain lengths. The permeability of the prodrugs was also assessed in a Caco-2 cell transwell model. All of the prodrugs were found to have reduced permeation in the apical-to-basolateral direction and enhanced permeation in the basolateral-to-apical direction relative to the parent compound 2, resulting in efflux ratios 5-28 times greater than 2. Additionally, Caco-2 cells were found to hydrolyze the prodrugs with SAR mirroring the serum stability results and a preference for hydrolysis on the apical side. Taken together, these results suggest that the described prodrug strategy will lead to lower than expected oral bioavailability of 2 and highlight the contribution of intestinal esterases for prodrug hydrolysis.

  3. Identification of novel nitroreductases from Bacillus cereus and their interaction with the CB1954 prodrug.

    PubMed

    Gwenin, Vanessa V; Poornima, Paramasivan; Halliwell, Jennifer; Ball, Patrick; Robinson, George; Gwenin, Chris D

    2015-12-01

    Directed enzyme prodrug therapy is a form of cancer chemotherapy in which bacterial prodrug-activating enzymes, or their encoding genes, are directed to the tumour before administration of a prodrug. The prodrug can then be activated into a toxic drug at the tumour site, reducing off-target effects. The bacterial nitroreductases are a class of enzymes used in this therapeutic approach and although very promising, the low turnover rate of prodrug by the most studied nitroreductase enzyme, NfnB from Escherichia coli (NfnB_Ec), is a major limit to this technology. There is a continual search for enzymes with greater efficiency, and as part of the search for more efficient bacterial nitroreductase enzymes, two novel enzymes from Bacillus cereus (strain ATCC 14579) have been identified and shown to reduce the CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) prodrug to its respective 2'-and 4'-hydroxylamine products. Both enzymes shared features characteristic of the nitro-FMN-reductase superfamily including non-covalently associated FMN, requirement for the NAD(P)H cofactor, homodimeric, could be inhibited by Dicoumarol (3,3'-methylenebis(4-hydroxy-2H-chromen-2-one)), and displayed ping pong bi bi kinetics. Based on the biochemical characteristics and nucleotide alignment with other nitroreductase enzymes, one enzyme was named YdgI_Bc and the other YfkO_Bc. Both B. cereus enzymes had greater turnover for the CB1954 prodrug compared with NfnB_Ec, and in the presence of added NADPH cofactor, YfkO_Bc had superior cell killing ability, and produced mainly the 4'-hydroxylamine product at low prodrug concentration. The YfkO_Bc was identified as a promising candidate for future enzyme prodrug therapy.

  4. Characterization of lipophilic gemcitabine prodrug-liposomal membrane interaction by differential scanning calorimetry.

    PubMed

    Castelli, Francesco; Sarpietro, Maria Grazia; Ceruti, Maurizio; Rocco, Flavio; Cattel, Luigi

    2006-01-01

    Gemcitabine is an anticancer agent rapidly deaminated to the inactive metabolite 2',2'-difluorodeoxyuridine. Its stability as well as bioavailability can be increased by making prodrugs. A series of lipophilic prodrugs of gemcitabine were synthesized by linking the 4-amino group with valeroyl, lauroyl, and stearoyl linear acyl derivatives. We studied, by the differential scanning calorimetry technique, and compared the interaction of pure gemcitabine and its prodrugs with dimyristoylphosphatidylcholine and distearoylphosphatidylcholine vesicles with the aim of demonstrating if the gemcitabine prodrug is more able than the pure gemcitabine to interact with lipid vesicles employed both as model biomembranes and as carriers in the transport of antitumor drugs. These studies, carried out by static and kinetic calorimetric measurements, give evidence that the increase of the prodrug's lipophilic character improves the interaction with lipid bilayers, favoring the absorption through the lipid barriers and allowing the liposomes to work (when the prodrug is inserted inside the vesicles) as a lipophilic carrier which is able to deliver the drug near the cell surface. The use of different prodrugs modified in their lipophilic character, of different kinds of vesicles (multilamellar and unilamellar), and of different kinds of vesicles forming phospholipids permitted us to determine the better equilibrium between in-vesicle solubility and through-vesicle diffusion of the drug, important in the preformulative studies of antitumor carriers based on phospholipid formulations. Such studies suggest that the prodrug lipophilic tail should modulate the transport and the release of gemcitabine inside the cellular compartments, and the efficiency of the liposomal system is related to the length of the prodrug's acyl chain which has to match the phospholipid acyl chain allowing or retarding the migration through the lipid release device.

  5. Laparoscopic donor nephrectomy.

    PubMed

    Deger, S; Giessing, M; Roigas, J; Wille, A H; Lein, M; Schönberger, B; Loening, S A

    2005-01-01

    Laparoscopic live donor nephrectomy (LDN) has removed disincentives of potential donors and may bear the potential to increase kidney donation. Multiple modifications have been made to abbreviate the learning curve while at the same time guarantee the highest possible level of medical quality for donor and recipient. We reviewed the literature for the evolution of the different LDN techniques and their impact on donor, graft and operating surgeon, including the subtleties of different surgical accesses, vessel handling and organ extraction. We performed a literature search (PubMed, DIMDI, medline) to evaluate the development of the LDN techniques from 1995 to 2003. Today more than 200 centres worldwide perform LDN. Hand-assistance has led to a spread of LDN. Studies comparing open and hand-assisted LDN show a reduction of operating and warm ischaemia times for the hand-assisted LDN. Different surgical access sites (trans- or retroperitoneal), different vessel dissection approaches, donor organ delivery techniques, delivery sites and variations of hand-assistance techniques reflect the evolution of LDN. Proper techniques and their combination for the consecutive surgical steps minimize both warm ischaemia time and operating time while offering the donor a safe minimally invasive laparoscopic procedure. LDN has breathed new life into the moribund field of living kidney donation. Within a few years LDN could become the standard approach in living kidney donation. Surgeons working in this field must be trained thoroughly and well acquainted with the subtleties of the different LDN techniques and their respective advantages and disadvantages.

  6. Annexin V-targeted enzyme prodrug therapy using cytosine deaminase in combination with 5-fluorocytosine.

    PubMed

    Van Rite, Brent D; Harrison, Roger G

    2011-08-01

    A fusion protein, consisting of cytosine deaminase (CD) linked to human annexin V, was created for use in an enzyme prodrug therapy targeted to the tumor vasculature and associated cancer cells in the primary tumor and distant metastases. The major finding of this study is that the CD-annexin V fusion protein in combination with the prodrug 5-fluorocytosine has significant cytotoxic activity against endothelial cells and two breast cancer cells lines in vitro that expose phosphatidylserine on their surface. The cytotoxicity experiments verified this novel enzyme prodrug system has the ability to produce therapeutic levels of 5-fluorouracil and thus appears promising.

  7. Use of enzyme inhibitors to evaluate the conversion pathways of ester and amide prodrugs: a case study example with the prodrug ceftobiprole medocaril.

    PubMed

    Eichenbaum, Gary; Skibbe, Jennifer; Parkinson, Andrew; Johnson, Mark D; Baumgardner, Dawn; Ogilvie, Brian; Usuki, Etsuko; Tonelli, Fred; Holsapple, Jeff; Schmitt-Hoffmann, Anne

    2012-03-01

    An approach was developed that uses enzyme inhibitors to support the assessment of the pathways that are responsible for the conversion of intravenously administered ester and amide prodrugs in different biological matrices. The methodology was applied to ceftobiprole medocaril (BAL5788), the prodrug of the cephalosporin antibiotic, ceftobiprole. The prodrug was incubated in plasma, postmitochondrial supernatant fractions from human liver (impaired and nonimpaired), kidney, and intestine as well as erythrocytes, in the presence and absence of different enzyme inhibitors (acetylcholinesterase, pseudocholinesterase, retinyl palmitoyl hydrolase, serine esterases, amidases, and cholinesterase). Hydrolysis was rapid, extensive, and not dependent on the presence of β-nicotinamide-adenine dinucleotide phosphate (reduced form) in all matrices tested, suggesting the involvement of carboxylesterases but not P450 enzymes. Hydrolysis in healthy human plasma was rapid and complete and only partially inhibited in the presence of paraoxonase inhibitors or in liver from hepatic impaired patients, suggesting involvement of nonparaoxonase pathways. The results demonstrate the utility of this approach in confirming the presence of multiple conversion pathways of intravenously administered prodrugs and in the case of BAL5788 demonstrated that this prodrug is unlikely to be affected by genetic polymorphisms, drug interactions, or other environmental factors that might inhibit or induce the enzymes involved in its conversion.

  8. Donation after circulatory death: burying the dead donor rule.

    PubMed

    Rodríguez-Arias, David; Smith, Maxwell J; Lazar, Neil M

    2011-08-01

    Despite continuing controversies regarding the vital status of both brain-dead donors and individuals who undergo donation after circulatory death (DCD), respecting the dead donor rule (DDR) remains the standard moral framework for organ procurement. The DDR increases organ supply without jeopardizing trust in transplantation systems, reassuring society that donors will not experience harm during organ procurement. While the assumption that individuals cannot be harmed once they are dead is reasonable in the case of brain-dead protocols, we argue that the DDR is not an acceptable strategy to protect donors from harm in DCD protocols. We propose a threefold alternative to justify organ procurement practices: (1) ensuring that donors are sufficiently protected from harm; (2) ensuring that they are respected through informed consent; and (3) ensuring that society is fully informed of the inherently debatable nature of any criterion to declare death.

  9. Development and characterization of nanoparticulate formulation of a water soluble prodrug of dexamethasone by HIP complexation

    PubMed Central

    Gaudana, Ripal; Parenky, Ashwin; Vaishya, Ravi; Samanta, Swapan K.; Mitra, Ashim K.

    2015-01-01

    The objective of this study was to develop and characterize a nanoparticulate-based sustained release formulation of a water soluble dipeptide prodrug of dexamethasone, valine–valine-dexamethasone (VVD). Being hydrophilic in nature, it readily leaches out in the external aqueous medium and hence partitions poorly into the polymeric matrix resulting in minimal entrapment in nanoparticles. Hence, hydrophobic ion pairing (HIP) complexation of the prodrug was employed with dextran sulphate as a complexing polymer. A novel, solid in oil in water emulsion method was employed to encapsulate the prodrug in HIP complex form in poly(lactic-co-glycolic acid) matrix. Nanoparticles were characterized with respect to size, zeta potential, crystallinity of entrapped drug and surface morphology. A significant enhancement in the entrapment of the prodrug in nanoparticles was achieved. Finally, a simple yet novel method was developed which can also be applicable to encapsulate other charged hydrophilic molecules, such as peptides and proteins. PMID:20939702

  10. Increasing oral absorption of polar neuraminidase inhibitors: a prodrug transporter approach applied to oseltamivir analogue.

    PubMed

    Gupta, Deepak; Varghese Gupta, Sheeba; Dahan, Arik; Tsume, Yasuhiro; Hilfinger, John; Lee, Kyung-Dall; Amidon, Gordon L

    2013-02-04

    Poor oral absorption is one of the limiting factors in utilizing the full potential of polar antiviral agents. The neuraminidase target site requires a polar chemical structure for high affinity binding, thus limiting oral efficacy of many high affinity ligands. The aim of this study was to overcome this poor oral absorption barrier, utilizing prodrug to target the apical brush border peptide transporter 1 (PEPT1). Guanidine oseltamivir carboxylate (GOCarb) is a highly active polar antiviral agent with insufficient oral bioavailability (4%) to be an effective therapeutic agent. In this report we utilize a carrier-mediated targeted prodrug approach to improve the oral absorption of GOCarb. Acyloxy(alkyl) ester based amino acid linked prodrugs were synthesized and evaluated as potential substrates of mucosal transporters, e.g., PEPT1. Prodrugs were also evaluated for their chemical and enzymatic stability. PEPT1 transport studies included [(3)H]Gly-Sar uptake inhibition in Caco-2 cells and cellular uptake experiments using HeLa cells overexpressing PEPT1. The intestinal membrane permeabilities of the selected prodrugs and the parent drug were then evaluated for epithelial cell transport across Caco-2 monolayers, and in the in situ rat intestinal jejunal perfusion model. Prodrugs exhibited a pH dependent stability with higher stability at acidic pHs. Significant inhibition of uptake (IC(50) <1 mM) was observed for l-valyl and l-isoleucyl amino acid prodrugs in competition experiments with [(3)H]Gly-Sar, indicating a 3-6 times higher affinity for PEPT1 compared to valacyclovir, a well-known PEPT1 substrate and >30-fold increase in affinity compared to GOCarb. The l-valyl prodrug exhibited significant enhancement of uptake in PEPT1/HeLa cells and compared favorably with the well-absorbed valacyclovir. Transepithelial permeability across Caco-2 monolayers showed that these amino acid prodrugs have a 2-5-fold increase in permeability as compared to the parent drug and

  11. Ester prodrug-loaded electrospun cellulose acetate fiber mats as transdermal drug delivery systems.

    PubMed

    Wu, Xiao-mei; Branford-White, Christopher J; Zhu, Li-min; Chatterton, Nichoals P; Yu, Deng-guang

    2010-08-01

    Cellulose acetate (CA) fibers loaded with the ester prodrugs of naproxen, including methyl ester, ethyl ester and isopropyl ester, were prepared through electrospinning using acetone/N,N-dimethylacetamide(DMAc)/ethanol (4:1:1, v/v/v) as solvent. The chemical and morphological characterizations of the medicated fibers were investigated by means of SEM, DSC, XRD and FTIR, as well as the studies of the drug release properties. The results indicated that the morphology and diameter of the fibers were influenced by the concentration of spinning solution, applied voltage, electrospun solvent and the surfactants. The average diameters of the fibers ranged between 100 and 500 nm for three prodrugs. There was good compatibility between CA and three prodrugs in the blended fibers, respectively. In vitro release indicated that constant drug release from the fiber was observed over 6 days. The prodrugs were successfully encapsulated into the fibers, and this system was stable in terms of effectiveness in release.

  12. Improved buccal delivery of opioid analgesics and antagonists with bitterless prodrugs.

    PubMed

    Hussain, M A; Aungst, B J; Koval, C A; Shefter, E

    1988-09-01

    Buccal delivery of opioid analgesics and antagonists is a useful way of improving bioavailability relative to the oral route. These compounds taste bitter, however. Various prodrugs of nalbuphine, naloxone, naltrexone, oxymorphone, butorphanol, and levallorphan, in which the 3-phenolic hydroxyl group was esterified, lacked a bitter taste. This taste difference was not due to differences in water solubility, suggesting that for these compounds the phenolic functional group is important for interaction with the taste receptor. In rats, nalbuphine, naloxone, and naltrexone administered buccally as prodrugs exhibited up to 90% bioavailability. In dogs, the bitter taste of buccally administered nalbuphine and naloxone caused salivation and swallowing, and bioavailability was low. Buccal dosing of the prodrugs of these compounds caused no adverse effects and the bioavailability ranged from 35 to 50%, a significant improvement relative to the oral bioavailability, which is 5% or less. The feasibility of buccal prodrug delivery using an adhesive patch formulation was demonstrated.

  13. Synthesis and evaluation of mutual prodrugs of ibuprofen with menthol, thymol and eugenol.

    PubMed

    Redasani, Vivekkumar K; Bari, Sanjay B

    2012-10-01

    The present works deals with simple and efficient method of improving therapeutic efficacy of racemic ibuprofen by retarding gastrointestinal side effects through masking of carboxylic group chemically. This is achieved by synthesis and evaluation of ester derivatives of ibuprofen as mutual prodrugs with naturally occurring phenolic and alcoholic compounds. Promoieties like menthol; thymol and eugenol were selected with the aim of getting synergistic effect as these are natural analgesic having traditional medicinal values. Prodrugs are found to be highly lipophilic as compared to parent drug. All the prodrugs are found to be highly stable at acidic pH while undergoes hydrolysis at neutral and alkaline pH as indicated by their t(1/2) values. Synthesized prodrugs derivatives show increased anti-inflammatory activity that might be attributed to synergistic effect as ibuprofen conjugates to natural analgesics. Ulcer index shows much reduction in gastric ulceration compared to ibuprofen concluding the successful masking of acidic group.

  14. Management to optimize organ procurement in brain dead donors.

    PubMed

    Mascia, L; Mastromauro, I; Viberti, S; Vincenzi, M; Zanello, M

    2009-03-01

    The demand for donor organs continues to exceed the number of organs available for transplantation. Many reasons may account for this discrepancy, such as the lack of consent, the absence of an experienced coordinator team able to solve logistical problems, the use of strict donor criteria, and suboptimal, unstandardized critical care management of potential organ donors. This has resulted in efforts to improve the medical care delivered to potential organ donors, so as to reduce organ shortages, improve organ procurement, and promote graft survival. The physiological changes that follow brain death entail a high incidence of complications jeopardizing potentially transplantable organs. Adverse events include cardiovascular changes, endocrine and metabolic disturbances, and disruption of internal homeostasis. Brain death also upregulates the release of pro-inflammatory molecules. Recent findings support the hypothesis that a preclinical lung injury characterized by an enhanced inflammatory response is present in potential donors and may predispose recipients to an adverse clinical prognosis following lung transplantation. In clinical practice, hypotension, diabetes insipidus, relative hypothermia, and natremia are more common than disseminated intravascular coagulation, cardiac arrhythmias, pulmonary oedema, acute lung injury, and metabolic acidosis. Strategies for the management of organ donors exist and consist of the normalization of donor physiology. Management has been complicated by the recent use of ''marginal'' donors and donors of advanced age or with ''extended'' criteria. Current guidelines suggest that the priority of critical care management for potential organ donors should be shifted from a ''cerebral protective'' strategy to a multimodal strategy aimed to preserve peripheral organ function.

  15. Synthesis, in vitro evaluation, and antileishmanial activity of water-soluble prodrugs of buparvaquone.

    PubMed

    Mäntylä, Antti; Garnier, Tracy; Rautio, Jarkko; Nevalainen, Tapio; Vepsälainen, Jouko; Koskinen, Ari; Croft, Simon L; Järvinen, Tomi

    2004-01-01

    Water-soluble phosphate prodrugs of buparvaquone (1), containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral drug delivery against cutaneous and visceral leishmaniasis. The successful prodrug synthesis involved a strong base; e.g., sodium hydride. Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethyl-buparvaquone (4b) prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent drug (prodrugs for the improved topical and oral bioavailability of 1. Buparvaquone and its prodrugs showed nanomolar or low-micromolar ED(50) activity values against species that cause cutaneous leishmaniasis, e.g., L. major, L. amazonensis, L. aethiopica, L. mexicana, and L. panamensis and also L. donovani, which is the causative agent of visceral leishmaniasis. From these results, the human skin permeation of the prodrugs 4a and 4b were studied in vitro. While no buparvaquone permeated across post mortem skin in vitro during 72 h of experiments, both prodrugs 4a and 4b permeated readily through the skin. In addition, 4b easily released the parent drug in human skin homogenate and, therefore, is a promising prodrug candidate to deliver buparvaquone through the skin for the treatment of cutaneous leishmaniasis.

  16. Anti-HIV Nucleoside Phosphonate GS-9148 and Its Prodrug GS-9131: Scale Up of a 2'-F Modified Cyclic Nucleoside Phosphonate and Synthesis of Selected Amidate Prodrugs.

    PubMed

    Mackman, Richard L

    2014-03-26

    Nucleoside phosphonate analogs are an important class of antiviral drugs for the treatment of HIV and HBV. The most recent nucleoside phosphonate to progress to clinical development is GS-9131, a cyclic nucleoside phosphonate (CNP). This unit contains procedures for the synthesis of the parent CNP 2'-Fd4AP (GS-9148) and selected monoamidate and bisamidate prodrugs, including the monoamidate clinical prodrug GS-9131. The first basic protocol of this unit details improved procedures for the preparation of 2'-Fd4AP and related phosphonate esters by introduction of a hydroxylmethyl phosphonate ester regioselectively and stereoselectively onto a furanose core via a glycal intermediate. The method described is believed to be robust and flexible, allowing for a variety of analogs with other nucleobases or furanose 2'-ring substitutions to be prepared. The preparation of monoamidate and bisamidate prodrugs either on the phosphonate diacid or its monophenyl ester is then described in the second and third basic protocols of this unit.

  17. Hypoxia-activated prodrugs: paths forward in the era of personalised medicine

    PubMed Central

    Hunter, Francis W; Wouters, Bradly G; Wilson, William R

    2016-01-01

    Tumour hypoxia has been pursued as a cancer drug target for over 30 years, most notably using bioreductive (hypoxia-activated) prodrugs that target antineoplastic agents to low-oxygen tumour compartments. Despite compelling evidence linking hypoxia with treatment resistance and adverse prognosis, a number of such prodrugs have recently failed to demonstrate efficacy in pivotal clinical trials; an outcome that demands reflection on the discovery and development of these compounds. In this review, we discuss a clear disconnect between the pathobiology of tumour hypoxia, the pharmacology of hypoxia-activated prodrugs and the manner in which they have been taken into clinical development. Hypoxia-activated prodrugs have been evaluated in the manner of broad-spectrum cytotoxic agents, yet a growing body of evidence suggests that their activity is likely to be dependent on the coincidence of tumour hypoxia, expression of specific prodrug-activating reductases and intrinsic sensitivity of malignant clones to the cytotoxic effector. Hypoxia itself is highly variable between and within individual tumours and is not treatment-limiting in all cancer subtypes. Defining predictive biomarkers for hypoxia-activated prodrugs and overcoming the technical challenges of assaying them in clinical settings will be essential to deploying these agents in the era of personalised cancer medicine. PMID:27070712

  18. Ester prodrugs of morphine improve transdermal drug delivery: a mechanistic study.

    PubMed

    Wang, Jhi-Joung; Sung, K C; Huang, Jeng-Fen; Yeh, Chih-Hui; Fang, Jia-You

    2007-07-01

    Two alkyl esters of morphine, morphine propionate (MPR) and morphine enanthate (MEN), were synthesized as potential prodrugs for transdermal delivery. The ester prodrugs could enhance transdermal morphine delivery. The mechanisms of this enhancing effect were elucidated in this study. Both prodrugs were more lipophilic than their parent drug as evaluated by the skin/vehicle partition coefficient (log P) and capacity factor (log K'). The in-vitro skin permeation of morphine and its prodrugs from pH 6 buffer was in the order of MEN > MPR > morphine. MPR and MEN respectively enhanced the transdermal delivery of morphine by 2- and 5-fold. A contrary result was observed when using sesame oil as the vehicle. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were readily hydrolysed to the parent drug when exposed to skin homogenate and esterase. Approximately 98% MPR and approximately 75% MEN were converted to morphine in an in-vitro permeation experiment. The viable epidermis/dermis contributed to a significant resistance to the permeation of ester prodrugs. According to the data of skin permeation across ethanol-, alpha-terpineol-, and oleic acid-pretreated skin, MEN was predominantly transported via lipid bilayer lamellae in the stratum corneum. The intercellular pathway was not important for either morphine or MPR permeation.

  19. Sustained release of metformin via red blood cell accumulated sulfenamide prodrug.

    PubMed

    Peura, Lauri; Huttunen, Kristiina M

    2014-07-01

    Metformin is a first-line antidiabetic drug to treat type 2 diabetes. It is rapidly eliminated from plasma but also accumulated into red blood cells (RBCs) from which it is slowly released back into plasma. The aim of the study was to evaluate whether the amount of metformin in the RBCs could be increased by a sulfenamide prodrug approach, which could provide longer duration of metformin in systemic circulation. Pharmacokinetic properties of metformin and its cyclohexyl sulfenamide prodrug were evaluated in plasma and in whole blood after intravenous and oral administration in rats. Once the sulfenamide prodrug reached the bloodstream, it was rapidly and efficiently accumulated into the RBCs, where it was converted to metformin by free thiols. The RBC-whole blood ratio of metformin was increased approximately from 42% to 96% when metformin was administered intravenously as its sulfenamide prodrug, and the proportion of metformin in the RBCs was found to be concentration and time independent. Because metformin was slowly liberated into plasma, the prodrug showed a sustained-release pharmacokinetic profile and longer plasma half-life for metformin after oral administration. Therefore, this sulfenamide prodrug has great potential to improve metformin therapy as the daily doses could be reduced.

  20. Assessment of the cellular internalization of thermolytic phosphorothioate DNA oligonucleotide prodrugs.

    PubMed

    Jain, Harsh V; Takeda, Kazuyo; Tami, Cecilia; Verthelyi, Daniela; Beaucage, Serge L

    2013-10-15

    The bioactivity of a CpG-containing phosphorothioate DNA oligonucleotide with thermolytic 2-(N-formyl-N-methylamino)ethyl (fma) thiophosphate groups in mice led us to investigate the parameters affecting the internalization of these thermosensitive DNA prodrugs in various cell lines. Flow cytometry and confocal microscopy analyses indicate that 5'-fluoresceinated fma-phosphorothioate DNA sequences are poorly internalized in Vero, HeLa and GC-2 cells. However, when four fma-thiophosphate groups of a 15-nucleotide long oligothymidylate prodrug are replaced with 3-(N,N-dimethylamino)prop-1-yl thiophosphate functions, internalization of the positively charged prodrug, under physiological conditions, increased fourfold in HeLa and 40-fold in Vero or GC-2 cells. No cytotoxic effects are observed in Vero cells even at an extracellular prodrug concentration of 50 μM over a period of 72 h. Confocal microscopy studies show that internalization of the positively charged oligothymidylate prodrug in Vero cells is time-dependent with early trafficking of the DNA sequence through endosomal vesicles and, eventually, to the nucleus of the cells. Thus, the incorporation of four 3-(N,N-dimethylamino)prop-1-yl thiophosphate groups into thermosentive fma-phosphorothioate DNA prodrugs is an attractive strategy for efficient cellular internalization of these nucleic acid-based drugs for potential therapeutic indications.

  1. Prodrugs for targeted tumor therapies: recent developments in ADEPT, GDEPT and PMT.

    PubMed

    Tietze, Lutz F; Schmuck, Kianga

    2011-01-01

    The treatment of cancer with common anti-proliferative agents generally suffers from an insufficient differentiation between normal and malignant cells which results in extensive side effects. To enhance the efficacy and reduce the normal tissue toxicity of anticancer drugs, numerous selective tumor therapies have emerged including the highly promising approaches ADEPT (Antibody-Directed Enzyme Prodrug Therapy), GDEPT (Gene-Directed Enzyme Prodrug Therapy) and PMT (Prodrug Monotherapy). These allow a selective release of cytotoxic agents from non-toxic prodrugs at the tumor site either by targeted antibody-enzyme conjugates, enzyme encoding genes or by exploiting physiological and metabolic aberrations in cancerous tissue. Herein, recent developments in the design and biological evaluation of prodrugs for use in ADEPT, GDEPT and PMT are reviewed. As a highlight, a series of novel glycosidic prodrugs based on the natural antibiotics CC-1065 and the duocarmycins will be discussed which show a therapeutic window of up to one million. Notably, the corresponding drugs have tremendously high cytotoxicities with IC(50) values of down to 110 fM.

  2. New Enzyme Prodrug and Methionine-Depletion Combination Therapy of Breast Cancer Designed for Effective Delivery to the Tumor

    DTIC Science & Technology

    2010-10-01

    AD_ ________________ Award Number: W81XWH-08-1-0722 TITLE: New Enzyme Prodrug and...14 Sept 2010 4. TITLE AND SUBTITLE New Enzyme Prodrug and Methionine-Depletion Combination Therapy of 5a. CONTRACT NUMBER Breast...to human endothelial cells, MCF-7 breast cancer cells, and MDA-MB-231 breast cancer cells grown in vitro. Tests with the enzyme prodrug over a

  3. Living Donor Liver Transplantation

    MedlinePlus

    ... instructions before and after surgery. • Have a compatible blood type. • Have an emotional tie with the recipient. • Not ... test is to find out if the donor's blood type matches the recipient’s blood type. Next, the transplant ...

  4. Dialing for Donors

    ERIC Educational Resources Information Center

    Schaffhauser, Dian

    2012-01-01

    When times get tough, grown children often turn to their parents for help--for some extra cash, even somewhere to stay. For colleges and universities, that role is filled by alumni donors. In 2011, with education budgets slashed across the country, giving accounted for 6.5 percent of college expenditures, according to the Council for Aid to…

  5. New Enzyme Prodrug and Methionine-Depletion Combination Therapy of Breast Cancer Designed for Effective Delivery to the Tumor

    DTIC Science & Technology

    2012-10-01

    to human endothelial cells, MCF-7 breast cancer cells, and MDA-MB-231 breast cancer cells grown in vitro. In vitro tests of both enzyme prodrug...methylselenol, was tested in vivo in SCID mice with implanted MDA-MB-231/GFP cancer cells using i.p. injection of the FP and the prodrug. The result was that...prodrug combination was tested in SCID mice with breast tumor xenografts for its effect as an enzyme prodrug by itself and also in combination with

  6. Acetal-linked paclitaxel prodrug micellar nanoparticles as a versatile and potent platform for cancer therapy.

    PubMed

    Gu, Yudan; Zhong, Yinan; Meng, Fenghua; Cheng, Ru; Deng, Chao; Zhong, Zhiyuan

    2013-08-12

    Endosomal pH-activatable paclitaxel (PTX) prodrug micellar nanoparticles were designed and prepared by conjugating PTX onto water-soluble poly(ethylene glycol)-b-poly(acrylic acid) (PEG-PAA) block copolymers via an acid-labile acetal bond to the PAA block and investigated for potent growth inhibition of human cancer cells in vitro. PTX was readily conjugated to PEG-PAA with high drug contents of 21.6, 27.0, and 42.8 wt % (denoted as PTX prodrugs 1, 2, and 3, respectively) using ethyl glycol vinyl ether (EGVE) as a linker. The resulting PTX conjugates had defined molecular weights and self-assembled in phosphate buffer (PB, pH 7.4, 10 mM) into monodisperse micellar nanoparticles with average sizes of 158.3-180.3 nm depending on PTX contents. The in vitro release studies showed that drug release from PTX prodrug nanoparticles was highly pH-dependent, in which ca. 86.9%, 66.4% and 29.0% of PTX was released from PTX prodrug 3 at 37 °C in 48 h at pH 5.0, 6.0, and pH 7.4, respectively. MTT assays showed that these pH-sensitive PTX prodrug nanoparticles exhibited high antitumor effect to KB and HeLa cells (IC(50) = 0.18 and 0.9 μg PTX equiv/mL, respectively) as well as PTX-resistant A549 cells. Notably, folate-decorated PTX prodrug micellar nanoparticles based on PTX prodrug 3 and 20 wt % folate-poly(ethylene glycol)-b-poly(D,L-lactide) (FA-PEG-PLA) displayed apparent targetability to folate receptor-overexpressing KB cells with IC(50) over 12 times lower than nontargeting PTX prodrug 3 under otherwise the same conditions. Furthermore, PTX prodrug nanoparticles could also load doxorubicin (DOX) to simultaneously release PTX and DOX under mildly acidic pH. These acetal-linked PTX prodrug micellar nanoparticles have appeared as a highly versatile and potent platform for cancer therapy.

  7. Peptide Prodrugs: Improved Oral Absorption of Lopinavir, a HIV Protease Inhibitor

    PubMed Central

    Agarwal, Sheetal; Boddu, S.H.S.; Jain, Ritesh; Samanta, Swapan; Pal, Dhananjay; Mitra, Ashim K.

    2008-01-01

    Lopinavir (LVR) is extensively metabolized by CYP3A4 and is prevented from entering the cells by membrane efflux pumps such as P-gp and MRP2. In an approach to evade the first-pass metabolism and efflux of LVR, peptide prodrugs of LVR [valine-valine-lopinavir (VVL) and glycine-valine-lopinavir (GVL)] were synthesized. Prodrugs were identified with 1H and 13C NMR spectra and LC/MS/MS was employed to evaluate their mass and purity. Solubility studies indicated that the prodrugs have much greater solubility as compared with LVR in water. In vitro evaluations were performed to determine affinities for efflux proteins (P-gp and MRP2) and CYP3A4 and permeabilities across intestinal barrier. Accumulation and transport data of VVL and GVL across MDCKII-MDR1 and MDCKII-MRP2 cells indicated evasion of prodrugs’ efflux by P-gp and MRP2 significantly. Permeability studies across Caco-2 cells indicated that the prodrugs are transported by peptide transporters and have increased permeability as compared with LVR. VVL and GVL exhibited significantly better degradation rate constants as compared with LVR in rat liver microsomes. Enzymatic stability studies in Caco-2 cell homogenate indicated that the peptide prodrugs are first converted to the ester intermediate and then finally to the parent drug. Overall, the advantages of utilizing peptide prodrugs include chemical modification of the compound to achieve targeted delivery via peptide transporters present across the intestinal epithelium, significant evasion of efflux and CYP3A4 mediated metabolism and significantly better solubility profiles. Therefore, in vitro studies demonstrated that peptide prodrug derivatization of LVR may be an effective strategy for bypassing its efflux and enhancing its systemic bioavailability. PMID:18455890

  8. Being a Living Donor: Risks

    MedlinePlus

    ... Living Donation / Being a Living Donor / Risks Facts History Organs Frequently Asked Questions Discussing Living Donation Types Related Non-Related Non-Directed Paired Donation Blood Type Incompatible Positive Crossmatch Being a Living Donor ...

  9. Flurbiprofen–antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling

    PubMed Central

    Ashraf, Zaman; Alamgeer; Kanwal, Munazza; Hassan, Mubashir; Abdullah, Sahar; Waheed, Mamuna; Ahsan, Haseeb; Kim, Song Ja

    2016-01-01

    Flurbiprofen–antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (–COOH) was temporarily masked by esterification with phenolic –OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (P<0.001) reduced the inflammation against carrageenan and egg albumin-induced paw edema at 4 hours of study. The reduction in the size of the inflamed paw showed that most of the compounds inhibited the later phase of inflammation. The prodrug 2-oxo-2H-chromen-7-yl-2-(2-fluorobiphenyl-4-yl)propanoate (4b) showed significant reduction in paw licking with percentage inhibition of 58%. It also exhibited higher analgesic activity, reducing the number of writhes with a percentage of 75%, whereas flurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer’s yeast-induced pyrexia model, and significant (P<0.001) reduction in rectal temperature was shown by all prodrugs at all times of assessment. The results of ulcerogenic activity showed that all prodrugs produced less GI irritation than flurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2) proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities

  10. National Marrow Donor Program

    DTIC Science & Technology

    2009-08-14

    Recipient Pair HLA typing project to characterize class I and class II alleles of donor/recipient paired samples from NMDP’s Repository was initiated...24 • Initiated investigation of the first class II non-ARS mismatch (DRB1*140101/1454) where both alleles have been seen in the same genotype... MHC Major Histocompatibility Complex B-LCLs B-Lymphocytic Cell Lines MICA MHC Class I-Like Molecule, Chain A BARDA Biomedical Advanced Research and

  11. Complications of donor apheresis.

    PubMed

    Winters, Jeffrey L

    2006-07-01

    A decreasing blood donor pool in the presence of increasing blood transfusion demands has resulted in the need to maximally utilize each blood donor. This has led to a trend in the increasing use of automated blood collections. While apheresis donation shares many reactions and injuries with whole blood donation, because of the differences, unique complications also exist. Overall, evidence in the literature suggests that the frequency of reactions to apheresis donation is less than that seen in whole blood donation, though the risk of reactions requiring hospitalization is substantially greater. The most common apheresis-specific reaction is hypocalcemia due to citrate anticoagulation, which, while usually mild, has the potential for severely injuring the donor. Other reactions to apheresis donation are uncommon (e.g., hypotension) or rare (e.g., air embolism). More worrisome, and in need of additional study, are the long-term effects of apheresis donation. Recent evidence suggests that repeated apheresis platelet donations may adversely effect thrombopoiesis as well as bone mineralization. Granulocyte donation has also been implicated in unexpected long-term consequences.

  12. Nanoassemblies from amphiphilic cytarabine prodrug for leukemia targeted therapy.

    PubMed

    Liu, Jing; Zhao, Dujuan; He, Wenxiu; Zhang, Huiyuan; Li, Zhonghao; Luan, Yuxia

    2017-02-01

    The anti-leukemia effect of cytarabine (Ara-C) is severely restricted by its high hydrophilic properties and rapid plasma degradation. Herein, a novel amphiphilic small molecular prodrug of Ara-C was developed by coupling a short aliphatic chain, hexanoic acid (HA) to 4-NH2 of the parent drug. Based on the amphiphilic nature, the resulting bioconjugate (HA-Ara) could spontaneously self-assemble into stable spherical nanoassemblies (NAs) with an extremely high drug loading (∼71wt%). Moreover, folate receptor (FR)-targeting NAs with high grafting efficient folic acid - bovine serum albumin (FA-BSA) conjugate immobilized on the surface (NAs/FA-BSA) was prepared. The results of MTT assays on FR-positive K562 cells and FR-negative A549 cells demonstrated higher cytotoxicity of HA-Ara NAs than the native drug. Especially, the IC50 values revealed that NAs/FA-BSA was 3 and 2-fold effective than non-targeted NAs after 24 and 48h treatment with K562 cells, respectively indicating FR-mediated enhanced anti-tumor efficacy. In vitro cellular uptake, larger accumulation of HA-Ara NAs were observed in comparative with the free FITC and the results further confirmed the selective uptake of NAs/FA-BSA in folate receptor enriched cancer cells. Above all, self-assembled HA-Ara NAs exhibited potential superiority for Ara-C delivery and FA-modified NAs would be an excellent candidate for targeting leukemia therapy.

  13. Synthesis and in vitro studies on a potential dopamine prodrug.

    PubMed

    Giannola, L I; De Caro, V; Giandalia, G; Siragusa, M G; Lamartina, L

    2008-10-01

    Dopamine delivery to the central nervous system (CNS) undergoes the permeability limitations of blood-brain barrier (BBB) which is a selective interface that excludes most water-soluble molecules from entering the brain. Neutral amino acids permeate the BBB by specific transport systems. Condensation of dopamine with neutral amino acids could afford potential prodrugs able to interact with the BBB endogenous transporters and easily enter the brain. The synthesis and characterization of the dopamine derivative 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (7) is described. The chemical and enzymatic stability of 7 was evaluated. The molecular weight (300 Da) and Log Papp (0.76) indicated that the physico-chemical characteristics of compound 7 are adequate to cross biological membranes. Compound 7 was enzymatically cleaved to free dopamine in rat brain homogenate (t1/2 = 460 min). In human plasma, the t1/2 of 7 was estimated comparable to that reported for L-DOPA. In view of a possible oral administration of 7, studies of its chemical behavior under conditions simulating those of the gastrointestinal tract showed that no dopamine production occurred; furthermore, 7 is able to permeate through a simulated intestinal mucosal membrane. The collected data suggest that compound 7 could beconsidered a very valuable candidate for subsequent in vivo evaluation.

  14. Click synthesis of a polyamidoamine dendrimer-based camptothecin prodrug

    PubMed Central

    Zolotarskaya, Olga Yu.; Xu, Leyuan; Valerie, Kristoffer; Yang, Hu

    2015-01-01

    In the present work we report on the click synthesis of a new camptothecin (CPT) prodrug based on anionic polyamidoamine (PAMAM) dendrimer intended for cancer therapy. We applied ‘click’ chemistry to improve polymer-drug coupling reaction efficiency. Specifically, CPT was functionalized with a spacer, 1-azido-3,6,9,12,15-pentaoxaoctadecan-18-oic acid (APO), via EDC/DMAP coupling reaction. In parallel, propargylamine (PPA) and methoxypoly(ethylene glycol) amine were conjugated to PAMAM dendrimer G4.5 in sequence using an effective coupling agent 4-(4,6-dimethoxy-(1,3,5)triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM). CPT-APO was then coupled to PEGylated PAMAM dendrimer G4.5-PPA via a click reaction using copper bromide/2,2’-bipyridine/ dimethyl sulfoxide (catalyst/ligand/solvent). Human glioma cells were exposed to the CPT-conjugate to determine toxicity and cell cycle effects using WST-1 assay and flow cytometry. The CPT-conjugate displayed a dose-dependent toxicity with an IC50 of 5 μM, a 185-fold increase relative to free CPT, presumably as a result of slow release. As expected, conjugated CPT resulted in G2/M arrest and cell death while the dendrimer itself had little to no toxicity. Altogether, highly efficient click chemistry allows for the synthesis of multifunctional dendrimers for sustained drug delivery. PMID:26640689

  15. Anticancer drug released from near IR-activated prodrug overcomes spatiotemporal limits of singlet oxygen.

    PubMed

    Rajaputra, Pallavi; Bio, Moses; Nkepang, Gregory; Thapa, Pritam; Woo, Sukyung; You, Youngjae

    2016-04-01

    Photodynamic therapy (PDT) is a cancer treatment modality where photosensitizer (PS) is activated by visible and near IR light to produce singlet oxygen ((1)O2). However, (1)O2 has a short lifetime (<40 ns) and cannot diffuse (<20 nm) beyond the cell diameter (e.g., ∼ 1800 nm). Thus, (1)O2 damage is both spatially and temporally limited and does not produce bystander effect. In a heterogeneous tumor, cells escaping (1)O2 damage can regrow after PDT treatment. To overcome these limitations, we developed a prodrug concept (PS-L-D) composed of a photosensitizer (PS), an anti-cancer drug (D), and an (1)O2-cleavable linker (L). Upon illumination of the prodrug, (1)O2 is generated, which damages the tumor and also releases anticancer drug. The locally released drug could cause spatially broader and temporally sustained damage, killing the surviving cancer cells after the PDT damage. In our previous report, we presented the superior activity of our prodrug of CA4 (combretastatin A-4), Pc-(L-CA4)2, compared to its non-cleavable analog, Pc-(NCL-CA4)2, that produced only PDT effects. Here, we provide clear evidence demonstrating that the released anticancer drug, CA4, indeed damages the surviving cancer cells over and beyond the spatial and temporal limits of (1)O2. In the limited light illumination experiment, cells in the entire well were killed due to the effect of released anti-cancer drug, whereas only a partial damage was observed in the pseudo-prodrug treated wells. A time-dependent cell survival study showed more cell death in the prodrug-treated cells due to the sustained damage by the released CA4. Cell cycle analysis and microscopic imaging data demonstrated the typical damage patterns by CA4 in the prodrug treated cells. A time-dependent histological study showed that prodrug-treated tumors lacked mitotic bodies, and the prodrug caused broader and sustained tumor size reduction compared to those seen in the tumors treated with the pseudo-prodrug. This data

  16. Computer-assisted design of pro-drugs for antimalarial atovaquone.

    PubMed

    Karaman, Rafik; Hallak, Hussein

    2010-10-01

    Density Functional Theory (DFT) and ab initio calculation results for the proton transfer reaction in Kirby's enzyme models 1-6 reveal that the reaction rate is largely dependent on the existence of a hydrogen bonding net in the reactants and the corresponding transition states. Further, the distance between the two reacting centers and the angle of the hydrogen bonding formed along the reaction path has profound effects on the rate. Hence, the study on the systems reported herein could provide a good basis for designing antimalarial (atovaquone) pro-drug systems that can be used to release the parent drug in a controlled manner. For example, based on the calculated log EM, the cleavage process for pro-drug 1Pro may be predicted to be about 10¹¹ times faster than that for a pro-drug 4Pro and about 10⁴ times faster than pro-drug 2Pro: rate (1Pro) > rate (2Pro > rate (4Pro). Thus, the rate by which the pro-drug releases the antimalarial drug can be determined according to the nature of the linker (Kirby's enzyme model 1-6).

  17. Development of an In Vitro Model to Screen CYP1B1-Targeted Anticancer Prodrugs.

    PubMed

    Wang, Zhiying; Chen, Yao; Drbohlav, Laura M; Wu, Judy Qiju; Wang, Michael Zhuo

    2016-12-01

    Cytochrome P450 1B1 (CYP1B1) is an anticancer therapeutic target due to its overexpression in a number of steroid hormone-related cancers. One anticancer drug discovery strategy is to develop prodrugs specifically activated by CYP1B1 in malignant tissues to cytotoxic metabolites. Here, we aimed to develop an in vitro screening model for CYP1B1-targeted anticancer prodrugs using the KLE human endometrial carcinoma cell line. KLE cells demonstrated superior stability of CYP1B1 expression relative to transiently transfected cells and did not express any appreciable amount of cognate CYP1A1 or CYP1A2, which would have compromised the specificity of the screening assay. The effect of two CYP1B1-targeted probe prodrugs on KLE cells was evaluated in the absence and presence of a CYP1B1 inhibitor to chemically "knock out" CYP1B1 activity (CYP1B1 inhibited). Both probe prodrugs were more toxic to KLE cells than to CYP1B1-inhibited KLE cells and significantly induced G0/G1 arrest and decreased the S phase in KLE cells. They also exhibited pro-apoptotic effects in KLE cells, which were attenuated in CYP1B1-inhibited KLE cells. In summary, a KLE cell-based model has been characterized to be suitable for identifying CYP1B1-targeted anticancer prodrugs and should be further developed and employed for screening chemical libraries.

  18. Design, Synthesis, and In Vitro Kinetics Study of Atenolol Prodrugs for the Use in Aqueous Formulations

    PubMed Central

    Qtait, Alaa; Dajani, Khulod Khayyat; Abu Lafi, Saleh

    2014-01-01

    Based on DFT, MP2, and the density functional from Truhlar group (hybrid GGA: MPW1k) calculations for an acid-catalyzed hydrolysis of nine Kirby's N-alkylmaleamic acids and two atenolol prodrugs were designed. The calculations demonstrated that the amide bond cleavage is due to intramolecular nucleophilic catalysis by the adjacent carboxylic acid group and the rate-limiting step is determined based on the nature of the amine leaving group. In addition, a linear correlation of the calculated and experimental rate values has drawn credible basis for designing atenolol prodrugs that are bitterless, are stable in neutral aqueous solutions, and have the potential to release the parent drug in a sustained release manner. For example, based on the calculated B3LYP/6-31 G (d,p) rates, the predicted t1/2 (a time needed for 50% of the prodrug to be converted into drug) values for atenolol prodrugs ProD 1-ProD 2 at pH 2 were 65.3 hours (6.3 hours as calculated by GGA: MPW1K) and 11.8 minutes, respectively. In vitro kinetic study of atenolol prodrug ProD 1 demonstrated that the t1/2 was largely affected by the pH of the medium. The determined t1/2 values in 1N HCl, buffer pH 2, and buffer pH 5 were 2.53, 3.82, and 133 hours, respectively. PMID:24526887

  19. Amorphous Solid Dispersions or Prodrugs: Complementary Strategies to Increase Drug Absorption.

    PubMed

    Rumondor, Alfred C F; Dhareshwar, Sundeep S; Kesisoglou, Filippos

    2016-09-01

    Maximizing oral bioavailability of drug candidates represents a challenge in the pharmaceutical industry. In recent years, there has been an increase in the use of amorphous solid dispersions (ASDs) to address this issue, where a growing number of solid dispersion formulations have been introduced to the market. However, an increase in solubility or dissolution rate through ASD does not always result in sufficient improvement of oral absorption because solubility limitations may still exist at high doses. Chemical modification in the form of a prodrug may offer an alternative approach for these cases. Although prodrugs have been primarily used to improve membrane permeability, examples are available in which prodrugs have been used to increase drug solubility beyond what can be achieved via formulation approaches. In this mini review, the role of ASDs and prodrugs as 2 complementary approaches in improving oral bioavailability of drug candidates is discussed. We discuss the fundamental principles of absorption and bioavailability, and review available literature on both solid dispersions and prodrugs, providing a summary of their use and examples of successful applications, and cover some of the biopharmaceutics evaluation aspects for these approaches.

  20. Somatostatin receptor-mediated specific delivery of paclitaxel prodrugs for efficient cancer therapy.

    PubMed

    Huo, Meirong; Zhu, Qinnv; Wu, Qu; Yin, Tingjie; Wang, Lei; Yin, Lifang; Zhou, Jianping

    2015-06-01

    In this study, a novel PTX prodrug, octreotide(Phe)-polyethene glycol-paclitaxel [OCT(Phe)-PEG-PTX], was successfully synthesized and used for targeted cancer therapy. A nontargeting conjugate, mPEG-PTX, was also synthesized and used as a control. Chemical structures of OCT(Phe)-PEG-PTX and mPEG-PTX were confirmed using (1) H nuclear magnetic resonance and circular dichroism. The drug contents in both the conjugates were 12.0% and 14.0%, respectively. Compared with the parent drug (PTX), OCT(Phe)-PEG-PTX, and mPEG-PTX prodrugs showed a 20,000- and 30,000-fold increase in water solubility, respectively. PTX release from mPEG-PTX and OCT(Phe)-PEG-PTX exhibited a pH-dependent profile. Moreover, compared with mPEG-PTX, OCT(Phe)-PEG-PTX exhibited significantly stronger cytotoxicity against NCI-H446 cells (SSTR overexpression) but comparable cytotoxicity against WI-38 cells (no SSTR expression). Results of confocal laser scanning microscopy revealed that the targeting prodrug labeled with fluorescence probe was selectively taken into tumor cells via SSTR-mediated endocytosis. In vivo investigation of prodrugs in nude mice bearing NCI-H446 cancer xenografts confirmed that OCT(Phe)-PEG-PTX prodrug exhibited stronger antitumor efficacy and lower systemic toxicity than mPEG-PTX and commercial Taxol. These results suggested that OCT(Phe)-PEG-PTX is a promising anticancer drug delivery system for targeted cancer therapy.

  1. Zanamivir Amidoxime- and N-Hydroxyguanidine-Based Prodrug Approaches to Tackle Poor Oral Bioavailability.

    PubMed

    Schade, Dennis; Kotthaus, Jürke; Riebling, Lukas; Kotthaus, Joscha; Müller-Fielitz, Helge; Raasch, Walter; Hoffmann, Anja; Schmidtke, Michaela; Clement, Bernd

    2015-09-01

    The neuraminidase (NA) inhibitor zanamivir (1) is potently active against a broad panel of influenza A and B strains, including mutant viruses, but suffers from pharmacokinetic (PK) shortcomings. Here, distinct prodrug approaches are described that aimed at overcoming zanamivir's lack of oral bioavailability. Lowering the high basicity of the 4-guanidino group in zanamivir and of a bioisosteric 4-acetamidine analog (5) by N-hydroxylation was deemed to be a plausible tactic. The carboxylic acid and glycerol side chain were also masked with different ester groups. The bioisosteric amidine 5 turned out to be potently active against a panel of H1N1 (IC50 = 2-10 nM) and H3N2 (IC50 = 5-10 nM) influenza A viruses (NA inhibition assay). In vitro PK studies showed that all prodrugs were highly soluble, exhibited low protein binding, and were bioactivated by N-reduction to the respective guanidines and amidines. The most promising prodrug candidates, amidoxime ester 7 and N-hydroxyguanidine ester 8, were subjected to in vivo bioavailability studies. Unfortunately, both prodrugs were not orally bioavailable to a convincing degree (F ≤ 3.7%, rats). This finding questions the general feasibility of improving the oral bioavailability of 1 by lipophilicity-increasing prodrug strategies, and suggests that intrinsic structural features represent key hurdles.

  2. Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of β-Diketo Acids.

    PubMed

    Nair, Vasu; Okello, Maurice

    2015-07-13

    HIV integrase, encoded at the 3'-end of the HIV pol gene, is essential for HIV replication. This enzyme catalyzes the incorporation of HIV DNA into human DNA, which represents the point of "no-return" in HIV infection. Integrase is a significant target in anti-HIV drug discovery. This review article focuses largely on the design of integrase inhibitors that are β-diketo acids constructed on pyridinone scaffolds. Methodologies for synthesis of these compounds are discussed. Integrase inhibition data for the strand transfer (ST) step are compared with in vitro anti-HIV data. The review also examines the issue of the lack of correlation between the ST enzymology data and anti-HIV assay results. Because this disconnect appeared to be a problem associated with permeability, prodrugs of these inhibitors were designed and synthesized. Prodrugs dramatically improved the anti-HIV activity data. For example, for compound, 96, the anti-HIV activity (EC50) improved from 500 nM for this diketo acid to 9 nM for its prodrug 116. In addition, there was excellent correlation between the IC50 and IC90 ST enzymology data for 96 (6 nM and 97 nM, respectively) and the EC50 and EC90 anti-HIV data for its prodrug 116 (9 nM and 94 nM, respectively). Finally, it was confirmed that the prodrug 116 was rapidly hydrolyzed in cells to the active compound 96.

  3. Interaction of lipophilic gemcitabine prodrugs with biomembrane models studied by Langmuir-Blodgett technique.

    PubMed

    Castelli, Francesco; Sarpietro, Maria Grazia; Rocco, Flavio; Ceruti, Maurizio; Cattel, Luigi

    2007-09-01

    The stability and bioavailability of anticancer agents, such as gemcitabine, can be increased by forming prodrugs. Gemcitabine is rapidly deaminated to the inactive metabolite (2('),2(')-difluorodeoxyuridine), thus to improve its stability a series of increasingly lipophilic gemcitabine prodrugs linked through the 4-amino group to valeroyl, lauroyl, and stearoyl acyl chains were synthesized. Studies of monolayer properties are important to improve understanding of biological phenomena involving lipid/gemcitabine or lipid/gemcitabine derivative interactions. The interfacial behavior of monolayers constituted by DMPC plus gemcitabine or lipophilic gemcitabine prodrugs at increasing molar fractions was studied at the air/water interface at temperatures below (10 degrees C) and above (37 degrees C) the lipid phase transition. The effect of the hydrophobic chain length of gemcitabine derivatives on the isotherm of pure DMPC was investigated by surface tension measurement, and the results are reported as molar fractions as a function of mean molecular area per molecule. The results show that the compounds interact with DMPC producing mixed monolayers that are subject to an expansion effect, depending on the prodrug chain length. The results give useful hints of the interaction of these prodrugs with biological membranes and increase knowledge on the incorporation site of such compounds, as a function of their lipophilicity, in a lipid carrier; they may lead to improved liposomal formulation design.

  4. Mechanism of brain targeting by dexibuprofen prodrugs modified with ethanolamine-related structures

    PubMed Central

    Li, Yanping; Zhou, Yangyang; Jiang, Jiayu; Wang, Xinyi; Fu, Yao; Gong, Tao; Sun, Xun; Zhang, Zhirong

    2015-01-01

    The first molecular insights into how prodrugs modified with ethanolamine-related structures target the brain were generated using an in vitro BBB model and in situ perfusion technique. Prodrugs were delivered safely and efficiently to the brain through tight interaction with the anionic membrane of brain capillary endothelial cells, observed as a shift in zeta potential, followed by uptake into the cells. Prodrugs III and IV carrying primary and secondary amine modifications appeared to enter the brain via energy-independent passive diffusion. In contrast, besides the passive diffusion, prodrugs I and II carrying tertiary amine modifications also appeared to enter via an active process that was energy and pH dependent but was independent of sodium or membrane potential. This active process involved, at least in part, the pyrilamine-sensitive H+/OC antiporter, for which the N,N-diethyl-based compound II showed a much lower affinity than the N,N-dimethyl-based compound I, likely due to steric hindrance. These new insights into brain-targeting mechanisms may help guide efforts to design new prodrugs. PMID:26154870

  5. Synthesis of a highly water-soluble acacetin prodrug for treating experimental atrial fibrillation in beagle dogs.

    PubMed

    Liu, Hui; Wang, Ya-Jing; Yang, Lei; Zhou, Mei; Jin, Man-Wen; Xiao, Guo-Sheng; Wang, Yan; Sun, Hai-Ying; Li, Gui-Rong

    2016-05-10

    We previously reported that duodenal administration of the natural flavone acacetin can effectively prevent the induction of experimental atrial fibrillation (AF) in canines; however, it may not be used intravenously to terminate AF due to its poor water-solubility. The present study was to design a water-soluble prodrug of acacetin and investigate its anti-AF effect in beagle dogs. Acacetin prodrug was synthesized by a three-step procedure. Aqueous solubility, bioconversion and anti-AF efficacy of acacetin prodrug were determined with different methodologies. Our results demonstrated that the synthesized phosphate sodium salt of acacetin prodrug had a remarkable increase of aqueous solubility in H2O and clinically acceptable solution (5% glucose or 0.9% NaCl). The acacetin prodrug was effectively converted into acacetin in ex vivo rat plasma and liver microsome, and in vivo beagle dogs. Intravenous infusion of acacetin prodrug (3, 6 and 12 mg/kg) terminated experimental AF without increasing ECG QTc interval in beagle dogs. The intravenous LD50 of acacetin prodrug was 721 mg/kg in mice. Our preclinical study indicates that the synthesized acacetin prodrug is highly water-soluble and safe; it effectively terminates experimental AF in beagle dogs and therefore may be a promising drug candidate for clinical trial to treat patients with acute AF.

  6. Synthesis and evaluation of water-soluble prodrugs of ursodeoxycholic acid (UDCA), an anti-apoptotic bile acid.

    PubMed

    Dosa, Peter I; Ward, Tim; Castro, Rui E; Rodrigues, Cecília M P; Steer, Clifford J

    2013-06-01

    Ursodeoxycholic acid (UDCA) is a bile acid with demonstrated anti-apoptotic activity in both in vitro and in vivo models. However, its utility is hampered by limited aqueous solubility. As such, water-soluble prodrugs of UDCA could have an advantage over the parent bile acid in indications where intravenous administration might be preferable, such as decreasing damage from stroke or acute kidney injury. Five phosphate prodrugs were synthesized, including one incorporating a novel phosphoryloxymethyl carboxylate (POMC) moiety. These prodrugs were highly water-soluble, but showed significant differences in chemical stability, with oxymethylphosphate prodrugs being the most unstable. In a series of NMR experiments, the POMC prodrug was bioactivated to UDCA by alkaline phosphatase (AP) faster than a prodrug containing a phosphate directly attached to the alcohol at the 3-position of UDCA. Both of these prodrugs showed significant anti-apoptotic activity in a series of in vitro assays, although the POMC prodrug required the addition of AP for activity, while the other compound was active without exogenous AP.

  7. Development of Platinum(iv) Complexes as Anticancer Prodrugs: the Story so Far

    NASA Astrophysics Data System (ADS)

    Wong, Daniel Yuan Qiang; Ang, Wee Han

    2012-06-01

    The serendipitous discovery of the antitumor properties of cisplatin by Barnett Rosenberg some forty years ago brought about a paradigm shift in the field of medicinal chemistry and challenged conventional thinking regarding the role of potentially toxic heavy metals in drugs. Platinum(II)-based anticancer drugs have since become some of the most effective and widely-used drugs in a clinician's arsenal and have saved countless lives. However, they are limited by high toxicity, severe side-effects and the incidence of drug resistance. In recent years, attention has shifted to stable platinum(IV) complexes as anticancer prodrugs. By exploiting the unique chemical and structural attributes of their scaffolds, these platinum(IV) prodrugs offer new strategies of targeting and killing cancer cells. This review summarizes the development of anticancer platinum(IV) prodrugs to date and some of the exciting strategies that utilise the platinum(IV) construct as targeted chemotherapeutic agents against cancer.

  8. Riluzole prodrugs for melanoma and ALS: design, synthesis, and in vitro metabolic profiling

    PubMed Central

    McDonnell, Mark E.; Vera, Matthew D.; Blass, Benjamin E.; Pelletier, Jeffrey C.; King, Richard C.; Fernandez-Metzler, Carmen; Smith, Garry R.; Wrobel, Jay; Chen, Suzie; Reitz, Allen B.

    2012-01-01

    Riluzole (1) is an approved therapeutic for the treatment of ALS and has also demonstrated antimelanoma activity in metabotropic glutamate GRM1 positive cell lines, a mouse xenograft assay and human clinical trials. Highly variable drug exposure following oral administration among patients, likely due to variable first pass effects from heterogeneous CYP1A2 expression, hinders its clinical use. In an effort to mitigate effects of this clearance pathway and uniformly administer riluzole at efficacious exposure levels, several classes of prodrugs of riluzole were designed, synthesized, and evaluated in multiple in vitro stability assays to predict in vivo drug levels. The optimal prodrug would possess the following profile: stability while transiting the digestive system, stability towards first pass metabolism, and metabolic lability in the plasma releasing riluzole. (S)-O-Benzyl serine derivative 9 was identified as the most promising therapeutically acceptable prodrug. PMID:22892214

  9. A core cross-linked polymeric micellar platium(IV) prodrug with enhanced anticancer efficiency.

    PubMed

    Hou, Jie; Shang, Jincai; Jiao, Chengbin; Jiang, Peiyue; Xiao, Huijie; Luo, Lan; Liu, Tongjun

    2013-07-01

    A core cross-linked polymeric micellar cisplatin(IV) conjugate prodrug is prepared by attaching the cisplatin(IV) to mPEG-b-PLL biodegradable copolymers to form micellar nanoparticles that can disintegrate to release the active anticancer agent cisplatin(II) in a mild reducing environment. Moreover, in vitro studies show that this cisplatin(IV) conjugate prodrug displays enhanced cytotoxicity against HepG2 cancer cells compared with cisplatin(II). Further studies demonstrate that the high cellular uptake and platinum-DNA adduct of this cisplatin(IV) conjugate prodrug can induce more cancer-cell apoptosis than cisplatin(II), which is responsible for its enhanced anticancer activity.

  10. Synthesis and Characterization of a New Peptide Prodrug of Glucosamine with Enhanced Gut Permeability

    PubMed Central

    Gilzad Kohan, Hamed; Kaur, Kamaljit; Jamali, Fakhreddin

    2015-01-01

    The aim of this study was to synthesize a peptide prodrug of glucosamine (GlcN) with increased gut permeability through the gut peptide transporter 1 (PepT1). Glycine-Valine ester derivative of GlcN (GVG) was synthesised using solid phase synthesis followed by characterization and evaluation of its physicochemical and intestinal stability. In addition, GVG was evaluated for its ability to be biotransformed to GlcN in the liver homogenate. In vitro absorption of the new prodrug through everted rat gut was also assessed. GVG demonstrated significant and meaningful increased gut permeability as compared with GlcN. It showed favorable stability in the gut and a quick cleavage to GlcN after exposure to the liver homogenate. In conclusion, a novel prodrug of glucosamine with superior gut permeability compared to GlcN was developed and successfully tested in vitro. PMID:25978315

  11. Novel multifunctional acyloxyalkyl ester prodrugs of 5-aminolevulinic acid display improved anticancer activity dependent on photoactivation

    NASA Astrophysics Data System (ADS)

    Berkovitch, G.; Nudelman, A.; Ehenberg, B.; Rephaeli, A.; Malik, Z.

    2009-06-01

    New approaches to PDT using multifunctional 5-aminolevulinic acid (ALA) based prodrugs activating mutual routes of toxicity are described. We investigated the mutual anti-cancer activity of ALA prodrugs which upon metabolic hydrolysis by unspecific esterases release ALA, formaldehyde or acetaldehye and the histone deacetylase inhibitor (HDACI) butyric acid. The most potent prodrug in this study was butyryloxyethyl 5-amino-4-oxopentanoate (AN-233) that stimulated a rapid biosynthesis of protoporphyrin IX (PpIX) in human glioblastoma U-251 cells and generated an efficient photodynamic destruction. AN-233 induced a considerable high level of intracellular ROS in the cells following light irradiation, reduction of mitochondrial activity, dissipation of the mitochondrial membrane potential resulting in necrotic and apoptotic cell death. The main advantage of AN-233 over ALA stems from its ability to induce photodamage at a significantly lower dose than ALA.

  12. Glutathione- and pH-responsive nonporous silica prodrug nanoparticles for controlled release and cancer therapy

    NASA Astrophysics Data System (ADS)

    Xu, Zhigang; Liu, Shiying; Kang, Yuejun; Wang, Mingfeng

    2015-03-01

    A myriad of drug delivery systems such as liposomes, micelles, polymers and inorganic nanoparticles (NPs) have been developed for cancer therapy. Very few of them, however, have the ability to integrate multiple functionalities such as specific delivery, high circulation stability, controllable release and good biocompatibility and biodegradability in a single system to improve the therapeutic efficacy. Herein, we report two types of stimuli-responsive nonporous silica prodrug NPs towards this goal for controlled release of anticancer drugs and efficient combinatorial cancer therapy. As a proof of concept, anticancer drugs camptothecin (CPT) and doxorubicin (DOX) were covalently encapsulated into silica matrices through glutathione (GSH)-responsive disulfide and pH-responsive hydrazone bonds, respectively, resulting in NPs with sizes tunable in the range of 50-200 nm. Both silica prodrug NPs showed stimuli-responsive controlled release upon exposure to a GSH-rich or acidic environment, resulting in improved anticancer efficacy. Notably, two prodrug NPs simultaneously taken up by HeLa cells showed a remarkable combinatorial efficacy compared to free drug pairs. These results suggest that the stimuli-responsive silica prodrug NPs are promising anticancer drug carriers for efficient cancer therapy.A myriad of drug delivery systems such as liposomes, micelles, polymers and inorganic nanoparticles (NPs) have been developed for cancer therapy. Very few of them, however, have the ability to integrate multiple functionalities such as specific delivery, high circulation stability, controllable release and good biocompatibility and biodegradability in a single system to improve the therapeutic efficacy. Herein, we report two types of stimuli-responsive nonporous silica prodrug NPs towards this goal for controlled release of anticancer drugs and efficient combinatorial cancer therapy. As a proof of concept, anticancer drugs camptothecin (CPT) and doxorubicin (DOX) were

  13. Drug-Initiated Synthesis of Polymer Prodrugs: Combining Simplicity and Efficacy in Drug Delivery†

    PubMed Central

    2016-01-01

    In the field of nanomedicine, the global trend over the past few years has been toward the design of highly sophisticated drug delivery systems with active targeting and/or imaging capabilities, as well as responsiveness to various stimuli to increase their therapeutic efficacy. However, providing sophistication generally increases complexity that could be detrimental in regards to potential pharmaceutical development. An emerging concept to design efficient yet simple drug delivery systems, termed the “drug-initiated” method, consists of growing short polymer chains from drugs in a controlled fashion to yield well-defined drug–polymer prodrugs. These materials are obtained in a reduced amount of synthetic steps and can be self-assembled into polymer prodrug nanoparticles, be incorporated into lipid nanocarriers or be used as water-soluble polymer prodrugs. This Perspective article will capture the recent achievements from the “drug-initiated” method and highlight the great biomedical potential of these materials. PMID:27041820

  14. Suppression of peak tailing of phosphate prodrugs in reversed-phase liquid chromatography.

    PubMed

    Zhang, Jin; Wang, Qinggang; Kleintop, Brent; Raglione, Thomas

    2014-09-01

    Peak tailing of phosphate prodrugs in acidic mobile phases was thoroughly investigated. The results indicated that both metal-phosphate interactions and silanophilic interactions contributed to the observed peak tailing. Column pretreatment with phosphate buffers was demonstrated to be an effective and robust approach in suppressing metal-phosphate interaction. Silanophilic interactions, such as hydrogen bonding interactions between protonated isolated silanol groups and partially deprotonated phosphate groups were mobile phase pH dependent. The combination of column pretreatment and volatile low pH mobile phase buffers can be used to mitigate peak tailing issues in developing MS compatible RPLC methods for phosphate prodrugs. The use of non-endcapped columns should be avoided in RPLC analysis for phosphate prodrugs due to large amount of residual silanol groups in the stationary phases.

  15. Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties

    PubMed Central

    2014-01-01

    Largazole is a potent and class I-selective histone deacetylase (HDAC) inhibitor purified from marine cyanobacteria and was demonstrated to possess antitumor activity. Largazole employs a unique prodrug strategy, via a thioester moiety, to liberate the bioactive species largazole thiol. Here we report alternate prodrug strategies to modulate the pharmacokinetic and pharmacodynamics profiles of new largazole-based compounds. The in vitro effects of largazole analogues on cancer cell proliferation and enzymatic activities of purified HDACs were comparable to the natural product. However, in vitro and in vivo histone hyperacetylation in HCT116 cells and implanted tumors, respectively, showed differences, particularly in the onset of action and oral bioavailability. These results indicate that, by employing a different approach to disguise the “warhead” moiety, the functional consequence of these prodrugs can be significantly modulated. Our data corroborate the role of the pharmacokinetic properties of this class of compounds to elicit the desired and timely functional response. PMID:25147612

  16. Synthesis of 1-O-(2'-acetoxy)benzoyl-alpha-D-2-deoxyglucopyranose, a novel aspirin prodrug.

    PubMed

    Truelove, J E; Hussain, A A; Kostenbauder, H B

    1980-02-01

    The synthesis and characterization of 1-O-(2'-acetoxy)benzoyl-alpha-D-2-deoxyglucopyranose, a novel aspirin prodrug, are described. 3,4,6-Tri-O-benzyl-alpha-D-2-deoxyglucopyranose was synthesized by methylating the anomeric hydroxyl group of 2-deoxyglucose, benzylating the 3-, 4-, and 6-hydroxy functional grups, and cleaving hydrolytically the anomeric methyl group. Reaction of the tribenzylated sugar with the acid chloride of aspirin and subsequent hydrogenolysis of the benzyl groups resulted in the prodrug, mp 128 degrees. The compound was further characterized by elemental analysis and PMR and 13C-NMR spectroscopy. In vitro, the compound cleaved to aspirin with a half-life of 7 min at 37 degrees. Prodrug cleavage was independent of pH over the pH 3--9 range.

  17. Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth

    PubMed Central

    Zhao, Yong; Tu, Mei-Juan; Yu, Yi-Feng; Wang, Wei-Peng; Chen, Qiu-Xia; Qiu, Jing-Xin; Yu, Ai-Xi; Yu, Ai-Ming

    2016-01-01

    Osteosarcoma (OS) is the most common form of primary malignant bone tumor and prevalent among children and young adults. Recently we have established a novel approach to bioengineering large quantity of microRNA-34a (miR-34a) prodrug for miRNA replacement therapy. This study is to evaluate combination treatment with miR-34a prodrug and doxorubicin, which may synergistically suppress human OS cell growth via RNA interference and DNA intercalation. Synergistic effects were indeed obvious between miR-34a prodrug and doxorubicin for the suppression of OS cell proliferation, as defined by Chou-Talalay method. The strongest antiproliferative synergism was achieved when both agents were administered simultaneously to the cells at early stage, which was associated with much greater degrees of late apoptosis, necrosis, and G2 cell cycle arrest. Alteration of OS cellular processes and invasion capacity was linked to the reduction of protein levels of miR-34a targeted (proto-)oncogenes including SIRT1, c-MET, and CDK6. Moreover, orthotopic OS xenograft tumor growth was repressed to a significantly greater degree in mouse models when miR-34a prodrug and doxorubicin were co-administered intravenously. In addition, multiple doses of miR-34a prodrug and doxorubicin had no or minimal effects on mouse blood chemistry profiles. The results demonstrate that combination of doxorubicin chemotherapy and miR-34a replacement therapy produces synergistic antiproliferative effects and it is more effective than monotherapy in suppressing OS xenograft tumor growth. These findings support the development of mechanism-based combination therapy to combat OS and bioengineered miR-34a prodrug represents a new natural miRNA agent. PMID:26518752

  18. Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth.

    PubMed

    Zhao, Yong; Tu, Mei-Juan; Yu, Yi-Feng; Wang, Wei-Peng; Chen, Qiu-Xia; Qiu, Jing-Xin; Yu, Ai-Xi; Yu, Ai-Ming

    2015-12-15

    Osteosarcoma (OS) is the most common form of primary malignant bone tumor and prevalent among children and young adults. Recently we have established a novel approach to bioengineering large quantity of microRNA-34a (miR-34a) prodrug for miRNA replacement therapy. This study is to evaluate combination treatment with miR-34a prodrug and doxorubicin, which may synergistically suppress human OS cell growth via RNA interference and DNA intercalation. Synergistic effects were indeed obvious between miR-34a prodrug and doxorubicin for the suppression of OS cell proliferation, as defined by Chou-Talalay method. The strongest antiproliferative synergism was achieved when both agents were administered simultaneously to the cells at early stage, which was associated with much greater degrees of late apoptosis, necrosis, and G2 cell cycle arrest. Alteration of OS cellular processes and invasion capacity was linked to the reduction of protein levels of miR-34a targeted (proto-)oncogenes including SIRT1, c-MET, and CDK6. Moreover, orthotopic OS xenograft tumor growth was repressed to a significantly greater degree in mouse models when miR-34a prodrug and doxorubicin were co-administered intravenously. In addition, multiple doses of miR-34a prodrug and doxorubicin had no or minimal effects on mouse blood chemistry profiles. The results demonstrate that combination of doxorubicin chemotherapy and miR-34a replacement therapy produces synergistic antiproliferative effects and it is more effective than monotherapy in suppressing OS xenograft tumor growth. These findings support the development of mechanism-based combination therapy to combat OS and bioengineered miR-34a prodrug represents a new natural miRNA agent.

  19. Hydrophilic prodrug approach for reduced pigment binding and enhanced transscleral retinal delivery of celecoxib.

    PubMed

    Malik, Pradip; Kadam, Rajendra S; Cheruvu, Narayan P S; Kompella, Uday B

    2012-03-05

    Transscleral retinal delivery of celecoxib, an anti-inflammatory and anti-VEGF agent, is restricted by its poor solubility and binding to the melanin pigment in choroid-RPE. The purpose of this study was to develop soluble prodrugs of celecoxib with reduced pigment binding and enhanced retinal delivery. Three hydrophilic amide prodrugs of celecoxib, celecoxib succinamidic acid (CSA), celecoxib maleamidic acid (CMA), and celecoxib acetamide (CAA) were synthesized and characterized for solubility and lipophilicity. In vitro melanin binding to natural melanin (Sepia officinalis) was estimated for all three prodrugs. In vitro transport studies across isolated bovine sclera and sclera-choroid-RPE (SCRPE) were performed. Prodrug with the highest permeability across SCRPE was characterized for metabolism and cytotoxicity and its in vivo transscleral delivery in pigmented rats. Aqueous solubilities of CSA, CMA, and CAA were 300-, 182-, and 76-fold higher, respectively, than celecoxib. Melanin binding affinity and capacity were significantly lower than for celecoxib for all three prodrugs. Rank order for the % in vitro transport across bovine sclera and SCRPE was CSA > CMA ~ CAA ~ celecoxib, with the transport being 8-fold higher for CSA than celecoxib. CSA was further assessed for its metabolic stability and in vivo delivery. CSA showed optimum metabolic stability in all eye tissues with only 10-20% conversion to parent celecoxib in 30 min. Metabolic enzymes responsible for bioconversion included amidases, esterase, and cytochrome P-450. In vivo delivery in pigmented BN rats showed that CSA had 4.7-, 1.4-, 3.3-, 6.0-, and 4.5-fold higher delivery to sclera, choroid-RPE, retina, vitreous, and lens than celecoxib. CSA has no cytotoxicity in ARPE-19 cells in the concentration range of 0.1 to 1000 μM. Celecoxib succinamidic acid, a soluble prodrug of celecoxib with reduced melanin binding, enhances transscleral retinal delivery of celecoxib.

  20. Lipophilic Prodrugs of SN38: Synthesis and in Vitro Characterization toward Oral Chemotherapy.

    PubMed

    Bala, Vaskor; Rao, Shasha; Li, Peng; Wang, Shudong; Prestidge, Clive A

    2016-01-04

    SN38 (7-ethyl-10-hydroxy camptothecin) is a potent anticancer agent belonging to the camptothecin family; however, its oral delivery is extensively restricted by poor solubility in pharmaceutically acceptable excipients and low transmucosal permeability. Lipid-based carriers are well-known for their ability to improve oral absorption and bioavailability of lipid soluble and highly permeable compounds. Thus, this study has focused on improving solubility in lipid excipients, controlling stability, and enhancing transmucosal permeability of SN38 by specific chemical modification. To achieve these aims, a series of lipophilic prodrugs were designed and synthesized by esterification at the C10 and/or C20 positon(s) of SN38 with dietary fatty acids of diverse hydrocarbon chain lengths. The solubility of these novel prodrugs in long-chain triglycerides was increased up to 444-fold, and cytotoxicity was significantly reduced in comparison to SN38. The prodrugs were stable in simulated gastric fluids but exhibited different rates of hydrolysis (t1/2 < 5 min to t1/2 > 2 h) in simulated intestinal fluids (in the presence of enzymes) depending on the alkyl chain length and the position modified. A predictable reconversion of prodrugs to SN38 in plasma was also confirmed. On the basis of these studies, SN38-undecanoate (C20) was identified as the optimal prodrug. Finally, in vitro permeability and uptake studies in rat intestinal mucosal membrane using an Ussing chamber showed significant improvement in transepithelial drug transport and cellular uptake. Together, these results indicate that well designed lipophilic prodrugs have potential for the efficacious and safe oral delivery of SN38.

  1. Delivery of a Protease-Activated Cytolytic Peptide Prodrug by Perfluorocarbon Nanoparticles.

    PubMed

    Jallouk, Andrew P; Palekar, Rohun U; Marsh, Jon N; Pan, Hua; Pham, Christine T N; Schlesinger, Paul H; Wickline, Samuel A

    2015-08-19

    Melittin is a cytolytic peptide derived from bee venom that inserts into lipid membranes and oligomerizes to form membrane pores. Although this peptide is an attractive candidate for treatment of cancers and infectious processes, its nonspecific cytotoxicity and hemolytic activity have limited its therapeutic applications. Several groups have reported the development of cytolytic peptide prodrugs that only exhibit cytotoxicity following activation by site-specific proteases. However, systemic administration of these constructs has proven difficult because of their poor pharmacokinetic properties. Here, we present a platform for the design of protease-activated melittin derivatives that may be used in conjunction with a perfluorocarbon nanoparticle delivery system. Although native melittin was substantially hemolytic (HD50: 1.9 μM) and cytotoxic (IC50: 2.4 μM), the prodrug exhibited 2 orders of magnitude less hemolytic activity (HD50: > 100 μM) and cytotoxicity (IC50: > 100 μM). Incubation with matrix metalloproteinase-9 (MMP-9) led to cleavage of the prodrug at the expected site and restoration of hemolytic activity (HD50: 3.4 μM) and cytotoxicity (IC50: 8.1 μM). Incubation of the prodrug with perfluorocarbon nanoparticles led to stable loading of 10,250 peptides per nanoparticle. Nanoparticle-bound prodrug was also cleaved and activated by MMP-9, albeit at a fourfold slower rate. Intravenous administration of prodrug-loaded nanoparticles in a mouse model of melanoma significantly decreased tumor growth rate (p = 0.01). Because MMPs and other proteases play a key role in cancer invasion and metastasis, this platform holds promise for the development of personalized cancer therapies directed toward a patient's individual protease expression profile.

  2. An overview of prodrug technology and its application for developing abuse-deterrent opioids.

    PubMed

    Gudin, Jeffrey A; Nalamachu, Srinivas R

    2016-01-01

    The Centers for Disease Control and Prevention has classified prescription drug abuse and overdose deaths as an epidemic. Prescription drug overdose is now the leading cause of injury death, with rates that have more than doubled since 1999. This crisis has developed concurrently with the increased prescribing and availability analgesic drugs, especially opioids, resulting from an effort on the part of clinicians to address a critical need for improved pain assessment and treatment. Clinicians have recognized that oftentimes, opioid analgesics are one of the few remaining options for patients who suffer with severe pain. A 2015 fact sheet issued by the Office of National Drug Policy stated: "While we must ensure better access to prescription medications to alleviate suffering, it is also vital that we do all we can to reduce the diversion and abuse of pharmaceuticals." The US Food and Drug Administration has issued guidance that encourages the research and development of abuse-deterrent formulation of opioids which have the potential to curtail abuse. Included among the recommended formulations for development of abuse-deterrent opioids are prodrugs. Prodrugs are chemically modified versions of pharmacological agents that must undergo a biochemical conversion following administration, often by enzymatic cleavage, to free the active drug. Prodrugs may be inherently abuse-deterrent because they are inactive or significantly less active until conversion to the active drug. This requirement for conversion in the GI tract can modify the pharmacokinetic profile and eliminate or reduce the euphoria when abusers change the route of administration. Abusers often attempt to extract the active drug for injection or insufflation. Prodrugs can be designed to be resistant to crushing or dissolving. In this article, we review the concept of prodrugs and introduce and examine the potential of abuse-deterrent opioid prodrugs.

  3. Acetal-linked polymeric prodrug micelles for enhanced curcumin delivery.

    PubMed

    Li, Man; Gao, Min; Fu, Yunlan; Chen, Chao; Meng, Xuan; Fan, Aiping; Kong, Deling; Wang, Zheng; Zhao, Yanjun

    2016-04-01

    On-demand curcumin delivery via stimuli-responsive micellar nanocarriers holds promise for addressing its solubility and stability problem. Polymer-curcumin prodrug conjugate micelle is one of such nanosystems. The diversity of linker and conjugation chemistry enabled the generation and optimization of different curcumin micelles with tunable stimuli-responsiveness and delivery efficiency. The aim of the current work was to generate and assess acetal-linked polymeric micelles to enrich the pH-responsive curcumin delivery platforms. Curcumin was slightly modified prior to conjugating to amphiphilic methoxy poly(ethylene glycol)-poly(lactic acid) (mPEG-PLA) copolymer via an acetal bond, whereas an ester bond-linked conjugate was used as the control. The acetal-containing micelles showed a hydrodynamic diameter of 91.1 ± 2.9(nm) and the accompanying core size of 63.5 ± 7.1 (nm) with a zeta potential of -10.9 ± 0.7(mV). Both control and pH-labile micelles displayed similar critical micelle concentration at 1.6 μM. The acetal-containing nanocarriers exhibited a pH-dependent drug release behavior, which was faster at lower pH values. The cytotoxicity study in HepG2 cells revealed a significantly lower IC50 at 51.7 ± 9.0(μM) for acetal-linked micelles in contrast to the control at 103.0 ± 17.8(μM), but the polymer residue showed no cytotoxicity upon drug release. The acetal-linked micellar nanocarrier could be a useful addition to the spectrum of currently available stimuli-responsive curcumin nano-formulations.

  4. Medicinal chemistry of antiviral/anticancer prodrugs subjected to phosphate conjugation.

    PubMed

    Kalász, H; Adem, A; Hasan, M Y; Adeghate, E; Ram, N; Gulyás, Zs; Tekes, K

    2010-08-01

    Certain xenobiotics are given in the "prodrug" form. Either the human body, or one compartment of the body, or the targeted virus itself metabolizes the prodrug into its active form. The bioprecursor form of drugs is used for a wide variety of reasons, namely: to make drug penetration into the target organ (mainly to the brain through the blood-brain-barrier) possible, eliminate unpleasant taste, alter (either increasing or decreasing) the half life of the active component or supply more than one active components to the body.

  5. Chemotherapy pro-drug activation by biocatalytic virus-like nanoparticles containing cytochrome P450.

    PubMed

    Sánchez-Sánchez, Lorena; Cadena-Nava, Rubén D; Palomares, Laura A; Ruiz-Garcia, Jaime; Koay, Melissa S T; Cornelissen, Jeroen J M T; Vazquez-Duhalt, Rafael

    2014-06-10

    This work shows, for the first time, the encapsulation of a highly relevant protein in the biomedical field into virus-like particles (VLPs). A bacterial CYP variant was effectively encapsulated in VLPs constituted of coat protein from cowpea chlorotic mottle virus (CCMV). The catalytic VLPs are able to transform the chemotherapeutic pro-drug, tamoxifen, and the emerging pro-drug resveratrol. The chemical nature of the products was identified, confirming similar active products than those obtained with human CYP. The enzymatic VLPs remain stable after the catalytic reaction. The potential use of these biocatalytic nanoparticles as targeted CYP carriers for the activation of chemotherapy drugs is discussed.

  6. Facile synthesis of the NNRTI microbicide MC-1220 and synthesis of its phosphoramidate prodrugs.

    PubMed

    Loksha, Yasser M; Pedersen, Erik B; La Colla, Paolo; Loddo, Roberta

    2016-01-21

    A facile and novel synthetic route to MC-1220 was achieved by condensation of 4,6-dichloro-N,N-5-trimethylpyrimidin-2-amine (1) with the sodium salt of 2,6-difluorophenylacetonitrile, followed by methylation and strong acidic hydrolysis. The prodrugs of MC-1220 were synthesized by reaction of chlorophosphoramidate derivatives (7a-e) or α-acetobromoglucose with the sodium salt of MC-1220. The stability and anti-HIV-1 activity of phosphoramidate prodrugs turned out to be comparable to those of the parent drug MC-1220.

  7. [Psychosomatic selection of living liver donors].

    PubMed

    Erim, Y; Senf, W

    2001-01-01

    In the Essen University Clinic for Psychotherapy and Psychosomatics, between January and December 2000, 54 potential liver donors and 12 kidney donors were examined. All the kidney donors were found to be suitable; 7 potential liver donors were rejected on psychosomatic grounds. Reasons for the rejection were addiction (1 donor), suspected financial dependency of the donor on the recipient (1 donor) and, in the case of one donor not related to the recipient, the apparent lack of a special emotional attachment. During the actual evaluation interview, 4 potential donors reversed their original decision. Such a psychosomatic evaluation is a great help for donors in clarifying their motives and their decision.

  8. Synthesis and Characterization of Silicate Ester Prodrugs and Poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) Block Copolymers for Formulation into Prodrug-Loaded Nanoparticles

    NASA Astrophysics Data System (ADS)

    Wohl, Adam Richard

    Fine control of the physical and chemical properties of customized materials is a field that is rapidly advancing. This is especially critical in pursuits to develop and optimize novel nanoparticle drug delivery. Specifically, I aim to apply chemistry concepts to test the hypothesis "Silicate ester prodrugs of paclitaxel, customized to have the proper hydrophobicity and hydrolytic lability, can be formulated with well-defined, biocompatible, amphiphilic block copolymers into nanoparticles that are effective drugs." Chapter 1 briefly describes the context and motivation of the scientific pursuits described in this thesis. In Chapter 2, a family of model silicate esters is synthesized, the hydrolysis rate of each compound is benchmarked, and trends are established based upon the steric bulk and leaving group ability of the silicate substituents. These trends are then applied to the synthesis of labile silicate ester prodrugs in Chapter 3. The bulk of this chapter focuses on the synthesis, hydrolysis, and cytotoxicity of prodrugs based on paclitaxel, a widely used chemotherapeutic agent. In Chapter 4, a new methodology for the synthesis of narrowly dispersed, "random" poly(lactic-co-glycolic acid) polymers by a constant infusion of the glycolide monomer is detailed. Using poly(ethylene glycol) as a macroinitiator, amphiphilic block copolymers were synthesized. Co-formulating a paclitaxel silicate and an amphiphilic block copolymer via flash nanoprecipitation led to highly prodrug-loaded, kinetically trapped nanoparticles. Studies to determine the structure, morphology, behavior, and efficacy of these nanoparticles are described in Chapter 5. Efforts to develop a general strategy for the selective end-functionalization of the polyether block of these amphiphilic block copolymers are discussed in Chapter 6. Examples of this strategy include functionalization of the polyether with an azide or a maleimide. Finally, Chapter 7 provides an outlook for future development of

  9. Effect of alginate microencapsulation on the catalytic efficiency and in vitro enzyme-prodrug therapeutic efficacy of cytosine deaminase and of recombinant E. coli expressing cytosine deaminase.

    PubMed

    Funaro, Michael G; Nemani, Krishnamurthy V; Chen, Zhihang; Bhujwalla, Zaver M; Griswold, Karl E; Gimi, Barjor

    2016-02-01

    Cytosine deaminase (CD) catalyses the enzymatic conversion of the non-toxic prodrug 5-fluorocytosine (5-FC) to the potent chemotherapeutic form, 5-fluorouracil (5-FU). Intratumoral delivery of CD localises chemotherapy dose while reducing systemic toxicity. Encapsulation in biocompatible microcapsules immunoisolates CD and protects it from degradation. We report on the effect of alginate encapsulation on the catalytic and functional activity of isolated CD and recombinant E. coli engineered to express CD (E. coli(CD)). Alginate microcapsules containing either CD or Escherichia coli(CD) were prepared using ionotropic gelation. Conversion of 5-FC to 5-FU was quantitated in unencapsulated and encapsulated CD/E. coli(CD) using spectrophotometry, with a slower rate of conversion observed following encapsulation. Both encapsulated CD/5-FC and E. coli(CD)/5-FC resulted in cell kill and reduced proliferation of 9 L rat glioma cells, which was comparable to direct 5-FU treatment. Our results show that encapsulation preserves the therapeutic potential of CD and E. coli(CD) is equally effective for enzyme-prodrug therapy.

  10. Donor cell leukemia.

    PubMed

    Ruiz-Arguelles, Alejandro

    2012-04-01

    Minimal residual disease refers to the tumour cells that are still present in a given patient after completion of a therapeutic scheme. The demonstration and quantification of residual neoplastic cells has a crucial impact in clinical decision making, for it might prompt continuation of treatment, while the absence of such cells might serve as evidence to withdraw therapy. Therefore, both sensitivity and specificity of the methods used to unravel residual neoplastic cells must be highly reliable and robust. Flow cytometry has been widely used for this purpose, and its clinical performance depends mainly on the criteria of interpretation, rather than in the technique by itself; molecular biology techniques have proved to be highly sensitive and specific but unfortunately they cannot be used in all patients or in all types of leukemia. Finally, the development of donor cell leukemia in transplanted patients, might mimic residual disease and add more confusion to an already controversial issue. These topics are discussed in this paper.

  11. Being Sherlock Holmes: the Internet as a tool for assessing live organ donors.

    PubMed

    Bramstedt, Katrina A; Katznelson, Steven

    2009-01-01

    Donor advocacy is a critical feature of live donor transplantation. Donor Advocates and Donor Advocate Teams (DAT) are now routine to the practice of live donor evaluation in the USA. Multidisciplinary in nature, DATs gather both medical and psychosocial information about potential live organ donors and then render a decision as to whether or not these individuals are suitable to participate. Because of the critical ethical and psychosocial concerns about live donation, thorough donor evaluations are essential. Additionally, the information gathered must be accurate, and this requires honest disclosure by the donor candidate. In this paper, we describe how DATs can use various forms of free, public content available on the Internet to aid live donor assessments. In this way, the DAT assumes somewhat of an investigative role; however, this is ethically justified in light of the DAT duty to protect the donor. The protective effect can also spread to the transplant program, in general, when inappropriate donors are excluded from the donation process.

  12. Testosterone 17beta-N,N-dimethylglycinate hydrochloride: A prodrug with a potential for nasal delivery of testosterone.

    PubMed

    Hussain, Anwar A; Al-Bayatti, Ansam A; Dakkuri, Adnan; Okochi, Kazuhiro; Hussain, Munir A

    2002-03-01

    The purpose of this study was to examine the potential of the nasal route for the systemic delivery of the poorly water-soluble drug testosterone (TS) using a water-soluble prodrug, TS 17beta-N,N-dimethylglycinate hydrochloride. The physicochemical properties of the prodrug, in vitro hydrolysis in human liver homogenate, and in vivo nasal and intravenous experiments were performed in rats. The aqueous solubility of the prodrug was more than 100 mg/mL, compared with 0.01 mg/mL for TS, and its log partition coefficient between 0.05 M, phosphate buffer (pH 6) and octanol was 2.4. The prodrug was found to generate TS in 33% human liver homogenate and was absorbed from the nasal cavity rapidly and quantitatively. The bioavailabilities of both the prodrug and TS after nasal administration of the prodrug were similar to that after equivalent intravenous doses. These studies in rats suggest that this water-soluble prodrug of TS may have therapeutic utility for the management of TS deficiency.

  13. Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme.

    PubMed

    Diez-Torrubia, Alberto; Cabrera, Silvia; de Castro, Sonia; García-Aparicio, Carlos; Mulder, Gwenn; De Meester, Ingrid; Camarasa, María-José; Balzarini, Jan; Velázquez, Sonsoles

    2013-01-01

    We herein report for the first time the successful use of the dipeptidyl peptidase IV (DPPIV/CD26) prodrug approach to guanine derivatives such as the antiviral acyclovir (ACV). The solution- and solid-phase synthesis of the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of acyclovir are reported. The synthesis of the demanding tetrapeptide amide prodrug of ACV 3 was first established in solution and successfully transferred onto solid support by using Ellman's dihydropyran (DHP) resin. In contrast with the valyl ester prodrug (valacyclovir, VACV), the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of ACV proved fully stable in PBS. Both prodrugs converted to VACV (for 4) or ACV (for 3) upon exposure to purified DPPIV/CD26 or human or bovine serum. Vildagliptin, a potent inhibitor of DPPIV/CD26 efficiently inhibited the DPPIV/CD26-catalysed hydrolysis reaction. Both amide and ester prodrugs of ACV showed pronounced anti-herpetic activity in cell culture and significantly improved the water solubility in comparison with the parent drug.

  14. Living donor kidney transplantation: "beauty and the beast"!

    PubMed

    Danovitch, Gabriel M

    2013-01-01

    The report by Terasaki and colleagues in 1995 that the outcomes of spousal and biologically unrelated transplants were essentially the same as for 1-haplotype matched living related transplants changed the course of clinical transplantation. This article, entitled metaphorically "Beauty and the Beast", describes the dramatic change in the practice of living donor transplantation that followed. In the ensuing two decades, biologically unrelated living donor transplantation became commonplace in the developed world and reached its apotheosis in cross-country living donor paired exchange programs that have made transplantation accessible to many whose donors were deemed "incompatible". Such exchanges can indeed be thought of as a "thing of beauty". Sadly, the same observation was abused to exploit vulnerable donors, and the "beast" in the form of transplant tourism became a feature of transplantation in the developing world. The responsibility of the transplant community to protect the welfare of living donors and their recipients and the key role of trust in the evaluation of living donors is discussed.

  15. Nasal chitosan microparticles target a zidovudine prodrug to brain HIV sanctuaries.

    PubMed

    Dalpiaz, Alessandro; Fogagnolo, Marco; Ferraro, Luca; Capuzzo, Antonio; Pavan, Barbara; Rassu, Giovanna; Salis, Andrea; Giunchedi, Paolo; Gavini, Elisabetta

    2015-11-01

    Zidovudine (AZT) is an antiretroviral drug that is a substrate of active efflux transporters (AETs) that extrude the drug from the central nervous system (CNS) and macrophages, which are considered to be sanctuaries of HIV. The conjugation of AZT to ursodeoxycholic acid is known to produce a prodrug (UDCA-AZT) that is able to elude the AET systems, indicating the potential ability of this prodrug to act as a carrier of AZT in the CNS and in macrophages. Here, we demonstrate that UDCA-AZT is able to permeate and remain in murine macrophages with an efficiency twenty times higher than that of AZT. Moreover, we propose the nasal administration of this prodrug in order to induce its uptake into the CNS. Chitosan chloride-based microparticles (CP) were prepared by spray-drying and were characterized with respect to size, morphology, density, water uptake and the dissolution profile of UDCA-AZT. The CP sample was then nasally administered to rats. All in vitro and in vivo measurements were also performed for a CP parent physical mixture. The CP sample was able to increase the dissolution rate of UDCA-AZT and to reduce water uptake with respect to its parent physical mixture, inducing better uptake of UDCA-AZT into the cerebrospinal fluid of rats, where the prodrug can act as an AZT carrier in macrophages.

  16. Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review

    PubMed Central

    Qandil, Amjad M.

    2012-01-01

    The design and the synthesis of prodrugs for nonsteroidal anti-inflammatory drugs (NSAIDs) have been given much attention by medicinal chemists, especially in the last decade. As a therapeutic group, NSAIDs are among the most widely used prescribed and over the counter (OTC) medications. The rich literature about potential NSAID prodrugs clearly shows a shift from alkyl, aryalkyl or aryl esters with the sole role of masking the carboxylic acid group, to more elaborate conjugates that contain carefully chosen groups to serve specific purposes, such as enhancement of water solubility and dissolution, nitric oxide release, hydrogen sulfide release, antioxidant activity, anticholinergic and acetylcholinesterase inhibitory (AChEI) activity and site-specific targeting and delivery. This review will focus on NSAID prodrugs that have been designed or were, later, found to possess intrinsic pharmacological activity as an intact chemical entity. Such intrinsic activity might augment the anti-inflammatory activity of the NSAID, reduce its side effects or transform the potential therapeutic use from classical anti-inflammatory action to something else. Reports discussed in this review will be those of NO-NSAIDs, anticholinergic and AChEI-NSAIDs, Phospho-NSAIDs and some miscellaneous agents. In most cases, this review will cover literature dealing with these NSAID prodrugs from the year 2006 and later. Older literature will be used when necessary, e.g., to explain the chemical and biological mechanisms of action. PMID:23247285

  17. Spiral assembly of amphiphilic cytarabine prodrug assisted by probe sonication: Enhanced therapy index for leukemia.

    PubMed

    Liu, Jing; Ma, Naxin; Zhao, Dujuan; Li, Zhonghao; Luan, Yuxia

    2015-12-01

    In order to overcome the drawbacks of cytarabine (Ara-C), such as low lipophilicity as well as short plasma half-life and rapid inactivation, a new derivative of Ara-C was designed by incorporation into the non-toxic material, oleic acid (OA), obtaining an amphiphilic small molecular weight prodrug (OA-Ara). By a simple amidation reaction, OA-Ara was synthesized successfully with a yield up to 61.32%. It was for the first time to see that the novel prodrug molecules could assemble into the unexpectedly spiral assembly under probe ultrasonication in aqueous solution. The oil/water partition coefficient (Ko/w) and the permeability of cell membrane of the prodrug were significantly increased compared with Ara-C molecules. In addition, OA-Ara molecules were stable in various pH solutions and artificial digestives, which indicated that it could be administrated orally. Cell viability assay showed that the prodrug displayed much higher antiproliferative effect against K562 and HL60 cells due to its improvement of the lipophilicity and penetrability of cell membrane. These findings demonstrate the feasibility of utilizing structural modification to broaden the clinic application of Ara-C and thus provide an effective new therapeutic alternative for leukemia.

  18. Nucleotide Analog Prodrug, Tenofovir Disoproxil, Enhances Lymphoid Cell Loading Following Oral Administration in Monkeys

    PubMed Central

    Durand-Gasselin, Lucie; Van Rompay, Koen K.A.; Vela, Jennifer E.; Henne, Ilana N.; Lee, William A.; Rhodes, Gerry R.; Ray, Adrian S.

    2009-01-01

    The antiviral drug tenofovir (TFV) is orally administered as the fumarate salt of its disoproxil prodrug (TFV disoproxil fumarate (TDF)). TFV is a di-anion at physiological pH and, as a result, has poor lipid membrane permeability. Administration of the lipophilic and cell permeable prodrug, TFV disoproxil, enhances the oral absorption of TFV. In order to determine if oral administration of TDF also increases distribution to sites of viral infection, the plasma and circulating lymphoid cell pharmacokinetics of TFV and its phosphorylated metabolites were assessed following a single oral TDF or subcutaneous TFV administration at doses yielding equivalent plasma exposures to TFV in macaques. Despite TFV disoproxil’s lack of plasma stability and undetectable levels in the first plasma samples taken, oral administration of TDF resulted in 7.9-fold higher peripheral blood mononuclear cell exposures to the active metabolite, TFV-diphosphate. The apparent plasma terminal half-life (t1/2) of TFV was also longer following oral TDF relative to subcutaneous TFV administration (median t1/2 of 15.3 and 3.9 h, respectively), suggesting broader distribution to cells and tissues outside of the central plasma compartment. In conclusion, the disoproxil pro-moiety not only enhances the oral absorption of TFV but also tissue and lymphoid cell loading. These results illustrate that administration of even a fleeting prodrug can increase target tissue loading and gives valuable insight for future prodrug development. PMID:19545170

  19. Synthesis, Screening and Pharmacokinetic Evaluation of Potential Prodrugs of Bupropion. Part One: In Vitro Development

    PubMed Central

    O’Byrne, Paul Matthew; Williams, Robert; Walsh, John J.; Gilmer, John F.

    2014-01-01

    In general, prodrugs are developed to circumvent deficiencies associated with the absorption, distribution, metabolism, excretion or toxicological (ADMET) profile associated with the active drug. In our study, we select bupropion, a drug with broad pharmacology incorporating dopaminergic, noradrenergic, nicotinic and cytokine modulation properties, but which is rapidly metabolized in vivo. We exploited its carbonyl and secondary amine functionality to facilitate the synthesis of bioprecursor prodrug forms with the sole objective of identifying analogues with enhanced properties over bupropion. A range of analogues were synthesized, ranging from N-methyl, N-benzyl, oximes, enol acetate and ether forms to examples where both functional groups were utilized to form oxadiazine, oxadiazinone, oxazolone and acetylated derivatives. We then developed an in vitro metabolic screen to simulate the human oral delivery route for these analogues. The selection of media in the screens contained a variety of pH, enzymatic and co-factor systems which mimic metabolic in vivo environments that drugs encounter when delivered orally. By coupling our in vitro screening tool to a selective hyphenated technique such as LC-MS, we were able to quickly select potential prodrugs for further in vitro and in vivo development. From the data generated, the N-alkylated bupropion analogues were shown to have the highest potential to act as bioprecursor prodrugs of bupropion. PMID:24830986

  20. A five-membered lactone prodrug of CBI-based analogs of the duocarmycins

    PubMed Central

    Uematsu, Mika; Brody, Daniel M.; Boger, Dale L.

    2014-01-01

    The preparation, characterization and examination of the CBI-based 5-membered lactone 5 capable of serving as a prodrug or protein (antibody) conjugation reagent are disclosed along with its incorporation into the corresponding CC-1065 and duocarmycin analog 6, and the establishment of their properties. PMID:26069351

  1. Naloxone pro-drug rescues morphine induced respiratory depression in Sprague-Dawley rats.

    PubMed

    Wallisch, Michael; El Rody, Nehad M; Huang, Baohua; Koop, Dennis R; Baker, James R; Olsen, George D

    2012-01-15

    Respiratory depression is the main obstacle for the safe administration of morphine for acute pain after injury. Due to this complication, new delivery methods are needed to insure that safe and effective doses of opioid analgesics are administered during emergencies. A depot formulation containing a naloxone pro-drug was designed to release the antidote when morphine causes dangerous hypoxic conditions in the blood. The aim of this work was to test the naloxone release in vivo in response to a severe overdose of morphine in the Sprague-Dawley rat model. Non-invasive two-chamber plethysmography was used to monitor and record respiration and to test the capability of the naloxone pro-drug to respond to and rescue morphine-induced respiratory depression in the animal. We show that the pro-drug formulation can both prevent and reverse severe morphine induced respiratory depression. The animal model demonstrates that co-administration of the naloxone pro-drug reliably antagonizes profound respiratory depressive effects of morphine.

  2. "Project ALERT's" Effects on Adolescents' Prodrug Beliefs: A Replication and Extension Study

    ERIC Educational Resources Information Center

    Clark, Heddy Kovach; Ringwalt, Chris L.; Hanley, Sean; Shamblen, Stephen R.

    2010-01-01

    This article represents a replication and extension of previous studies of the effects of "Project ALERT", a school-based substance use prevention program, on the prodrug beliefs of adolescents. Specifically, the authors' research examined "Project ALERT's" effects on adolescents' intentions to use substances in the future, beliefs about substance…

  3. Combined strategies of apomorphine diester prodrugs and nanostructured lipid carriers for efficient brain targeting

    NASA Astrophysics Data System (ADS)

    Liu, Kuo-Sheng; Wen, Chih-Jen; Yen, Tzu-Chen; Sung, K. C.; Ku, Ming-Chuan; Wang, Jhi-Joung; Fang, Jia-You

    2012-03-01

    Our aim is to develop nanostructured lipid carriers (NLCs) for loading the apomorphine diester prodrugs, diacetyl apomorphine (DAA) and diisobutyryl apomorphine (DIA), into the brain. NLCs were prepared using sesame oil/cetyl palmitate as the lipid matrices. Experiments were performed with the objective of evaluating the physicochemical characteristics, drug release, safety and brain-targeting efficacy of the NLCs. The size of regular NLCs (N-NLCs) was 214 nm. The addition of Forestall (FE) and polyethylene glycol (PEG) to the NLCs (P-NLCs) increased the particle diameter to 250 nm. The zeta potentials of N-NLCs and P-NLCs were respectively shown to be - 21 and 48 mV. Diester prodrugs were more lipophilic and more chemically stable than the parent apomorphine. The hydrolysis study indicated that the prodrugs underwent bioconversion in plasma and brain extract, with DAA exhibiting faster degradation than DIA. Sustained release was achieved through the synergistic effect of integrating strategies of prodrugs and NLCs, with the longer carbon chain showing the slower release (DIA < DAA). None of the NLCs tested here exhibited a toxicity problem according to the examination of neutrophil lactate dehydrogenase (LDH) release and hemolysis. Results of a bioimaging study in mice showed that P-NLCs largely accumulated in the brain. The distribution duration of the fluorescent dye in the brain region was also prolonged by the nanocarriers.

  4. Water-soluble acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury

    PubMed Central

    Liu, Hui; Yang, Lei; Wu, Hui-Jun; Chen, Kui-Hao; Lin, Feng; Li, Gang; Sun, Hai-Ying; Xiao, Guo-Sheng; Wang, Yan; Li, Gui-Rong

    2016-01-01

    The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of acacetin prodrug (10 mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats. The cardioprotective effects were further confirmed with the parent compound acacetin in an ex vivo rat regional ischemia/reperfusion heart model. Molecular mechanism analysis revealed that acacetin prevented the ischemia/reperfusion-induced reduction of the anti-oxidative proteins SOD-2 and thioredoxin, suppressed the release of inflammation cytokines TLR4, IL-6 and TNFα, and decreased myocyte apoptosis induced by ischemia/reperfusion. Our results demonstrate the novel evidence that acacetin prodrug confer significant in vivo cardioprotective effect against ischemia/reperfusion injury by preventing the reduction of endogenous anti-oxidants and the release of inflammatory cytokines, thereby inhibiting cardiomyocytes apoptosis, which suggests that the water-soluble acacetin prodrug is likely useful in the future as a new drug candidate for treating patients with acute coronary syndrome. PMID:27819271

  5. Urinary biomarkers after donor nephrectomy.

    PubMed

    Hoogendijk-van den Akker, Judith M; Warlé, Michiel C; van Zuilen, Arjan D; Kloke, Heinrich J; Wever, Kim E; d'Ancona, Frank C H; Ӧzdemir, Denise M D; Wetzels, Jack F M; Hoitsma, Andries J

    2015-05-01

    As the beginning of living-donor kidney transplantation, physicians have expressed concern about the possibility that unilateral nephrectomy can be harmful to a healthy individual. To investigate whether the elevated intra-abdominal pressure (IAP) during laparoscopic donor nephrectomy causes early damage to the remaining kidney, we evaluated urine biomarkers after laparoscopic donor nephrectomy. We measured albumin and alpha-1-microglobulin (α-1-MGB) in urine samples collected during and after open and laparoscopic donor nephrectomy and laparoscopic cholecystectomy and colectomy. Additionally, kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were measured in urine samples collected during and after laparoscopic donor nephrectomy and colectomy. The same biomarkers were studied in patients randomly assigned to standard or low IAP during laparoscopic donor nephrectomy. We observed a peak in urinary albumin excretion during all procedures. Urine α-1-MGB rose in the postoperative period with a peak on the third postoperative day after donor nephrectomy. Urine α-1-MGB did not increase after laparoscopic cholecystectomy and colectomy. After laparoscopic nephrectomy, we observed slight increases in urine KIM-1 during surgery and in urine NGAL at day 2-3 after the procedure. After laparoscopic colectomy, both KIM-1 and NGAL were increased in the postoperative period. There were no differences between the high- and low-pressure procedure. Elevated urinary α-1-MGB suggests kidney damage after donor nephrectomy, occurring irrespective of IAP during the laparoscopic procedure.

  6. Synthesis and in vitro stability of amino acid prodrugs of 6-β-naltrexol for microneedle-enhanced transdermal delivery

    PubMed Central

    Eldridge, Joshua A.; Milewski, Mikolaj; Stinchcomb, Audra L.; Crooks, Peter A.

    2014-01-01

    A small library of amino acid ester prodrugs of 6-β-naltrexol (NTXOL, 1) was prepared in order to investigate the candidacy of these prodrugs for microneedle-enhanced transdermal delivery. Six amino acid ester prodrugs were synthesized (6a-f). 6b, 6d, and 6e were stable enough at skin pH (pH 5.0) to move forward to studies in 50% human plasma. The lead compound (6e) exhibited the most rapid bioconversion to NTXOL in human plasma (t½ = 2.2 ± 0.1 h). PMID:25442314

  7. Efficient activation of a visible light-activatable CA4 prodrug through intermolecular photo-unclick chemistry in mitochondria.

    PubMed

    Bio, Moses; Rajaputra, Pallavi; Lim, Irene; Thapa, Pritam; Tienabeso, Bomaonye; Hurst, Robert E; You, Youngjae

    2017-02-07

    Photo-unclick chemistry mediates visible and near IR-controlled drug release via a singlet oxygen (SO)-cleavable linker. Due to the limited diffusion distance of SO in biological systems, a photosensitizer and the SO-cleavable linker have been conjugated in one molecule or mixed in nano-drug delivery systems. In this communication, we demonstrate a new strategy to activate prodrugs with photo-unclick chemistry in an intermolecular fashion using an SO-cleavable CA4 prodrug and a mitochondria-specific photosensitizer, protoporphyrin IX, formed from prodrug hexyl-5-aminolevulinate.

  8. Carboxypeptidase-G2-based gene-directed enzyme-prodrug therapy: a new weapon in the GDEPT armoury.

    PubMed

    Hedley, Douglas; Ogilvie, Lesley; Springer, Caroline

    2007-11-01

    Gene-directed enzyme-prodrug therapy (GDEPT) aims to improve the therapeutic ratio (benefit versus toxic side-effects) of cancer chemotherapy. A gene encoding a 'suicide' enzyme is introduced into the tumour to convert a subsequently administered non-toxic prodrug into an active drug selectively in the tumour, but not in normal tissues. Significant effects can now be achieved in vitro and in targeted experimental models, and GDEPT therapies are entering the clinic. Our group has developed a GDEPT system that uses the bacterial enzyme carboxypeptidase G2 to convert nitrogen mustard prodrugs into potent DNA crosslinking agents, and a clinical trial of this system is pending.

  9. Reevaluating the dead donor rule.

    PubMed

    Collins, Mike

    2010-04-01

    The dead donor rule justifies current practice in organ procurement for transplantation and states that organ donors must be dead prior to donation. The majority of organ donors are diagnosed as having suffered brain death and hence are declared dead by neurological criteria. However, a significant amount of unrest in both the philosophical and the medical literature has surfaced since this practice began forty years ago. I argue that, first, declaring death by neurological criteria is both unreliable and unjustified but further, the ethical principles which themselves justify the dead donor rule are better served by abandoning that rule and instead allowing individuals who have suffered severe and irreversible brain damage to become organ donors, even though they are not yet dead and even though the removal of their organs would be the proximal cause of death.

  10. Stepwise-activable multifunctional peptide-guided prodrug micelles for cancerous cells intracellular drug release

    NASA Astrophysics Data System (ADS)

    Zhang, Jing; Li, Mengfei; Yuan, Zhefan; Wu, Dan; Chen, Jia-da; Feng, Jie

    2016-10-01

    A novel type of stepwise-activable multifunctional peptide-guided prodrug micelles (MPPM) was fabricated for cancerous cells intracellular drug release. Deca-lysine sequence (K10), a type of cell-penetrating peptide, was synthesized and terminated with azido-glycine. Then a new kind of molecule, alkyne modified doxorubicin (DOX) connecting through disulfide bond (DOX-SS-alkyne), was synthesized. After coupling via Cu-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry reaction, reduction-sensitive peptide-guided prodrug was obtained. Due to the amphiphilic property of the prodrug, it can assemble to form micelles. To prevent the nanocarriers from unspecific cellular uptake, the prodrug micelles were subsequently modified with 2,3-dimethyl maleic anhydride to obtain MPPM with a negatively charged outer shell. In vitro studies showed that MPPM could be shielded from cells under psychological environment. However, when arriving at mild acidic tumor site, the cell-penetrating capacity of MPPM would be activated by charge reversal of the micelles via hydrolysis of acid-labile β-carboxylic amides and regeneration of K10, which enabled efficient internalization of MPPM by tumor cells as well as following glutathione- and protease-induced drug release inside the cancerous cells. Furthermore, since the guide peptide sequences can be accurately designed and synthesized, it can be easily changed for various functions, such as targeting peptide, apoptotic peptide, even aptamers, only need to be terminated with azido-glycine. This method can be used as a template for reduction-sensitive peptide-guided prodrug for cancer therapy.

  11. Synergistic antitumor activity of a self-assembling camptothecin and capecitabine hybrid prodrug for improved efficacy.

    PubMed

    Ma, Wang; Su, Hao; Cheetham, Andrew G; Zhang, Weifang; Wang, Yuzhu; Kan, QuanCheng; Cui, Honggang

    2017-01-10

    The direct use of anticancer drugs to create their own nanostructures is an emerging concept in the field of drug delivery to obtain nanomedicines of high drug loading and high reproducibility, and the combination use of two or more drugs has been a proven clinical strategy to enhance therapeutic outcomes. We report here the synthesis, assembly and cytotoxicity evaluation of self-assembling hybrid prodrugs containing both camptothecin (CPT) and a capecitabine (Cap) analogue. CPT and Cap molecules were conjugated onto a short β-sheet-forming peptide (Sup35) to yield three different self-assembling prodrugs (dCPT-Sup35, CPT-Cap-Sup35 and dCap-Sup35). We found that the chemical structure of conjugated drugs could strongly influence their assembled morphology as well as their structural stability in aqueous solution. With a decrease in number of CPT units, the resulting nanostructures exhibited a morphological transformation from nanofibers (dCPT-Sup35) to filaments (CPT-Cap-Sup35) then to spherical particles (dCap-Sup35). Notably, the hybrid CPT-Cap prodrug showed a synergistic effect and significantly enhanced potency against three esophageal adenocarcinoma cell lines compared with the two homo-prodrugs (dCPT-Sup35 and dCap-Sup35) as well as free parent drugs (CPT, 5-Fu and CPT/5-FU mixture (1:1)). We believe this work represents a conceptual advancement in integrating two structurally distinct drugs of different action mechanisms into a single self-assembling hybrid prodrug to construct self-deliverable nanomedicines for more effective combination chemotherapy.

  12. Folate receptor-mediated enhanced and specific delivery of far-red light-activatable prodrugs of combretastatin A-4 to FR-positive tumor.

    PubMed

    Nkepang, Gregory; Bio, Moses; Rajaputra, Pallavi; Awuah, Samuel G; You, Youngjae

    2014-12-17

    We examined the concept of a novel prodrug strategy in which anticancer drug can be locally released by visible/near IR light, taking advantage of the photodynamic process and photo-unclick chemistry. Our most recently formulated prodrug of combretastatin A-4, Pc-(L-CA4)2, showed multifunctionality for fluorescence imaging, light-activated drug release, and the combined effects of PDT and local chemotherapy. In this formulation, L is a singlet oxygen cleavable linker. Here, we advanced this multifunctional prodrug by adding a tumor-targeting group, folic acid (FA). We designed and prepared four FA-conjugated prodrugs 1-4 (CA4-L-Pc-PEGn-FA: n = 0, 2, 18, ∼45) and one non-FA-conjugated prodrug 5 (CA4-L-Pc-PEG18-boc). Prodrugs 3 and 4 had a longer PEG spacer and showed higher hydrophilicity, enhanced uptake to colon 26 cells via FR-mediated mechanisms, and more specific localization to SC colon 26 tumors in Balb/c mice than prodrugs 1 and 2. Prodrug 4 also showed higher and more specific uptake to tumors, resulting in selective tumor damage and more effective antitumor efficacy than non-FA-conjugated prodrug 5. FR-mediated targeting seemed to be an effective strategy to spare normal tissues surrounding tumors in the illuminated area during treatment with this prodrug.

  13. Folate Receptor-Mediated Enhanced and Specific Delivery of Far-Red Light-Activatable Prodrugs of Combretastatin A-4 to FR-Positive Tumor

    PubMed Central

    2015-01-01

    We examined the concept of a novel prodrug strategy in which anticancer drug can be locally released by visible/near IR light, taking advantage of the photodynamic process and photo-unclick chemistry. Our most recently formulated prodrug of combretastatin A-4, Pc-(L-CA4)2, showed multifunctionality for fluorescence imaging, light-activated drug release, and the combined effects of PDT and local chemotherapy. In this formulation, L is a singlet oxygen cleavable linker. Here, we advanced this multifunctional prodrug by adding a tumor-targeting group, folic acid (FA). We designed and prepared four FA-conjugated prodrugs 1–4 (CA4-L-Pc-PEGn-FA: n = 0, 2, 18, ∼45) and one non-FA-conjugated prodrug 5 (CA4-L-Pc-PEG18-boc). Prodrugs 3 and 4 had a longer PEG spacer and showed higher hydrophilicity, enhanced uptake to colon 26 cells via FR-mediated mechanisms, and more specific localization to SC colon 26 tumors in Balb/c mice than prodrugs 1 and 2. Prodrug 4 also showed higher and more specific uptake to tumors, resulting in selective tumor damage and more effective antitumor efficacy than non-FA-conjugated prodrug 5. FR-mediated targeting seemed to be an effective strategy to spare normal tissues surrounding tumors in the illuminated area during treatment with this prodrug. PMID:25351441

  14. National Marrow Donor Program

    DTIC Science & Technology

    2008-11-17

    associated with similar survival after hematopoietic cell transplantation for acute leukemia . Accepted for poster presentation. o Nguyen Y, Al-Lehibi A...New Drug AML Acute Myelogenous Leukemia ICRHER International Consortium for Research on Health Effects of Radiation ARS Acute Radiation Syndrome ...Control: Part II o Radiation Detection, Monitoring & Protection Laboratory Exercise & Quiz o Diagnosis & Management of the Acute Radiation Syndrome (ARS

  15. Living kidney donors and ESRD.

    PubMed

    Ross, Lainie Friedman

    2015-07-01

    There are more than 325 living kidney donors who have developed end-stage renal disease and have been listed on the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) deceased donor kidney wait list. The OPTN/UNOS database records where these kidney donors are listed and, if they donated after April 1994, where that donation occurred. These 2 locations are often not the same. In this commentary, I examine whether a national living donor registry should be created and whether transplantation centers should be notified when one of their living kidney donors develops end-stage renal disease. I consider and refute 5 potential objections to center notification. I explain that transplantation centers should look back at these cases and input data into a registry to attempt to identify patterns that could improve donor evaluation protocols. Creating a registry and mining the information it contains is, in my view, our moral and professional responsibility to future patients and the transplantation endeavor. As individuals and as a community, we need to acknowledge the many unknown risks of living kidney donation and take responsibility for identifying these risks. We then must share information about these risks, educate prospective donors about them, and attempt to minimize them.

  16. [Kidney grafts from elderly donors].

    PubMed

    Hiesse, Christian; Pessione, Fabienne; Cohen, Sophie

    2003-06-07

    FROM AN EPIDEMIOLOGICAL POINT OF VIEW: The epidemiology of renal transplantation had greatly changed over the past 10 years. The increasing number of patients with renal failure and candidates for transplantation increases the demand for grafts, whereas the sampling rate of organs remains stable. The mean age of the donors is rising, hence underlining the question of the use of organs of so-called "borderline" quality. THE WEAK POINTS OF ELDERLY GRAFTS: Aging of the kidneys affects the structure of the parenchyma and renal function, which decreases, notably in hypertensive persons. The elderly graft exhibits a critical mass of nephrons that is insufficient to fulfil the functional requirements of a poorly equipped recipient. The recipient is more sensitive to the added agressions: prolonged ischemia and immunological and medicinal agressions. THE RESULTS OF RENAL GRAFT FROM ELDERLY DONORS: They are quantitatively and qualitatively inferior to those of renal transplants from "ideal" donors. The donor's age is a significant factor influencing negatively influences the survival of the transplanted kidney, but dependent on past vascular history. Good results regarding the maintenance of dialysis are obtained by selecting the donors and by avoiding added risk factors. THE ASSESSMENT OF A GRAFT FROM AN ELDERLY DONOR: This, basically, relies on clinical criteria: donor's history, cause of death and accurate measurement of the renal function. A biopsy of the graft, at the time of sampling, provides useful information. TRANSPLANTATION STRATEGY OF A GRAFT FROM AN ELDERLY DONOR: Donor-recipient matching by age is a common approach. Grafting of both kidneys in the same recipient is a method presently under assessment. The episode of ischemia must be reduced and the immunosuppressive therapy adapted.

  17. Topical iontophoretic delivery of ionizable, biolabile aciclovir prodrugs: A rational approach to improve cutaneous bioavailability.

    PubMed

    Chen, Yong; Alberti, Ingo; Kalia, Yogeshvar N

    2016-02-01

    The objective was to investigate the topical iontophoretic delivery of a series of amino acid ester prodrugs of aciclovir (ACV-X, where ACV=aciclovir and X=Arg, Gly, Ile, Phe, Trp and Val) as a means to enhance cutaneous delivery of ACV. The newly synthesized prodrugs were characterized by (1)H NMR and high resolution mass spectrometry. Analytical methods using HPLC-UV were developed for their quantification and each method was validated. Investigation of solution stability as a function of pH showed that all ACV-X prodrugs were relatively stable in acid conditions at pH 2.0 and pH 5.5 for up to 8h but susceptible to extensive hydrolysis at pH 7.4 and under alkaline conditions (pH 10). No ACV-X hydrolysis was observed after contact for 2h with the external surface of porcine stratum corneum. However, there was significant hydrolysis following contact with the dermal surface of dermatomed porcine skin, in particular, for ACV-Arg. Passive transport of ACV and ACV-X prodrugs from aqueous solution after 2h was below the limit of detection. Iontophoresis of ACV at 0.5 mA/cm(2) for 2h led to modest ACV skin deposition (QDEP,ACV) of 4.6 ± 0.3 nmol/cm(2). In contrast, iontophoresis of ACV-X prodrugs under the same conditions produced order of magnitude increases in cutaneous deposition of ACV species, that is, QDEP,TOTAL=QDEP,ACV+QDEP,ACV-X. QDEP,TOTAL for ACV-Gly, ACV-Val, ACV-Ile, ACV-Phe, ACV-Trp and ACV-Arg was 412.8 ± 44.0, 358.8 ± 66.8, 434.1 ± 68.2, 249.8 ± 81.4, 156.1 ± 76.3, 785.9 ± 78.1 nmol/cm(2), respectively. The extent of bioconversion of ACV-X to ACV in the skin was high and the proportion of ACV present ranged from 81% to 100%. The skin retention ratio, a measure of the selectivity of ACV species for deposition over permeation after iontophoretic delivery of ACV-X prodrugs, was dependent on both the rate of transport and the susceptibility to hydrolysis of the prodrugs. Skin deposition of ACV and its six prodrugs were investigated further as a

  18. Preparation and Pharmacological Evaluation of Novel Orally Active Ester Prodrugs of Ketoprofen with Non-Ulcerogenic Property.

    PubMed

    Dhakane, Valmik D; Thakare, Vishnu N; Dongare, Sakharam B; Bhale, Pravin S; Mule, Yoginath B; Bandgar, Babasaheb P; Chavan, Hemant V

    2016-06-01

    This study investigates anti-inflammatory activity with improved pharmacokinetic and non-ulcerogenic properties of various novel synthesized prodrugs of ketoprofen in experimental animals. Prodrugs 3a, 3f and 3k were found to possess significant anti-inflammatory activity with almost non-ulcerogenic potential than standard drug ketoprofen (1) in both normal and inflammation-induced rats. The experimental findings elicited higher AUC and plasma concentration at 1 and 2 h indicating improved oral bioavailability as compared to parent drug ketoprofen. These prodrugs are found to have no gastric ulceration with retained anti-inflammatory activity. Therefore, present experimental findings demonstrated significant improvement of various pharmacokinetic properties with non-ulcerogenic potential of ester prodrugs of ketoprofen.

  19. Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

    SciTech Connect

    Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J.

    2014-09-24

    We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

  20. Design and synthesis of imidazole N-H substituted amide prodrugs as inhibitors of hepatitis C virus replication.

    PubMed

    Zong, Xi; Cai, Jin; Chen, Junqing; Wang, Peng; Zhou, Gaoxin; Chen, Bo; Li, Wei; Ji, Min

    2015-08-15

    Twenty-five novel imidazole N-H substituted Daclatasvir (BMS-790052, DCV) analogues (8a-8y) were designed and synthesized as potential prodrugs. Structure modifications were performed in order to improve potency and pharmacokinetic (PK) properties. All target compounds were evaluated in a hepatitis C virus (HCV) genotype 1b replicon, and the 2-oxoethyl acetate substituted compound 8t showed similar anti-HCV activity (EC50 = 0.08 nM) to that of the lead compound Daclatasvir. Moreover, the utility of prodrug 8t was demonstrated through similar exposure of the parent compound when the prodrugs were dosed in vivo. PK studies showed that prodrug 8t was an ideal candidate for a slower and sustained release form of Daclatasvir.

  1. Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

    NASA Astrophysics Data System (ADS)

    Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J.

    2011-03-01

    We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

  2. Synthesis and characterization of brain penetrant prodrug of neuroprotective D-264: Potential therapeutic application in the treatment of Parkinson's disease.

    PubMed

    Dholkawala, Fahd; Voshavar, Chandrashekhar; Dutta, Aloke K

    2016-06-01

    Parkinson's disease (PD) is one of the major debilitating neurodegenerative disorders affecting millions of people worldwide. Progressive loss of dopamine neurons resulting in development of motor dysfunction and other related non-motor symptoms is the hallmark of PD. Previously, we have reported on the neuroprotective property of a potent D3 preferring agonist D-264. In our goal to increase the bioavailability of D-264 in the brain, we have synthesized a modified cysteine based prodrug of D-264 and evaluated its potential in crossing the blood-brain barrier. Herein, we report the synthesis of a novel modified cysteine conjugated prodrug of potent neuroprotective D3 preferring agonist D-264 and systematic evaluation of the hydrolysis pattern of the prodrug to yield D-264 at different time intervals in rat plasma and brain homogenates using HPLC analysis. Furthermore, we have also performed in vivo experiments with the prodrug to evaluate its enhanced brain penetration ability.

  3. How to Motivate Whole Blood Donors to Become Plasma Donors

    PubMed Central

    2014-01-01

    This study tested the efficacy of interventions to recruit new plasma donors among whole blood donors. A sample of 924 donors was randomized to one of three conditions: control; information only by nurse; and information plus self-positive image message by nurse (SPI). Participants in the control condition only received a leaflet describing the plasma donation procedure. In the two experimental conditions the leaflet was explained face-to-face by a nurse. The dependent variables were the proportion of new plasma donors and the number of donations at six months. Overall, 141 (15.3%) new plasma donors were recruited at six months. There were higher proportions of new plasma donors in the two experimental conditions compared to the control condition (P < .001); the two experimental conditions did not differ. Also, compared to the control condition, those in the experimental conditions (all Ps < .001) gave plasma more often (information only by nurse:  d = .26; SPI: d = .32); the SPI intervention significantly outperformed (P < .05) the information only by nurse condition. The results suggest that references to feelings of SPI such as feeling good and being proud and that giving plasma is a rewarding personal experience favor a higher frequency of plasma donation. PMID:25530909

  4. How to motivate whole blood donors to become plasma donors.

    PubMed

    Godin, Gaston; Germain, Marc

    2014-01-01

    This study tested the efficacy of interventions to recruit new plasma donors among whole blood donors. A sample of 924 donors was randomized to one of three conditions: control; information only by nurse; and information plus self-positive image message by nurse (SPI). Participants in the control condition only received a leaflet describing the plasma donation procedure. In the two experimental conditions the leaflet was explained face-to-face by a nurse. The dependent variables were the proportion of new plasma donors and the number of donations at six months. Overall, 141 (15.3%) new plasma donors were recruited at six months. There were higher proportions of new plasma donors in the two experimental conditions compared to the control condition (P < .001); the two experimental conditions did not differ. Also, compared to the control condition, those in the experimental conditions (all Ps < .001) gave plasma more often (information only by nurse:  d = .26; SPI: d = .32); the SPI intervention significantly outperformed (P < .05) the information only by nurse condition. The results suggest that references to feelings of SPI such as feeling good and being proud and that giving plasma is a rewarding personal experience favor a higher frequency of plasma donation.

  5. Identification of novel enzyme-prodrug combinations for use in cytochrome P450-based gene therapy for cancer.

    PubMed

    Baldwin, Alex; Huang, Zeqi; Jounaidi, Youssef; Waxman, David J

    2003-01-01

    Gene-directed enzyme prodrug therapy can be used to increase the therapeutic activity of anti-cancer prodrugs that undergo liver cytochrome P450 (CYP)-catalyzed prodrug to active drug conversion. The present report describes a cell-culture-based assay to identify CYP gene-CYP prodrug combinations that generate bystander cytotoxic metabolites and that may potentially be useful for CYP-based gene therapy for cancer. A panel of rat liver microsomes, comprising distinct subsets of drug-inducible hepatic CYPs, was evaluated for prodrug activation in a four-day 9L gliosarcoma cell growth inhibition assay. A strong NADPH- and liver microsome-dependent increase in 9L cytotoxicity was observed for the CYP prodrugs cyclophosphamide, ifosfamide, and methoxymorpholinyl doxorubicin (MMDX) but not with three other CYP prodrugs, procarbazine, dacarbazine, and tamoxifen. MMDX activation was potentiated approximately 250-fold by liver microsomes from dexamethasone-induced rats (IC(50) (MMDX) approximately 0.1nM), suggesting that dexamethasone-inducible CYP3A enzymes contribute to activation of this novel anthracycline anti-tumor agent. This CYP3A dependence was verified in studies using liver microsomes from uninduced male and female rats and by using the CYP3A-selective inhibitors troleandomycin and ketoconazole. These findings highlight the advantages of using cell culture assays to identify novel CYP prodrug-CYP gene combinations that are characterized by production of cell-permeable, cytotoxic metabolites and that may potentially be incorporated into CYP-based gene therapies for cancer treatment.

  6. Design, synthesis and in vitro/in vivo evaluation of orally bioavailable prodrugs of a catechol-O-methyltransferase inhibitor.

    PubMed

    Rautio, Jarkko; Leppänen, Jukka; Lehtonen, Marko; Laine, Krista; Koskinen, Mikko; Pystynen, Jarmo; Savolainen, Jouko; Sairanen, Mikko

    2010-04-15

    Compound 1 is an investigational, nanomolar inhibitor of catechol-O-methyltransferase (COMT) that suffers from poor oral bioavailability, most probably due to its low lipophilicity throughout most of the gastrointestinal tract and, to a lesser extent, its rapid systemic clearance. Several lipophilic esters were designed as prodrugs and synthesized in an attempt to optimize presystemic drug absorption. A modest twofold increase in 6-h exposure of 1 was observed with two prodrugs, compared to that of 1, after oral treatment in rats.

  7. Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: interaction with the transporters on Caco-2 cells.

    PubMed

    Katragadda, Suresh; Jain, Ritesh; Kwatra, Deep; Hariharan, Sudharshan; Mitra, Ashim K

    2008-10-01

    In vivo systemic absorption of the amino acid prodrugs of acyclovir (ACV) after oral administration was evaluated in rats. Stability of the prodrugs, L-alanine-ACV (AACV), L-serine-ACV (SACV), L-isoleucine-ACV (IACV), gamma-glutamate-ACV (EACV) and L-valine-ACV (VACV) was evaluated in various tissues. Interaction of these prodrugs with the transporters on Caco-2 cells was studied. In vivo systemic bioavailability of these prodrugs upon oral administration was evaluated in jugular vein cannulated rats. The amino acid ester prodrugs showed affinity towards various amino acid transporters as well as the peptide transporter on the Caco-2 cells. In terms of stability, EACV was most enzymatically stable compared to other prodrugs especially in liver homogenate. In oral absorption studies, ACV and AACV showed high terminal elimination rate constants (lambda(z)). SACV and VACV exhibited approximately five-fold increase in area under the curve (AUC) values relative to ACV (p<0.05). C(max(T)) (maximum concentration) of SACV was observed to be 39+/-22 microM in plasma which is 2 times better than VACV and 15 times better than ACV. C(last(T)) (concentration at the last time point) of SACV was observed to be 0.18+/-0.06 microM in plasma which is two times better than VACV and three times better than ACV. Amino acid ester prodrugs of ACV were absorbed at varying amounts (C(max)) and eliminated at varying rates (lambda(z)) thereby leading to varying extents (AUC). The amino acid ester prodrug SACV owing to its enhanced stability, higher AUC and better concentration at last time point seems to be a promising candidate for the oral treatment of herpes infections.

  8. Pronounced Hypoxia in Models of Murine and Human Leukemia: High Efficacy of Hypoxia-Activated Prodrug PR-104

    PubMed Central

    Benito, Juliana; Shi, Yuexi; Szymanska, Barbara; Carol, Hernan; Boehm, Ingrid; Lu, Hongbo; Konoplev, Sergej; Fang, Wendy; Zweidler-McKay, Patrick A.; Campana, Dario; Borthakur, Gautam; Bueso-Ramos, Carlos; Shpall, Elizabeth; Thomas, Deborah A.; Jordan, Craig T.; Kantarjian, Hagop; Wilson, William R.; Lock, Richard; Andreeff, Michael; Konopleva, Marina

    2011-01-01

    Recent studies indicate that interactions between leukemia cells and the bone marrow (BM) microenvironment promote leukemia cell survival and confer resistance to anti-leukemic drugs. There is evidence that BM microenvironment contains hypoxic areas that confer survival advantage to hematopoietic cells. In the present study we investigated whether hypoxia in leukemic BM contributes to the protective role of the BM microenvironment. We observed a marked expansion of hypoxic BM areas in immunodeficient mice engrafted with acute lymphoblastic leukemia (ALL) cells. Consistent with this finding, we found that hypoxia promotes chemoresistance in various ALL derived cell lines. These findings suggest to employ hypoxia-activated prodrugs to eliminate leukemia cells within hypoxic niches. Using several xenograft models, we demonstrated that administration of the hypoxia-activated dinitrobenzamide mustard, PR-104 prolonged survival and decreased leukemia burden of immune-deficient mice injected with primary acute lymphoblastic leukemia cells. Together, these findings strongly suggest that targeting hypoxia in leukemic BM is feasible and may significantly improve leukemia therapy. PMID:21853076

  9. Synthesis, stability studies, anti-inflammatory activity and ulcerogenicity of morpholinoalkyl ester prodrugs of niflumic acid.

    PubMed

    Talath, Sirajunisa; Gadad, Andanappa K

    2006-01-01

    In search for potential prodrugs for anti-inflammatory drug candidates in the niflumate series, novel morpholinoalkyl ester prodrugs of niflumic acid (CAS 4394-00-7) 5a-b were prepared by esterification of appropriate morpholinylalkyl alcohols 3a-b with niflumic acid 4 in the presence of dicyclohexyl carbodiimide (DCC) and catalyst dimethylamino pyridine (DMAP) at 0-5 degrees C. The structures were confirmed by elemental and spectral data (UV, IR, 1H-NMR, 13C-NMR, and EI-MS). The ester prodrugs 5a-b showed better solubility than the parent drug niflumic acid 4 in simulated gastric fluid (SGF) and phosphate buffer (pH 7.4). The in vitro hydrolysis studies were conducted at pH 1.3 (SGF), phosphate buffer (pH 7.4) and in human plasma diluted with phosphate buffer (pH 7.4) at 37+/-0.5 degrees C using HPLC with UV detection. The ester prodrugs 5a-b were quantitatively hydrolyzed to the parent drug niflumic acid 4 by enzymatic and/or chemical means. It is observed that an increase in the carbon chain length rendered the prodrugs 5a-b more stable in phosphate buffer (pH 7.4) than in pH 1.3 (SGF), but they were rapidly hydrolyzed in human plasma at 37+/-0.5 degrees C. They exhibited longer hydrolytic half-lives of 16.11-53.30 h in aqueous buffer solutions (pH 1.3 and 7.4) and 1.63-2.73 min in human plasma, respectively. The title compounds were evaluated in vivo for anti-inflammatory activity in carrageenan induced rat paw oedema model in rats at the doses 45, 90, 150 mg/kg b.w. The test compounds exhibited good anti-inflammatory activity (46.6-53.2 % at the dose of 150 mg/kg b. w.) with respect to niflumic acid (78.7 % at the dose of 90 mg/kg b.w.). The compounds were also screened for in vivo ulcerogenicity, it was observed that the prodrug 5b was significantly less irritating to gastric mucosa than compound 5a and the parent drug niflumic acid 4 following single and chronic oral administration in rats.

  10. Bioprinting cell-laden matrigel for radioprotection study of liver by pro-drug conversion in a dual-tissue microfluidic chip.

    PubMed

    Snyder, J E; Hamid, Q; Wang, C; Chang, R; Emami, K; Wu, H; Sun, W

    2011-09-01

    The objective of this paper is to introduce a novel cell printing and microfluidic system to serve as a portable ground model for the study of drug conversion and radiation protection of living liver tissue analogs. The system is applied to study behavior in ground models of space stress, particularly radiation. A microfluidic environment is engineered by two cell types to prepare an improved higher fidelity in vitro micro-liver tissue analog. Cell-laden Matrigel printing and microfluidic chips were used to test radiation shielding to liver cells by the pro-drug amifostine. In this work, the sealed microfluidic chip regulates three variables of interest: radiation exposure, anti-radiation drug treatment and single- or dual-tissue culture environments. This application is intended to obtain a scientific understanding of the response of the multi-cellular biological system for long-term manned space exploration, disease models and biosensors.

  11. Targeted anti-cancer prodrug based on carbon nanotube with photodynamic therapeutic effect and pH-triggered drug release

    NASA Astrophysics Data System (ADS)

    Fan, Jianquan; Zeng, Fang; Xu, Jiangsheng; Wu, Shuizhu

    2013-09-01

    Herein, we describe a multifunctional anti-cancer prodrug system based on water-dispersible carbon nanotube (CNT); this prodrug system features active targeting, pH-triggered drug release, and photodynamic therapeutic properties. For this prodrug system (with the size of 100-300 nm), an anti-cancer drug, doxorubicin (DOX), was incorporated onto CNT via a cleavable hydrazone bond; and a targeting ligand (folic acid) was also coupled onto CNT. This prodrug can preferably enter folate receptor (FR)-positive cancer cells and undergo intracellular release of the drug triggered by the reduced pH. The targeted CNT-based prodrug system can cause lower cell viability toward FR-positive cells compared to the non-targeted ones. Moreover, the CNT carrier exhibits photodynamic therapeutic (PDT) action; and the cell viability of FR-positive cancer cells can be further reduced upon light irradiation. The dual effects of pH-triggered drug release and PDT increase the therapeutic efficacy of the DOX-CNT prodrug. This study may offer some useful insights on designing and improving the applicability of CNT for other drug delivery systems.

  12. NIR Fluorogenic Dye as a Modular Platform for Prodrug Assembly: Real-Time in vivo Monitoring of Drug Release.

    PubMed

    Redy-Keisar, Orit; Ferber, Shiran; Satchi-Fainaro, Ronit; Shabat, Doron

    2015-06-01

    The ability to monitor drug release in vivo provides essential pharmacological information. We developed a new modular approach for the preparation of theranostic prodrugs with a turn-ON near-infrared (NIR) fluorescence mode of action. The prodrugs release their chemotherapeutic cargo and an active cyanine fluorophore upon reaction with a specific analyte. The prodrug platform is based on the fluorogenic dye QCy7; upon removal of a triggering substrate, the dye fluoresces, and the free drug is released. The evaluated camptothecin prodrug was activated by endogenous hydrogen peroxide produced in tumor cells in vitro and in vivo. Drug release and in vitro cytotoxicity were correlated with the emitted fluorescence. The prodrug activation was effectively imaged in real time in mice bearing tumors. The modular design of the QCy7 fluorogenic platform should allow the preparation of numerous other prodrugs with various triggering substrates and chemotherapeutic agents. We anticipate that the development of real-time in vivo monitoring tools such as that described herein will pave the way for personalized therapy.

  13. Constitutive Triglyceride Turnover into the Mesenteric Lymph Is Unable to Support Efficient Lymphatic Transport of a Biomimetic Triglyceride Prodrug.

    PubMed

    Han, Sifei; Hu, Luojuan; Quach, Tim; Simpson, Jamie S; Trevaskis, Natalie L; Porter, Christopher J H

    2016-02-01

    The triglyceride (TG) mimetic prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) biochemically integrates into intestinal lipid transport and lipoprotein assembly pathways and thereby promotes the delivery of mycophenolic acid (MPA) into the lymphatic system. As lipoprotein (LP) formation occurs constitutively, even in the fasted state, the current study aimed to determine whether lymphatic transport of 2-MPA-TG was dependent on coadministered exogenous lipid. In vitro incubation of the prodrug with rat digestive fluid and in situ intestinal perfusion experiments revealed that hydrolysis and absorption of the prodrug were relatively unaffected by the quantity of lipid in formulations. In vivo studies in rats, however, showed that the lymphatic transport of TG and 2-MPA-TG was significantly higher following administration with higher quantities of lipid and that oleic acid (C18:1) was more effective in promoting prodrug transport than lipids with higher degrees of unsaturation. The recovery of 2-MPA-TG and TG in lymph correlated strongly (R(2) = 0.99) and more than 97% of the prodrug was associated with chylomicrons. Inhibition of LP assembly by Pluronic L81 simultaneously inhibited the lymphatic transport of 2-MPA-TG and TG. In conclusion, although the TG mimetic prodrug effectively incorporates into TG resynthetic pathways, lipid coadministration is still required to support efficient lymphatic transport.

  14. Donor states in inverse opals

    SciTech Connect

    Mahan, G. D.

    2014-09-21

    We calculate the binding energy of an electron bound to a donor in a semiconductor inverse opal. Inverse opals have two kinds of cavities, which we call octahedral and tetrahedral, according to their group symmetry. We put the donor in the center of each of these two cavities and obtain the binding energy. The binding energies become very large when the inverse opal is made from templates with small spheres. For spheres less than 50 nm in diameter, the donor binding can increase to several times its unconfined value. Then electrons become tightly bound to the donor and are unlikely to be thermally activated to the semiconductor conduction band. This conclusion suggests that inverse opals will be poor conductors.

  15. Donor states in inverse opals

    NASA Astrophysics Data System (ADS)

    Mahan, G. D.

    2014-09-01

    We calculate the binding energy of an electron bound to a donor in a semiconductor inverse opal. Inverse opals have two kinds of cavities, which we call octahedral and tetrahedral, according to their group symmetry. We put the donor in the center of each of these two cavities and obtain the binding energy. The binding energies become very large when the inverse opal is made from templates with small spheres. For spheres less than 50 nm in diameter, the donor binding can increase to several times its unconfined value. Then electrons become tightly bound to the donor and are unlikely to be thermally activated to the semiconductor conduction band. This conclusion suggests that inverse opals will be poor conductors.

  16. Donor selection in heart transplantation

    PubMed Central

    Emani, Sitaramesh; Sai-Sudhakar, Chittoor B.; Higgins, Robert S. D.; Whitson, Bryan A.

    2014-01-01

    There is increased scrutiny on the quality in health care with particular emphasis on institutional heart transplant survival outcomes. An important aspect of successful transplantation is appropriate donor selection. We review the current guidelines as well as areas of controversy in the selection of appropriate hearts as donor organs to ensure optimal outcomes. This decision is paramount to the success of a transplant program as well as recipient survival and graft function post-transplant. PMID:25132976

  17. Self-assemblies of pH-activatable PEGylated multiarm poly(lactic acid-co-glycolic acid)-doxorubicin prodrugs with improved long-term antitumor efficacies.

    PubMed

    Ding, Jianxun; Li, Di; Zhuang, Xiuli; Chen, Xuesi

    2013-10-01

    Two pH-activatable star-shaped prodrugs are synthesized through the condensation reaction between Y- or dumbbell-shaped poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PEG-PLGA) copolymer and acid-sensitive cis-aconityl-doxorubicin. The prodrugs self-assemble into micelles with favorable hydrodynamic radii and relatively low critical micelle concentrations. In vitro DOX release from prodrug micelles is accelerated by the decrease of the PLGA content or at the late endosomal pH. The efficient cellular uptake and intracellular DOX release of the prodrug micelles are confirmed and the improved long-term anti-proliferative activities of prodrug micelles are revealed. These features suggest that the prodrugs provide a favorable approach to construct effective polymeric drug delivery systems for malignancy therapy.

  18. Bone marrow transplantation across major histocompatibility barriers. V. Protection of mice from lethal graft-vs. -host disease by pretreatment of donor cells with monoclonal anti-Thy-1. 2 coupled to the toxin ricin

    SciTech Connect

    Vallera, D.A.; Youle, R.J.; Neville, D.M. Jr.; Kersey, J.H.

    1982-03-01

    A new method has been devised to eliminate T cells from murine bone marrow grafts across major histocompatibility barriers and thus prevent graft-vs.-host disease (GVHD). The method utilizes a monoclonal antibody directed at the Thy-1.2 antigen but is complement independent. To make anti-Thy-1.2 toxic, the antibody is covalently linked to the toxin ricin. Ricin ordinarily binds, enters, and kills cells through receptors containing galactose. The hybrid protein, anti-Thy-1.2-ricin, can enter and kill cells via the Thy-1.2 receptor. In the presence of lactose the usual entry route for ricin is largely blocked and the hybrid is shown to be a highly selective reagent that is T cell specific in its inhibition of mitogen-stimulated splenocytes. We have used a model of severe and fatal GVHD where BALB/c splenocytes and bone marrow cells are given to irradiated C57BL/6 recipients. Over 90% of these mice die by day 70, exhibiting signs of GVHD. When donor cells are pretreated with 0.5 microgram/ml of anti-Thy-1.2-ricin plus 200 mM lactose before injection, 10 of 11 animals survive through day 70 without signs of GVHD. These studies demonstrate that ricin linked to monoclonal antibodies may have utility related to the prevention of GVHD in human bone marrow transplantation.

  19. Motivations for Giving of Alumni Donors, Lapsed Donors and Non-Donors: Implications for Christian Higher Education

    ERIC Educational Resources Information Center

    Rugano, Emilio Kariuki

    2011-01-01

    This descriptive and causal comparative study sought to identify motivations for alumni donor acquisition and retention in Christian institutions of higher learning. To meet this objective, motivations for alumni donors, lapsed donors, and non-donors were analyzed and compared. Data was collected through an electronic survey of a stratified sample…

  20. Chemoenzymatic Syntheses and Anti-HIV-1 Activity of Glucose-Nucleoside Conjugates as Prodrugs

    PubMed Central

    Rodríguez-Pérez, Tatiana; Fernández, Susana; Sanghvi, Yogesh S.; Detorio, Mervi; Schinazi, Raymond F.; Gotor, Vicente; Ferrero, Miguel

    2010-01-01

    Phosphodiester linked conjugates of various nucleosides such as d4U, d4T, IdUrd, ddI, ddA, virazole, ara-A and ara-C containing a glucosyl moiety have been described. These compounds were designed to act as prodrugs, where the corresponding 5′-monophosphates may be generated intracellularly. The synthesis of the glycoconjugates was achieved in good yields by condensation of a glucosyl phosphoramidite 7 with nucleosides in the presence of an activating agent. It was demonstrated that the glucose-conjugates improve water solubility of the nucleoside analogues, for example up to 31-fold for ara-A conjugate compared to ara-A alone. The new conjugates were tested for their anti-HIV-1 activity in human lymphocytes. These derivatives offer a convenient design for potential prodrug candidates with the possibility to improve the physicochemical properties and therapeutic activity of nucleoside analogues. PMID:21077659

  1. Design, synthesis, and application of novel triclosan prodrugs as potential antimalarial and antibacterial agents.

    PubMed

    Mishra, Satyendra; Karmodiya, Krishanpal; Parasuraman, Prasanna; Surolia, Avadhesha; Surolia, Namita

    2008-05-15

    A number of new triclosan-conjugated analogs bearing biodegradable ester linkage have been synthesized, characterized and evaluated for their antimalarial and antibacterial activities. Many of these compounds exhibit good inhibition against Plasmodium falciparum and Escherichia coli. Among them tertiary amine containing triclosan-conjugated prodrug (5) inhibited both P. falciparum (IC(50); 0.62microM) and E. coli (IC(50); 0.26microM) at lower concentrations as compared to triclosan. Owing to the presence of a cleavable ester moiety, these new prodrugs are hydrolyzed under physiological conditions and parent molecule, triclosan, is released. Further, introduction of tertiary/quaternary functionality increases their cellular uptake. These properties impart them with higher potency to their antimalarial as well as antibacterial activities. The best compound among them 5 shows close to four-fold enhanced activities against P. falciparum and E. coli cultures as compared to triclosan.

  2. Far-red light activatable, multifunctional prodrug for fluorescence optical imaging and combinational treatment.

    PubMed

    Bio, Moses; Rajaputra, Pallavi; Nkepang, Gregory; You, Youngjae

    2014-04-24

    We recently developed "photo-unclick chemistry", a novel chemical tool involving the cleavage of aminoacrylate by singlet oxygen, and demonstrated its application to visible light-activatable prodrugs. In this study, we prepared an advanced multifunctional prodrug, Pc-(L-CA4)2, composed of the fluorescent photosensitizer phthalocyanine (Pc), an SO-labile aminoacrylate linker (L), and a cytotoxic drug combretastatin A-4 (CA4). Pc-(L-CA4)2 had reduced dark toxicity compared with CA4. However, once illuminated, it showed improved toxicity similar to CA4 and displayed bystander effects in vitro. We monitored the time-dependent distribution of Pc-(L-CA4)2 using optical imaging with live mice. We also effectively ablated tumors by the illumination with far-red light to the mice, presumably through the combined effects of photodynamic therapy (PDT) and released chemotherapy drug, without any sign of acute systemic toxicity.

  3. Mesenchymal stem cells as cellular vehicles for prodrug gene therapy against tumors.

    PubMed

    Amara, Ikrame; Touati, Walid; Beaune, Philippe; de Waziers, Isabelle

    2014-10-01

    Gene-directed enzyme prodrug therapy (GDEPT) consists of targeted delivery to tumor cells of a suicide gene responsible for the in situ conversion of a prodrug into cytotoxic metabolites. One of the major impediments of GDEPT is to target specifically the tumor cells with the suicide gene. Among gene delivery methods, mesenchymal stem cells (MSCs) have emerged recently as potential cellular vehicles for gene delivery. MSCs are particularly suited for gene transduction. They exhibit remarkable migratory property towards tumors and their metastases and they are weakly immunogenic. This review will summarize the current knowledge about MSCs engineered to express different suicide genes (cytosine deaminase, thymidine kinase, carboxylesterase, cytochrome P450) to elicit a significant antitumor response against brain tumors, ovarian, hepatocellular, pancreatic, renal or medullary thyroid carcinomas, breast or prostate cancer and pulmonary metastases. The potential side effects of these MSC-based tumor therapies will also be considered to highlight certain aspects that need to be improved prior to clinical use.

  4. Galactosyl prodrug of palmitoylethanolamide: synthesis, stability, cell permeation and cytoprotective activity.

    PubMed

    Luongo, Elvira; Russo, Roberto; Avagliano, Carmen; Santoro, Anna; Melisi, Daniela; Orefice, Nicola Salvatore; Raso, Giuseppina Mattace; Meli, Rosaria; Magliocca, Salvatore; Nieddu, Maria; Santiago, Gilvandete Maria Pinheiro; Boatto, Gianpiero; Calignano, Antonio; Rimoli, Maria Grazia

    2014-10-01

    N-Palmitoylethanolamide (PEA) is emerging as a novel therapeutic agent in the treatment of neuropathic pain and neurodegenerative diseases. Unfortunately, PEA poorly reaches the central nervous system (CNS), after peripheral administration, since it is inactivated through intracellular hydrolysis by lipid amidases. Since prodrug approach is one of the most popular methods used to increase cell permeability, the aim of this paper consists in the synthesis of a new galactosyl prodrug of PEA, the palmitoylethanolamide-succinamyl-D-galactos-6'-yl ester (PEAGAL). Biological experiments both in neuroblastoma and in C6 glioma cells, together with quantitative analyses performed through a LC-MS-MS technique, demonstrate the better efficacy of PEAGAL compared to PEA and its higher cell permeation. Our results encourage further experiments in animal models of neuropathic pain and of neurological disorders and/or neurodegenerative diseases, in order to promote a more effective peripherally administrated derivative of PEA.

  5. Copper-free click-chemistry platform to functionalize cisplatin prodrugs.

    PubMed

    Pathak, Rakesh K; McNitt, Christopher D; Popik, Vladimir V; Dhar, Shanta

    2014-06-02

    The ability to rationally design and construct a platform technology to develop new platinum(IV) [Pt(IV)] prodrugs with functionalities for installation of targeting moieties, delivery systems, fluorescent reporters from a single precursor with the ability to release biologically active cisplatin by using well-defined chemistry is critical for discovering new platinum-based therapeutics. With limited numbers of possibilities considering the sensitivity of Pt(IV) centers, we used a strain-promoted azide-alkyne cycloaddition approach to provide a platform, in which new functionalities can easily be installed on cisplatin prodrugs from a single Pt(IV) precursor. The ability of this platform to be incorporated in nanodelivery vehicle and conjugation to fluorescent reporters were also investigated.

  6. Discovery of a new HIV-1 inhibitor scaffold and synthesis of potential prodrugs of indazoles.

    PubMed

    Kim, Se-Ho; Markovitz, Benjamin; Trovato, Richard; Murphy, Brett R; Austin, Harry; Willardsen, Adam J; Baichwal, Vijay; Morham, Scott; Bajji, Ashok

    2013-05-15

    A new oxazole scaffold showing great promise in HIV-1 inhibition has been discovered by cell-based screening of an in-house library and scaffold modification. Follow-up SAR study focusing on the 5-aryl substituent of the oxazole core has identified 4k (EC50=0.42μM, TI=50) as a potent inhibitor. However, the analogues suffered from poor aqueous solubility. To address this issue, we have developed broadly applicable potential prodrugs of indazoles. Among them, N-acyloxymethyl analogue 11b displayed promising results (i.e., increased aqueous solubility and susceptibility to enzymatic hydrolysis). Further studies are warranted to fully evaluate the analogues as the potential prodrugs with improved physiochemical and PK properties.

  7. Preparation of well-defined ibuprofen prodrug micelles by RAFT polymerization.

    PubMed

    Hasegawa, Urara; van der Vlies, André J; Wandrey, Christine; Hubbell, Jeffrey A

    2013-09-09

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat acute pain, fever, and inflammation and are being explored in a new indication in cancer. Side effects associated with long-term use of NSAIDs such as gastrointestinal damage and elevated risk of stroke, however, can limit their use and exploration in new indications. Here we report a facile method to prepare well-defined amphiphilic diblock copolymer NSAID prodrugs by direct reversible addition-fragmentation transfer (RAFT) polymerization of the acrylamide derivative of ibuprofen (IBU), a widely used NSAID. The synthesis and self-assembling behavior of amphiphilic diblock copolymers (PEG-PIBU) having a hydrophilic poly(ethylene glycol) block and a hydrophobic IBU-bearing prodrug block were investigated. Release profiles of IBU from the micelles by hydrolysis were evaluated. Furthermore, the antiproliferative action of the IBU-containing micelles in human cervical carcinoma (HeLa) and murine melanoma (B16-F10) cells was assessed.

  8. Far-Red Light Activatable, Multifunctional Prodrug for Fluorescence Optical Imaging and Combinational Treatment

    PubMed Central

    2015-01-01

    We recently developed “photo-unclick chemistry”, a novel chemical tool involving the cleavage of aminoacrylate by singlet oxygen, and demonstrated its application to visible light-activatable prodrugs. In this study, we prepared an advanced multifunctional prodrug, Pc-(L-CA4)2, composed of the fluorescent photosensitizer phthalocyanine (Pc), an SO-labile aminoacrylate linker (L), and a cytotoxic drug combretastatin A-4 (CA4). Pc-(L-CA4)2 had reduced dark toxicity compared with CA4. However, once illuminated, it showed improved toxicity similar to CA4 and displayed bystander effects in vitro. We monitored the time-dependent distribution of Pc-(L-CA4)2 using optical imaging with live mice. We also effectively ablated tumors by the illumination with far-red light to the mice, presumably through the combined effects of photodynamic therapy (PDT) and released chemotherapy drug, without any sign of acute systemic toxicity. PMID:24694092

  9. The Independent Living Donor Advocate: An Essential Role for Living Kidney Donation.

    PubMed

    Robbins, Karen C

    2014-01-01

    Prior to 2007, living kidney donors who donated a kidney to a person with chronic kidney disease were screened, educated, and cared for by the same healthcare team caring for the recipient of the transplant. The independent living donor advocate or advocate team was created out of the need to ensure that the rights of the person donating a kidney are protected, respected, and maintained. Transplant programs must now have an advocate or advocate team who is separate from the recipient healthcare team to provide objective support for the donor, without regard for the recipient, and avoid any perception of a conflict of interest between the donor and recipient.

  10. Evaluation of antimalarial activity and toxicity of a new primaquine prodrug.

    PubMed

    Davanço, Marcelo Gomes; Aguiar, Anna Caroline Campos; Dos Santos, Leandro Alves; Padilha, Elias Carvalho; Campos, Michel Leandro; de Andrade, Cleverton Roberto; da Fonseca, Luiz Marcos; Dos Santos, Jean Leandro; Chin, Chung Man; Krettli, Antoniana Ursine; Peccinini, Rosangela Gonçalves

    2014-01-01

    Plasmodium vivax is the most prevalent of the five species causing malaria in humans. The current available treatment for P. vivax malaria is limited and unsatisfactory due to at least two drawbacks: the undesirable side effects of primaquine (PQ) and drug resistance to chloroquine. Phenylalanine-alanine-PQ (Phe-Ala-PQ) is a PQ prodrug with a more favorable pharmacokinetic profile compared to PQ. The toxicity of this prodrug was evaluated in in vitro assays using a human hepatoma cell line (HepG2), a monkey kidney cell line (BGM), and human red blood cells deficient in the enzyme glucose-6-phosphate-dehydrogenase (G6PD). In addition, in vivo toxicity assays were performed with rats that received multiple doses of Phe-Ala-PQ to evaluate biochemical, hematological, and histopathological parameters. The activity was assessed by the inhibition of the sporogonic cycle using a chicken malaria parasite. Phe-Ala-PQ blocked malaria transmission in Aedes mosquitoes. When compared with PQ, it was less cytotoxic to BGM and HepG2 cells and caused less hemolysis of G6PD-deficient red blood cells at similar concentrations. The prodrug caused less alteration in the biochemical parameters than did PQ. Histopathological analysis of the liver and kidney did show differences between the control and Phe-Ala-PQ-treated groups, but they were not statistically significant. Taken together, the results highlight the prodrug as a novel lead compound candidate for the treatment of P. vivax malaria and as a blocker of malaria transmission.

  11. Evaluation of Antimalarial Activity and Toxicity of a New Primaquine Prodrug

    PubMed Central

    Davanço, Marcelo Gomes; Aguiar, Anna Caroline Campos; dos Santos, Leandro Alves; Padilha, Elias Carvalho; Campos, Michel Leandro; de Andrade, Cleverton Roberto; da Fonseca, Luiz Marcos; dos Santos, Jean Leandro; Chin, Chung Man; Krettli, Antoniana Ursine; Peccinini, Rosangela Gonçalves

    2014-01-01

    Plasmodium vivax is the most prevalent of the five species causing malaria in humans. The current available treatment for P. vivax malaria is limited and unsatisfactory due to at least two drawbacks: the undesirable side effects of primaquine (PQ) and drug resistance to chloroquine. Phenylalanine-alanine-PQ (Phe-Ala-PQ) is a PQ prodrug with a more favorable pharmacokinetic profile compared to PQ. The toxicity of this prodrug was evaluated in in vitro assays using a human hepatoma cell line (HepG2), a monkey kidney cell line (BGM), and human red blood cells deficient in the enzyme glucose-6-phosphate-dehydrogenase (G6PD). In addition, in vivo toxicity assays were performed with rats that received multiple doses of Phe-Ala-PQ to evaluate biochemical, hematological, and histopathological parameters. The activity was assessed by the inhibition of the sporogonic cycle using a chicken malaria parasite. Phe-Ala-PQ blocked malaria transmission in Aedes mosquitoes. When compared with PQ, it was less cytotoxic to BGM and HepG2 cells and caused less hemolysis of G6PD-deficient red blood cells at similar concentrations. The prodrug caused less alteration in the biochemical parameters than did PQ. Histopathological analysis of the liver and kidney did show differences between the control and Phe-Ala-PQ-treated groups, but they were not statistically significant. Taken together, the results highlight the prodrug as a novel lead compound candidate for the treatment of P. vivax malaria and as a blocker of malaria transmission. PMID:25133630

  12. Platinum(IV) prodrug conjugated Pd@Au nanoplates for chemotherapy and photothermal therapy.

    PubMed

    Shi, Saige; Chen, Xiaolan; Wei, Jingping; Huang, Yizhuan; Weng, Jian; Zheng, Nanfeng

    2016-03-14

    Owing to the excellent near infrared (NIR) light absorption and efficient passive targeting toward tumor tissue, two-dimensional (2D) core-shell PEGylated Pd@Au nanoplates have great potential in both photothermal therapy and drug delivery systems. In this work, we successfully conjugate Pd@Au nanoplates with a platinum(IV) prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)2] to obtain a nanocomposite (Pd@Au-PEG-Pt) for combined photothermal-chemotherapy. The prepared Pd@Au-PEG-Pt nanocomposite showed excellent stability in physiological solutions and efficient Pt(IV) prodrug loading. Once injected into biological tissue, the Pt(IV) prodrug was easily reduced by physiological reductants (e.g. ascorbic acid or glutathione) into its cytotoxic and hydrophilic Pt(II) form and released from the original nanocomposite, and the NIR laser irradiation could accelerate the release of Pt(II) species. More importantly, Pd@Au-PEG-Pt has high tumor accumulation (29%ID per g), which makes excellent therapeutic efficiency at relatively low power density possible. The in vivo results suggested that, compared with single therapy the combined thermo-chemotherapy treatment with Pd@Au-PEG-Pt resulted in complete destruction of the tumor tissue without recurrence, while chemotherapy using Pd@Au-PEG-Pt without irradiation or photothermal treatment using Pd@Au-PEG alone did not. Our work highlights the prospects of a feasible drug delivery strategy of the Pt prodrug by using 2D Pd@Au nanoplates as drug delivery carriers for multimode cancer treatment.

  13. In vivo and in situ tracking cancer chemotherapy by highly photostable NIR fluorescent theranostic prodrug.

    PubMed

    Wu, Xumeng; Sun, Xuanrong; Guo, Zhiqian; Tang, Jianbin; Shen, Youqing; James, Tony D; Tian, He; Zhu, Weihong

    2014-03-05

    In vivo monitoring of the biodistribution and activation of prodrugs is urgently required. Near infrared (NIR) fluorescence-active fluorophores with excellent photostability are preferable for tracking drug release in vivo. Herein, we describe a NIR prodrug DCM-S-CPT and its polyethylene glycol-polylactic acid (PEG-PLA) loaded nanoparticles as a potent cancer therapy. We have conjugated a dicyanomethylene-4H-pyran derivative as the NIR fluorophore with camptothecin (CPT) as the anticancer drug using a disulfide linker. In vitro experiments verify that the high intracellular glutathione (GSH) concentrations in tumor cells cause cleavage of the disulfide linker, resulting in concomitantly the active drug CPT release and significant NIR fluorescence turn-on with large Stokes shift (200 nm). The NIR fluorescence of DCM-S-CPT at 665 nm with fast response to GSH can act as a direct off-on signal reporter for the GSH-activatable prodrug. Particularly, DCM-S-CPT possesses much better photostability than ICG, which is highly desirable for in situ fluorescence-tracking of cancer chemotherapy. DCM-S-CPT has been successfully utilized for in vivo and in situ tracking of drug release and cancer therapeutic efficacy in living animals by NIR fluorescence. DCM-S-CPT exhibits excellent tumor-activatable performance when intravenously injected into tumor-bearing nude mice, as well as specific cancer therapy with few side effects. DCM-S-CPT loaded in PEG-PLA nanoparticles shows even higher antitumor activity than free CPT, and is also retained longer in the plasma. The tumor-targeting ability and the specific drug release in tumors make DCM-S-CPT as a promising prodrug, providing significant advances toward deeper understanding and exploration of theranostic drug-delivery systems.

  14. ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria.

    PubMed

    Miley, Galen P; Pou, Sovitj; Winter, Rolf; Nilsen, Aaron; Li, Yuexin; Kelly, Jane X; Stickles, Allison M; Mather, Michael W; Forquer, Isaac P; Pershing, April M; White, Karen; Shackleford, David; Saunders, Jessica; Chen, Gong; Ting, Li-Min; Kim, Kami; Zakharov, Lev N; Donini, Cristina; Burrows, Jeremy N; Vaidya, Akhil B; Charman, Susan A; Riscoe, Michael K

    2015-09-01

    ELQ-300 is a preclinical candidate that targets the liver and blood stages of Plasmodium falciparum, as well as the forms that are crucial to transmission of disease: gametocytes, zygotes, and ookinetes. A significant obstacle to the clinical development of ELQ-300 is related to its physicochemical properties. Its relatively poor aqueous solubility and high crystallinity limit absorption to the degree that only low blood concentrations can be achieved following oral dosing. While these low blood concentrations are sufficient for therapy, the levels are too low to establish an acceptable safety margin required by regulatory agencies for clinical development. One way to address the challenging physicochemical properties of ELQ-300 is through the development of prodrugs. Here, we profile ELQ-337, a bioreversible O-linked carbonate ester prodrug of the parent molecule. At the molar equivalent dose of 3 mg/kg of body weight, the delivery of ELQ-300 from ELQ-337 is enhanced by 3- to 4-fold, reaching a maximum concentration of drug in serum (C max) of 5.9 μM by 6 h after oral administration, and unlike ELQ-300 at any dose, ELQ-337 provides single-dose cures of patent malaria infections in mice at low-single-digit milligram per kilogram doses. Our findings show that the prodrug strategy represents a viable approach to overcome the physicochemical limitations of ELQ-300 to deliver the active drug to the bloodstream at concentrations sufficient for safety and toxicology studies, as well as achieving single-dose cures.

  15. Direct chemical grafted curcumin on halloysite nanotubes as dual-responsive prodrug for pharmacological applications.

    PubMed

    Massaro, M; Amorati, R; Cavallaro, G; Guernelli, S; Lazzara, G; Milioto, S; Noto, R; Poma, P; Riela, S

    2016-04-01

    Covalently functionalized halloysite nanotubes (HNTs) were successfully employed as dual-responsive nanocarriers for curcumin (Cur). Particularly, we synthesized HNT-Cur prodrug with a controlled curcumin release on dependence of both intracellular glutathione (GSH) and pH conditions. In order to obtain HNT-Cur produgs, halloysite was firstly functionalized with cysteamine through disulphide linkage. Afterwards, curcumin molecules were chemically conjugated to the amino end groups of halloysite via Schiff's base formation. The successful functionalization of halloysite was proved by thermogravimetric analysis, FT-IR spectroscopy, dynamic light scattering and scanning electron microscopy. Experimental data confirmed the presence of curcumin on HNT external surface. Moreover, we investigated the kinetics of curcumin release by UV-vis spectroscopy, which highlighted that HNT-Cur prodrug possesses dual stimuli-responsive ability upon exposure to GSH-rich or acidic environment. In vitro antiproliferative and antioxidant properties of HNT-Cur prodrug were studied with the aim to explore their potential applications in pharmaceutics. This work puts forward an efficient strategy to prepare halloysite based nanocarriers with controlled drug delivery capacity through direct chemical grafting with stimuli-responsive linkage.

  16. Lymph cancer chemotherapy: delivery of doxorubicin–gemcitabine prodrug and vincristine by nanostructured lipid carriers

    PubMed Central

    Ni, Shuqin; Qiu, Lei; Zhang, Guodong; Zhou, Haiyan; Han, Yong

    2017-01-01

    Purpose Radiation and chemotherapy are the most common course of treatment for B-cell lymphoma. Doxorubicin (DOX), gemcitabine (GEM), and vincristine (VCR) are the commonly used antilymphoma chemotherapeutic drugs. The aim of this study is to construct a novel drug delivery system for the combination delivery of the three drugs on lymphoma. Materials and methods DOX–GEM prodrug was synthesized. Novel nanostructured lipid carriers (NLCs) containing DOX–GEM prodrug and VCR were prepared and used to treat B-cell lymphoma through in vivo treatment to a lymph cancer animal model. The systemic toxicity of the nanomedicine was also evaluated during the treatment. Results DOX–GEM prodrug and VCR-loaded NLCs (DOX–GEM VCR NLCs) exhibited the highest antitumor effect in B-cell lymphoma cells and lymphoma animal xenografts when compared with the single drug-loaded NLCs and the drug solutions. Conclusion It could be concluded that the highest antitumor effect can be achieved by the system due to the stable drug-loading capacity, attractive anticancer therapeutic effects, and reduced toxicities in human Burkitt’s lymphoma cell line and mice-bearing cancer model. The resulting DOX–GEM VCR NLCs could be an efficient antilymph cancer agent and could be developed further for the treatment of other tumors. PMID:28280326

  17. A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer.

    PubMed

    Levy, Oren; Brennen, W Nathaniel; Han, Edward; Rosen, David Marc; Musabeyezu, Juliet; Safaee, Helia; Ranganath, Sudhir; Ngai, Jessica; Heinelt, Martina; Milton, Yuka; Wang, Hao; Bhagchandani, Sachin H; Joshi, Nitin; Bhowmick, Neil; Denmeade, Samuel R; Isaacs, John T; Karp, Jeffrey M

    2016-06-01

    Despite considerable advances in prostate cancer research, there is a major need for a systemic delivery platform that efficiently targets anti-cancer drugs to sites of disseminated prostate cancer while minimizing host toxicity. In this proof-of-principle study, human mesenchymal stem cells (MSCs) were loaded with poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) that encapsulate the macromolecule G114, a thapsigargin-based prostate specific antigen (PSA)-activated prodrug. G114-particles (∼950 nm in size) were internalized by MSCs, followed by the release of G114 as an intact prodrug from loaded cells. Moreover, G114 released from G114 MP-loaded MSCs selectively induced death of the PSA-secreting PCa cell line, LNCaP. Finally, G114 MP-loaded MSCs inhibited tumor growth when used in proof-of-concept co-inoculation studies with CWR22 PCa xenografts, suggesting that cell-based delivery of G114 did not compromise the potency of this pro-drug in-vitro or in-vivo. This study demonstrates a potentially promising approach to assemble a cell-based drug delivery platform, which inhibits cancer growth in-vivo without the need of genetic engineering. We envision that upon achieving efficient homing of systemically infused MSCs to cancer sites, this MSC-based platform may be developed into an effective, systemic 'Trojan Horse' therapy for targeted delivery of therapeutic agents to sites of metastatic PCa.

  18. A novel prodrug strategy to improve the oral absorption of O-desmethylvenlafaxine

    PubMed Central

    Liu, Mingyuan; Sun, Yantong; Zhao, Sen; Li, Youxin; Piao, Riyang; Yang, Yan; Gu, Jingkai

    2016-01-01

    O-Desmethylvenlafaxine (desvenlafaxine, ODV) is the active metabolite of venlafaxine, with similar activity and less risk for pharmacokinetic drug interactions compared to its parent compound venlafaxine. The purpose of this study was to design a series of esters of ODV and assess their potential as ODV prodrugs with improved bioavailability and brain uptake. Seven esters were synthesized and pharmacokinetic screening was performed in rats. The monoester formed on the phenolic hydroxyl of ODV (ODVP-1, ODVP-2, ODVP-3 and ODVP-5) could be degraded to ODV in rat plasma. These four compounds confirmed as possible prodrugs were then studied to evaluated the relative bioavailability of ODV they produced in beagle dogs. ODVP-1, ODVP-2 and ODVP-3 demonstrated higher relative bioavailability of ODV. Finally, ODVP-1, ODVP-2 and ODVP-3 were studied to evaluate their brain uptake in rats. The concentration of ODV in the rat plasma, brain and hypothalamus after administration of ODVP-1, ODVP-2 or ODVP-3 was higher compared with that of ODV. The higher bioavailability, improved pharmacokineics properties and more rapid penetration and translation of ODV suggest that ODVP-1, ODVP-2 or ODVP-3 may warrant further development and application as ODV prodrugs. PMID:27588083

  19. Prodrug delivery of novel PTP1B inhibitors to enhance insulin signalling.

    PubMed

    Erbe, D V; Klaman, L D; Wilson, D P; Wan, Z-K; Kirincich, S J; Will, S; Xu, X; Kung, L; Wang, S; Tam, S; Lee, J; Tobin, J F

    2009-06-01

    A growing percentage of the population is resistant to two key hormones - insulin and leptin - as a result of increased obesity, often leading to significant health consequences such as type 2 diabetes. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of signalling by both of these hormones, so that inhibitors of this enzyme may provide promise for correcting endocrine abnormalities in both diabetes and obesity. As with other tyrosine phosphatases, identification of viable drug candidates targeting PTP1B has been elusive because of the nature of its active site. Beginning with novel phosphotyrosine mimetics, we have designed some of the most potent PTP1B inhibitors. However, their highly acidic structures limit intrinsic permeability and pharmacokinetics. Ester prodrugs of these inhibitors improve their drug-like properties with the goal of delivering these nanomolar inhibitors to the cytoplasm of cells within target tissues. In addition to identifying prodrugs that is able to deliver active drugs into cells to inhibit PTP1B and increase insulin signalling, these compounds were further modified to gain a variety of cleavage properties for targeting activity in vivo. One such prodrug candidate improved insulin sensitivity in ob/ob mice, with lowered fasting blood glucose levels seen in the context of lowered fasting insulin levels following 4 days of intraperitoneal dosing. The results presented in this study highlight the potential for design of orally active drug candidates targeting PTP1B, while also delineating the considerable challenges remaining.

  20. Studies on synthesis, stability, release and pharmacodynamic profile of a novel diacerein-thymol prodrug.

    PubMed

    Dhaneshwar, Suneela; Patel, Vriha; Patil, Dipmala; Meena, Gourav

    2013-01-01

    Involvement of oxidative stress, leading to chondrocyte senescence and cartilage ageing has been implicated in the pathogenesis of osteoarthritis (OA). New efforts to prevent the development and progression of OA include strategies and interventions aimed at reducing oxidative damage in articular cartilage using antioxidants as adjuncts to conservative therapy. Diacerein is an anthraquinone derivative with a marked disease modifying effect on OA owing to IL-1 β inhibition. In the present work an attempt was made at design and development of a co-drug of diacerein with antioxidant thymol. Structural elucidation was carried out by spectral analysis. When release kinetics of prodrug was studied in phosphate buffer (pH 7.4) and small intestinal homogenates of rats, 91% and 94% diacerein was available respectively at the end of 4.5 h. Chemical linkage of thymol with diacerein improved its lipophilicity and hence bioavailability. Screening of prodrug in Freud's adjuvant-induced arthritis and ulcerogenic potential by Rainsford's cold stress model exhibited significant reduction in paw volume, joint diameter and ulcer index with superior anti-inflammatory/anti-arthritic activities than the standards. Results of histopathology of tibio-tarsal joint indicated that animals treated with diacerein exhibited moderate synovitis while thymol and physical mixture-treated animals showed mild synovitis. Interestingly in prodrug-treated animals synovitis was not observed. The results of this study underline the promising potential of co-drug of diacerein and thymol in the management of OA.

  1. A novel prodrug strategy to improve the oral absorption of O-desmethylvenlafaxine.

    PubMed

    Liu, Mingyuan; Sun, Yantong; Zhao, Sen; Li, Youxin; Piao, Riyang; Yang, Yan; Gu, Jingkai

    2016-09-01

    O-Desmethylvenlafaxine (desvenlafaxine, ODV) is the active metabolite of venlafaxine, with similar activity and less risk for pharmacokinetic drug interactions compared to its parent compound venlafaxine. The purpose of this study was to design a series of esters of ODV and assess their potential as ODV prodrugs with improved bioavailability and brain uptake. Seven esters were synthesized and pharmacokinetic screening was performed in rats. The monoester formed on the phenolic hydroxyl of ODV (ODVP-1, ODVP-2, ODVP-3 and ODVP-5) could be degraded to ODV in rat plasma. These four compounds confirmed as possible prodrugs were then studied to evaluated the relative bioavailability of ODV they produced in beagle dogs. ODVP-1, ODVP-2 and ODVP-3 demonstrated higher relative bioavailability of ODV. Finally, ODVP-1, ODVP-2 and ODVP-3 were studied to evaluate their brain uptake in rats. The concentration of ODV in the rat plasma, brain and hypothalamus after administration of ODVP-1, ODVP-2 or ODVP-3 was higher compared with that of ODV. The higher bioavailability, improved pharmacokineics properties and more rapid penetration and translation of ODV suggest that ODVP-1, ODVP-2 or ODVP-3 may warrant further development and application as ODV prodrugs.

  2. Mono- and di-bromo platinum(IV) prodrugs via oxidative bromination: synthesis, characterization, and cytotoxicity.

    PubMed

    Xu, Zoufeng; Wang, Zhigang; Yiu, Shek-Man; Zhu, Guangyu

    2015-12-14

    Platinum(IV)-based anticancer prodrugs have attracted much attention due to their relative inertness under physiological conditions, being activated inside cells, and their capacity for functionalization with a variety of small-molecule or macromolecule moieties. Novel asymmetric platinum(IV) compounds synthesized through expedient and unique methods are desired. Here we utilize N-bromosuccinimide (NBS) and carry out oxidative bromination on platinum(II) drugs, namely cisplatin, carboplatin, and oxaliplatin, to obtain asymmetric and mono-bromo platinum(IV) prodrugs. Different solvents are used to obtain various compounds, and the compounds are further functionalized. Di-bromo compounds are also obtained through NBS-directed oxidative bromination in ethanol. The crystal structures of representative compounds are discussed, and the reduction potentials of some compounds are examined. A cytotoxicity test shows that the mono- and di-bromo platinum(IV) compounds are active against human ovarian cancer cells. Our study enriches the family of asymmetric platinum(IV) prodrugs and provides with a convenient strategy to obtain brominated platinum(IV) complexes.

  3. A traceless reversible polymeric colistin prodrug to combat multidrug-resistant (MDR) gram-negative bacteria.

    PubMed

    Zhu, Chongyu; Schneider, Elena K; Wang, Jiping; Kempe, Kristian; Wilson, Paul; Velkov, Tony; Li, Jian; Davis, Thomas P; Whittaker, Michael R; Haddleton, David M

    2017-02-05

    Colistin methanesulfonate (CMS) is the only prodrug of colistin available for clinical use for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria. Owing to its slow and variable release, an alternative is urgently required to improve effectiveness. Herein we describe a PEGylated colistin prodrug whereby the PEG is attached via a cleavable linker (col-aaPEG) introducing an acetic acid terminated poly (ethylene glycol) methyl ether (aaPEG) onto the Thr residue of colistin. Due to the labile ester containing link, this prodrug is converted back into active colistin in vitro within 24h. Compared to CMS, it showed a similar or better antimicrobial performance against two MDR isolates of Pseudomonas aeruginosa and Acinetobacter baumannii through in vitro disk diffusion, broth dilution and time-kill studies. In a mouse infection model, col-aaPEG displayed acceptable bacterial killing against P. aeruginosa ATCC 27853 and no nephrotoxicity was found after systemic administration, suggesting it to be a potential alternative for CMS.

  4. Lipophilic pyrazinoic acid amide and ester prodrugs stability, activation and activity against M. tuberculosis.

    PubMed

    Simões, Marta Filipa; Valente, Emília; Gómez, M José Rodríguez; Anes, Elsa; Constantino, Luís

    2009-06-28

    Pyrazinamide (PZA) is active against M. tuberculosis and is a first line agent for the treatment of human tuberculosis. PZA is itself a prodrug that requires activation by a pyrazinamidase to form its active metabolite pyrazinoic acid (POA). Since the specificity of cleavage is dependent on a single bacterial enzyme, resistance to PZA is often found in tuberculosis patients. Esters of POA have been proposed in the past as alternatives to PZA however the most promising compounds were rapidly degraded in the presence of serum. In order to obtain compounds that could survive during the transport phase, we synthesized lipophilic ester and amide POA derivatives, studied their activity against M. tuberculosis, their stability in plasma and rat liver homogenate and also their activation by a mycobacterial homogenate. The new lipophilic ester prodrugs were found to be active in concentrations 10-fold lower than those needed for PZA to kill sensitive M. tuberculosis and also have a suitable stability in the presence of plasma. Amides of POA although more stable in plasma have lower activity. The reason can probably be found in the rate of activation of both types of prodrugs; while esters are easily activated by mycobacterial esterases, amides are resistant to activation and are not transformed into POA at a suitable rate.

  5. Synthesis and analysis of activity of a potential anti-melanoma prodrug with a hydrazine linker.

    PubMed

    Frąckowiak-Wojtasek, Bożena; Gąsowska-Bajger, Beata; Mazurek, Magdalena; Raniszewska, Agnieszka; Logghe, Marieke; Smolarczyk, Ryszard; Cichoń, Tomasz; Szala, Stanisław; Wojtasek, Hubert

    2014-01-01

    A potential anti-melanoma prodrug containing a phenolic activator, a hydrazine linker, and a nitrogen mustard effector - (N-{4-[bis-(2-chloroethyl)amino]benzoyl}-N'-(4-hydroxybenzyl)hydrazine) has been synthesized in seven steps. Spectrophotometric measurements of its oxidation by tyrosinase showed a rapid increase of absorbance at 337 nm. HPLC analysis demonstrated that two major products were formed. However, during the reaction one of the products was converted into the other. The stable product with a maximum of absorption at 337 nm was isolated and identified as 5,6-dihydroxy-1H-indazol-1-yl 4-[bis-(2-chloroethyl)amino]benzoate. It was formed by a cyclization of the enzymatically generated o-quinone. This reaction was unexpected, since the acylated hydrazine nitrogen atom should not be sufficiently nucleophilic to attack the o-quinone ring. This cyclization prevented the effector release from the enzyme-activated prodrug. As a result, the prodrug showed only limited specificity for B16-F10 murine melanoma cells compared to reference cell lines. When applied in solid tumors in mice it showed slightly higher activity than the parent mustard drug (4-[bis-(2-chloroethyl)amino]benzoic cid), but significantly lower activity than melphalan, a commercial mustard drug with a structure resembling tyrosine, occasionally used in the treatment of melanoma.

  6. Macromolecular Prodrugs of Ribavirin: Structure-Function Correlation as Inhibitors of Influenza Infectivity.

    PubMed

    Riber, Camilla Frich; Hinton, Tracey M; Gajda, Paulina; Zuwala, Kaja; Tolstrup, Martin; Stewart, Cameron; Zelikin, Alexander N

    2017-01-03

    The requirement for new antiviral therapeutics is an ever present need. Particularly lacking are broad spectrum antivirals that have low toxicity. We develop such agents based on macromolecular prodrugs whereby both the polymer chain and the drug released from the polymer upon cell entry have antiviral effects. Specifically, macromolecular prodrugs were designed herein based on poly(methacrylic acid) and ribavirin. Structure-function parameter space was analyzed via the synthesis of 10 polymer compositions varied by molar mass and drug content. Antiviral activity was tested in cell culture against both low and high pathogenic strains of influenza. Lead compounds were successfully used to counter infectivity of influenza in chicken embryos. The lead composition with the highest activity against influenza was also active against another respiratory pathogen, respiratory syncytial virus, providing opportunity to potentially treat infection by the two pathogens with one antiviral agent. In contrast, structure-function activity against the herpes simplex virus was drastically different, revealing limitations of the broad spectrum antiviral agents based on macromolecular prodrugs.

  7. Harnessing chemoselective imine ligation for tethering bioactive molecules to platinum(IV) prodrugs.

    PubMed

    Wong, Daniel Yuan Qiang; Lau, Jia Yi; Ang, Wee Han

    2012-05-28

    Platinum(II) anticancer drugs are among the most effective and often used chemotherapeutic drugs. In recent years, there has been increasing interest in exploiting inert platinum(IV) scaffolds as a prodrug strategy to mitigate the limitations of platinum(II) anticancer complexes. In this prodrug strategy, the axial ligands are released concomitantly upon intracellular reduction to the active platinum(II) congener, offering the possibility of conjugating bioactive co-drugs which may synergistically enhance cytotoxicity on cancer cells. Existing techniques of tethering bioactive molecules to the axial positions of platinum(IV) prodrugs suffer from limited scope, poor yields and low reliability. This report explores the applications of current chemoselective ligation chemistries to platinum(IV) anticancer complexes with the aim of addressing the aforementioned limitations. Here, we describe the synthesis of a platinum(IV) complex bearing an aromatic aldehyde functionality and explored the scope of imine ligation with various hydrazide and aminooxy functionalized substrates. As a proof of concept, we tethered a six sequence long peptide mimetic (AMVSEF) of the anti-inflammatory protein, ANXA1.

  8. Dipeptide Prodrug Approach to Evade Efflux Pumps and CYP3A4 Metabolism of Lopinavir

    PubMed Central

    Patel, Mitesh; Sheng, Ye; Mandava, Nanda K.; Pal, Dhananjay; Mitra, Ashim K.

    2014-01-01

    Oral absorption of lopinavir (LPV) is limited due to P-glycoprotein (P-gp) and multidrug resistance-associated protein2 (MRP2) mediated efflux by intestinal epithelial cells. Moreover, LPV is extensively metabolized by CYP3A4 enzymes. In the present study, dipeptide prodrug approach was employed to circumvent efflux pumps (P-gp and MRP2) and CYP3A4 mediated metabolism of LPV. Valine-isoleucine-LPV (Val-Ile-LPV) was synthesized and identified by LCMS and NMR techniques. The extent of LPV and Val-Ile-LPV interactions with P-gp and MRP2 was studied by uptake and transport studies across MDCK-MDR1 and MDCK-MRP2 cells. To determine the metabolic stability, time and concentration dependent degradation study was performed in liver microsomes. Val-Ile-LPV exhibited significantly higher aqueous solubility relative to LPV. This prodrug generated higher stability under acidic pH. Val-Ile-LPV demonstrated significantly lower affinity towards P-gp and MRP2 relative to LPV. Transepithelial transport of Val-Ile-LPV was significantly higher in the absorptive direction (apical to basolateral) relative to LPV. Importantly, Val-Ile-LPV was recognized as an excellent substrate by peptide transporter. Moreover, Val-Ile-LPV displayed significantly higher metabolic stability relative to LPV. Results obtained from this study suggested that dipeptide prodrug approach is a viable option to elevate systemic levels of LPV following oral administration PMID:25261710

  9. A Prodrug Approach to the Use of Coumarins as Potential Therapeutics for Superficial Mycoses

    PubMed Central

    Mercer, Derry K.; Robertson, Jennifer; Wright, Kristine; Miller, Lorna; Smith, Shane; Stewart, Colin S.; O′Neil, Deborah A.

    2013-01-01

    Superficial mycoses are fungal infections of the outer layers of the skin, hair and nails that affect 20–25% of the world's population, with increasing incidence. Treatment of superficial mycoses, predominantly caused by dermatophytes, is by topical and/or oral regimens. New therapeutic options with improved efficacy and/or safety profiles are desirable. There is renewed interest in natural product-based antimicrobials as alternatives to conventional treatments, including the treatment of superficial mycoses. We investigated the potential of coumarins as dermatophyte-specific antifungal agents and describe for the first time their potential utility as topical antifungals for superficial mycoses using a prodrug approach. Here we demonstrate that an inactive coumarin glycone, esculin, is hydrolysed to the antifungal coumarin aglycone, esculetin by dermatophytes. Esculin is hydrolysed to esculetin β-glucosidases. We demonstrate that β-glucosidases are produced by dermatophytes as well as members of the dermal microbiota, and that this activity is sufficient to hydrolyse esculin to esculetin with concomitant antifungal activity. A β-glucosidase inhibitor (conduritol B epoxide), inhibited antifungal activity by preventing esculin hydrolysis. Esculin demonstrates good aqueous solubility (<6 g/l) and could be readily formulated and delivered topically as an inactive prodrug in a water-based gel or cream. This work demonstrates proof-of-principle for a therapeutic application of glycosylated coumarins as inactive prodrugs that could be converted to an active antifungal in situ. It is anticipated that this approach will be applicable to other coumarin glycones. PMID:24260474

  10. Synthesis and Antitumor Properties of BQC-Glucuronide, a Camptothecin Prodrug for Selective Tumor Activation.

    PubMed

    Prijovich, Zeljko M; Burnouf, Pierre-Alain; Chou, Hua-Cheng; Huang, Ping-Ting; Chen, Kai-Chuan; Cheng, Tian-Lu; Leu, Yu-Lin; Roffler, Steve R

    2016-04-04

    Major limitations of camptothecin anticancer drugs (toxicity, nonselectivity, water insolubility, inactivation by human serum albumin) may be improved by creating glucuronide prodrugs that rely on beta-glucuronidase for their activation. We found that the camptothecin derivative 5,6-dihydro-4H-benzo[de]quinoline-camptothecin (BQC) displays greater cytotoxicity against cancer cells than the clinically used camptothecin derivatives SN-38 and topotecan even in the presence of human serum albumin. We synthesized the prodrug BQC-glucuronide (BQC-G), which was 4000 times more water soluble and 20-40 times less cytotoxic than BQC. Importantly, even in the presence of human serum albumin, BQC-G was efficiently hydrolyzed by beta-glucuronidase and produced greater cytotoxicity (IC50 = 13 nM) than camptothecin, 9-aminocamptothecin, SN-38, or topotecan (IC50 > 3000, 1370, 48, and 28 nM, respectively). BQC-G treatment of mice bearing human colon cancer xenografts with naturally or artificially elevated beta-glucuronidase activity produced significant antitumor activity, showing that BQC-G is a potent prodrug suitable for selective intratumoral drug activation.

  11. Synthesis of a Gemcitabine Prodrug for Remote Loading into Liposomes and Improved Therapeutic Effect.

    PubMed

    May, Jonathan P; Undzys, Elijus; Roy, Aniruddha; Li, Shyh-Dar

    2016-01-20

    The chemotherapeutic gemcitabine was actively and stably loaded into lipid nanoparticles through the formation of a prodrug. Gemcitabine was chemically modified to increase the lipophilicity and introduce a weak base moiety for remote loading. Several derivatives were synthesized and screened for their potential to be good liposomal drug candidates for remote loading by studying their solubility, stability, cytotoxicity, and loading efficiency. Two morpholino derivatives of GEM (22 and 23) were chosen as the preferred prodrugs for this purpose as they possessed the best loading efficiencies (100% for drug-to-lipid ratio of 0.36 w/w). This is a considerable improvement over a passive loading strategy where typical loading efficiencies are on the order of ∼10-20% for a drug-to-lipid ratio of ∼0.01. Liposomes loaded with these two prodrugs were studied in an s.c. tumor model in vivo and showed improved therapeutic effect over free GEM (∼2-fold) and saline control (8- to 10-fold). This work demonstrates how chemical modification of a known hydrophilic drug can lead to improved loading, stability, and drug delivery in vivo.

  12. Photo-triggered fluorescent theranostic prodrugs as DNA alkylating agents for mechlorethamine release and spatiotemporal monitoring.

    PubMed

    Cao, Yanting; Pan, Rong; Xuan, Weimin; Wei, Yongyi; Liu, Kejian; Zhou, Jiahong; Wang, Wei

    2015-06-28

    We describe a new theranostic strategy for selective delivery and spatiotemporal monitoring of mechlorethamine, a DNA alkylating agent. A photo-responsive prodrug is designed and composed of a photolabile o-nitrophenylethyl group, a DNA alkylating mechlorethamine drug and a coumarin fluorophore. Masking of the "N" in mechlorethamine in a positively charged state in the prodrug renders it inactive, non-toxic, selective and non-fluorescent. Indeed, the stable prodrug shows negligible cytotoxicity towards normal cells with and without UV activation and is completely non-fluorescent. However, upon photo-irradiation, the active mechlorethamine is released and induces efficient DNA cross-links, accompanied by a strong fluorescence enhancement (152 fold). Furthermore, DNA cross-linking activity from the release can be transformed into anticancer activity observed in in vitro studies of tumor cells. Importantly, the drug release progress and the movement can be conveniently monitored by fluorescence spectroscopy. The mechanistic study proves that the DNA cross-linking activity is mainly due to the release of DNA alkylating mechlorethamine. Altogether, the studies show the power of the theranostic strategy for efficient therapy in cancer treatment.

  13. Synergistic penetration of ethosomes and lipophilic prodrug on the transdermal delivery of acyclovir.

    PubMed

    Zhou, Yan; Wei, Yu-Hui; Zhang, Guo-Qiang; Wu, Xin-An

    2010-04-01

    The aim of this study was to investigate the lipophilic prodrug as a means of promoting acyclovir (ACV) that exhibited biphasic insolubility into the ethosomes for optimum skin delivery. Acyclovir Palmitate (ACV-C(16)) was synthesized as the lipophilic prodrug of ACV. The ethosomal system and the liposomal system bearing ACV or ACV-C(16) were prepared, respectively. The systems were characterized for shape, zeta potential value, particle size, and entrapment efficiency. Franz diffusion cells and confocal laser scanning microscopy were used for the percutaneous absorption studies. The results showed that the entrapment efficiency of ACV-C(16) ethosomes (87.75%) were much higher than that of ACV ethosomes (39.13%). The quantity of drug in the skin from ACV-C(16) ethosomes at the end of the 24 h transdermal experiment (622.89 microg/cm(2)) was 5.30 and 3.43 times higher than that from ACV-C(16) hydroalcoholic solution and ACV ethosomes, respectively. This study indicated that the binary combination of the lipophilic prodrug ACV-C(16) and the ethosomes synergistically enhanced ACV absorption into the skin.

  14. Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug

    PubMed Central

    Hardeland, Rüdiger; Pandi-Perumal, SR

    2005-01-01

    Melatonin, originally discovered as a hormone of the pineal gland, is also produced in other organs and represents, additionally, a normal food constituent found in yeast and plant material, which can influence the level in the circulation. Compared to the pineal, the gastrointestinal tract contains several hundred times more melatonin, which can be released into the blood in response to food intake and stimuli by nutrients, especially tryptophan. Apart from its use as a commercial food additive, supraphysiological doses have been applied in medical trials and pure preparations are well tolerated by patients. Owing to its amphiphilicity, melatonin can enter any body fluid, cell or cell compartment. Its properties as an antioxidant agent are based on several, highly diverse effects. Apart from direct radical scavenging, it plays a role in upregulation of antioxidant and downregulation of prooxidant enzymes, and damage by free radicals can be reduced by its antiexcitatory actions, and presumably by contributions to appropriate internal circadian phasing, and by its improvement of mitochondrial metabolism, in terms of avoiding electron leakage and enhancing complex I and complex IV activities. Melatonin was shown to potentiate effects of other antioxidants, such as ascorbate and Trolox. Under physiological conditions, direct radical scavenging may only contribute to a minor extent to overall radical detoxification, although melatonin can eliminate several of them in scavenger cascades and potentiates the efficacy of antioxidant vitamins. Melatonin oxidation seems rather important for the production of other biologically active metabolites such as N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), which have been shown to also dispose of protective properties. Thus, melatonin may be regarded as a prodrug, too. AMK interacts with reactive oxygen and nitrogen species, conveys protection to mitochondria, inhibits and downregulates

  15. Cadaveric donor selection and management.

    PubMed

    Studer, Sean M; Orens, Jonathan B

    2004-12-01

    The current availability of lung donors is far exceeded by the number of potential transplant recipients who are waiting for an organ. This disparity results in significant morbidity and mortality for those on the waiting list. Although it is desirable to increase overall consent rates for organ donation, doing so requires an intervention to affect societal response. In contrast, increased procurement of organs from marginal donors and improved donor management may be realized through increased study and practice changes within the transplant community. Transplantation of organs from marginal or extended-criteria donors may result in some increase in complications or mortality, but this possibility must be weighed against the morbidity and risk of death risk faced by individuals on the waiting list. The effects of this trade-off are currently being studied in kidney transplantation, and perhaps in the near future lung transplantation may benefit from a similar analysis. Until that time, the limited data regarding criteria for donor acceptability must be incorporated into practice to maximize the overall benefits of lung transplantation.

  16. Dengue antibodies in blood donors

    PubMed Central

    Ribas-Silva, Rejane Cristina; Eid, Andressa Ahmad

    2012-01-01

    Background Dengue is an urban arbovirus whose etiologic agent is a virus of the genus Flavorius with four distinct antigen serotypes (DENV-1, DENV-2, DENV-3 and DENV-4) that is transmitted to humans through the bite of the mosquito Aedes aegypti. The Campo Mourão region in Brazil is endemic for dengue fever. Obtective The aim of this study was to evaluate the presence of IgG and IgM antibodies specific to the four serotypes of dengue in donors of the blood donor service in the city of Campo Mourão. Methods Epidemiological records were evaluated and 4 mL of peripheral blood from 213 blood donors were collected in tubes without anticoagulant. Serum was then obtained and immunochromatographic tests were undertaken (Imuno-Rápido Dengue IgM/IgGTM). Individuals involved in the study answered a social and epidemiological questionnaire on data which included age, gender and diagnosis of dengue. Results Only three (1.4%) of the 213 blood tests were positive for IgG anti-dengue antibodies. No donors with IgM antibody, which identifies acute infection, were identified. Conclusions The results of the current analysis show that the introduction of quantitative or molecular serological methods to determine the presence of anti-dengue antibodies or the detection of the dengue virus in blood donors in endemic regions should be established so that the quality of blood transfusions is guaranteed. PMID:23049418

  17. Both the H2S biosynthesis inhibitor aminooxyacetic acid and the mitochondrially targeted H2S donor AP39 exert protective effects in a mouse model of burn injury.

    PubMed

    Ahmad, Akbar; Szabo, Csaba

    2016-11-01

    Hydrogen sulfide (H2S) exerts beneficial as well as deleterious effects in various models of critical illness. Here we tested the effect of two different pharmacological interventions: (a) inhibition of H2S biosynthesis using the cystathionine-beta-synthase (CBS)/cystathionine-gamma-lyase (CSE) inhibitor aminooxyacetic acid (AOAA) and the mitochondrially targeted H2S donor [10-oxo-10-[4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy]decyl]triphenyl-phosphonium (AP39). A 30% body surface area burn injury was induced in anesthetized mice; animals were treated with vehicle, AOAA (10mg/kg i.p. once or once a day for 6days), or AP39 (0.3mg/kg/day once or once a day for 6days). In two separate groups, animals were sacrificed, at 24h post-burn or on Day 7 post-burn, blood and lungs were collected and the following parameters were evaluated: myeloperoxidase (MPO) and malondialdehyde (MDA) in lung homogenates, plasma cytokines (Luminex analysis) and circulating indicators of organ dysfunction (Vetscan analysis). Lung MPO levels (an index of neutrophil infiltration) and MDA levels (an index of oxidative stress) were significantly increased in response to burn injury both at 24h and at 7days; both AOAA and AP39 attenuated these increases. From a panel of inflammatory cytokines (TNFα, IL-1β, IL-6, IL-10, MCP-1, MIP-2, VEGF and IFNγ) in the plasma, IL-6 and IL-10 levels were markedly elevated at 24h and VEGF was slightly elevated. IL-6 remained highly elevated at 7days post-burn while IL-10 levels decreased, but remained slightly elevated over baseline 7days post-burn. The changes in cytokine levels were attenuated both by AP39 and AOAA at both time points studied. The burn-induced increases in the organ injury markers ALP and ALT, amylase and creatinine were reduced by both AOAA and AP39. We conclude that both H2S biosynthesis inhibition (using AOAA) and H2S donation (using AP39) suppresses inflammatory mediator production and reduces multi-organ injury in a murine model of burn

  18. New water-soluble prodrugs of HIV protease inhibitors based on O-->N intramolecular acyl migration.

    PubMed

    Hamada, Yoshio; Ohtake, Jun; Sohma, Youhei; Kimura, Tooru; Hayashi, Yoshio; Kiso, Yoshiaki

    2002-12-01

    To improve the low water-solubility of HIV protease inhibitors, we synthesized water-soluble prodrugs of KNI-272 and KNI-279 which are potent HIV-1 protease inhibitors consisting of an Apns-Thz core structure (Apns; allophenylnorstatine, Thz; thiazolidine-4-carboxylic acid) as an inhibitory machinery. The prodrugs, which contained an O-acyl peptidomimetic structure with an ionized amino group leading to the increase of water-solubility, were designed to regenerate the corresponding parent drugs based on the O-->N intramolecular acyl migration reaction at the alpha-hydroxy-beta-amino acid residue, that is allophenylnorstatine. The synthetic prodrugs 3, 4, 6, and 7 improved the water-solubility (>300mg/mL) more than 4000-fold in comparison with the parent compounds, which is the practically acceptable value as water-soluble drugs. These prodrugs were stable as an HCl salt and in a strongly acidic solution corresponding to gastric juice (pH 2.0), and could be converted to the parent compounds promptly in the aqueous condition from slightly acidic to basic pH at 37 degrees C, with the suitable migration rate, via a five-membered ring intermediate. Using a similar method, we synthesized a prodrug (12) of ritonavir, a clinically useful HIV-1 protease inhibitor as an anti-AIDS drug. In contrast to the prodrugs 3, 4, 6, and 7, the prodrug 12 was very slowly converted to ritonavir probably through a six-membered ring intermediate, with the t(1/2) value of 32h that may not be suitable for practical use.

  19. Genetically engineered theranostic mesenchymal stem cells for the evaluation of the anticancer efficacy of enzyme/prodrug systems.

    PubMed

    Nouri, Faranak Salman; Wang, Xing; Hatefi, Arash

    2015-02-28

    Over the past decade, various enzyme/prodrug systems such as thymidine kinase/ganciclovir (TK/GCV), yeast cytosine deaminase/5-fluorocytosine (yCD/5-FC) and nitroreductase/CB1954 (NTR/CB1954) have been used for stem cell mediated suicide gene therapy of cancer. Yet, no study has been conducted to compare and demonstrate the advantages and disadvantages of using one system over another. Knowing that each enzyme/prodrug system has its own strengths and weaknesses, we utilized mesenchymal stem cells (MSCs) as a medium to perform for the first time a comparative study that illustrated the impact of subtle differences among these systems on the therapeutic outcome. For therapeutic purposes, we first genetically modified MSCs to stably express a panel of four suicide genes including TK (TK007 and TK(SR39) mutants), yeast cytosine deaminase:uracil phosphoribosyltransferase (yCD:UPRT) and nitroreductase (NTR). Then, we evaluated the anticancer efficacies of the genetically engineered MSCs in vitro and in vivo by using SKOV3 cell line which is sensitive to all four enzyme/prodrug systems. In addition, all MSCs were engineered to stably express luciferase gene making them suitable for quantitative imaging and dose-response relationship studies in animals. Considering the limitations imposed by the prodrugs' bystander effects, our findings show that yCD:UPRT/5-FC is the most effective enzyme/prodrug system among the ones tested. Our findings also demonstrate that theranostic MSCs are a reliable medium for the side-by-side evaluation and screening of the enzyme/prodrug systems at the preclinical level. The results of this study could help scientists who utilize cell-based, non-viral or viral vectors for suicide gene therapy of cancer make more informed decisions when choosing enzyme/prodrug systems.

  20. Prediction of Nanoparticle Prodrug Metabolism by Pharmacokinetic Modeling of Biliary Excretion

    PubMed Central

    Stern, Stephan T.; Zou, Peng; Skoczen, Sarah; Xie, Sherwin; Liboiron, Barry; Harasym, Troy; Tardi, Paul; Mayer, LawrenceD.; McNeil, Scott E.

    2013-01-01

    Pharmacokinetic modeling and simulation is a powerful tool for the prediction of drug concentrations in the absence of analytical techniques that allow for direct quantification. The present study applied this modeling approach to determine active drug release from a nanoparticle prodrug formulation. A comparative pharmacokinetic study of a nanoscale micellar docetaxel (DTX) prodrug, Procet 8, and commercial DTX formulation, Taxotere, was conducted in bile duct cannulated rats. The nanoscale (~40 nm) size of the Procet 8 formulation resulted in confinement within the plasma space and high prodrug plasma concentrations. Ex vivo prodrug hydrolysis during plasma sample preparation resulted in unacceptable error that precluded direct measurement of DTX concentrations. Pharmacokinetic modeling of Taxotere and Procet 8 plasma concentrations, and their associated biliary metabolites, allowed for prediction of the DTX concentration profile and DTX bioavailability, and thereby evaluation of Procet 8 metabolism. Procet 8 plasma decay and in vitro plasma hydrolytic rates were identical, suggesting systemic clearance of the prodrug was primarily metabolic. The Procet 8 and Taxotere plasma profiles, and associated docetaxel hydroxy-tert-butyl carbamate (HDTX) metabolite biliary excretion, were best fit by a two compartment model, with both linear and non-linear DTX clearance, and first order Procet 8 hydrolysis. The model estimated HDTX clearance rate agreed with in vitro literature values, supporting the predictability of the proposed model. Model simulation at the 10 mg DTX equivalent/kg dose level predicted DTX formation rate-limited kinetics and a peak plasma DTX concentration of 39 ng/mL at 4h for Procet 8, in comparison to 2826 ng/mL for Taxotere. As a result of nonlinear DTX clearance, the DTX AUCinf for the Procet 8 formulation was predicted to be 2.6 times lower than Taxotere (775 vs. 2017 h x ng/mL, respectively), resulting in an absolute bioavailability estimate of

  1. Anti-HIV efficacy and biodistribution of nucleoside reverse transcriptase inhibitors delivered as squalenoylated prodrug nanoassemblies.

    PubMed

    Hillaireau, Hervé; Dereuddre-Bosquet, Nathalie; Skanji, Rym; Bekkara-Aounallah, Fawzia; Caron, Joachim; Lepêtre, Sinda; Argote, Sébastien; Bauduin, Laurent; Yousfi, Rahima; Rogez-Kreuz, Christine; Desmaële, Didier; Rousseau, Bernard; Gref, Ruxandra; Andrieux, Karine; Clayette, Pascal; Couvreur, Patrick

    2013-07-01

    Due to their hydrophilic nature, most nucleoside reverse transcriptase inhibitors (NRTIs) display a variable bioavailability after oral administration and a poor control over their biodistribution, thus hampering their access to HIV sanctuaries. The limited cellular uptake and activation in the triphosphate form of NRTIs further restrict their efficacy and favour the emergence of viral resistance. We have shown that the conjugation of squalene (sq) to the nucleoside analogues dideoxycytidine (ddC) and didanosine (ddI) leads to amphiphilic prodrugs (ddC-sq and ddI-sq) that spontaneously self-organize in water as stable nanoassemblies of 100-300 nm. These nanoassemblies can also be formulated with polyethylene glycol coupled to either cholesterol (Chol-PEG) or squalene (sq-PEG). When incubated with peripheral blood mononuclear cells (PBMCs) in vitro infected with HIV, the NRTI-sq prodrugs enhanced the antiviral efficacy of the parent NRTIs, with a 2- to 3-fold decrease of the 50% effective doses and a nearly 2-fold increase of the selectivity index. This was also the case with HIV-1 strains resistant to ddC and/or ddI. The enhanced antiviral activity of ddI-sq was correlated with an up to 5-fold increase in the intracellular concentration of the corresponding pharmacologically active metabolite ddA-TP. The ddI-sq prodrug was further investigated in vivo by the oral route, the preferred route of administration of NRTIs. Pharmacokinetics studies performed on rats showed that the prodrug maintained low amounts of free ddI in the plasma. Administration of (3)H-ddI-sq led to radioactivity levels higher in the plasma and relevant organs in HIV infection as compared to administration of free (3)H-ddI. Taken together, these results show the potential of the squalenoylated prodrugs of NRTIs to enhance their absorption and improve their biodistribution, but also to enhance their intracellular delivery and antiviral efficacy towards HIV-infected cells.

  2. Platinum(iv) prodrug conjugated Pd@Au nanoplates for chemotherapy and photothermal therapy

    NASA Astrophysics Data System (ADS)

    Shi, Saige; Chen, Xiaolan; Wei, Jingping; Huang, Yizhuan; Weng, Jian; Zheng, Nanfeng

    2016-03-01

    Owing to the excellent near infrared (NIR) light absorption and efficient passive targeting toward tumor tissue, two-dimensional (2D) core-shell PEGylated Pd@Au nanoplates have great potential in both photothermal therapy and drug delivery systems. In this work, we successfully conjugate Pd@Au nanoplates with a platinum(iv) prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)2] to obtain a nanocomposite (Pd@Au-PEG-Pt) for combined photothermal-chemotherapy. The prepared Pd@Au-PEG-Pt nanocomposite showed excellent stability in physiological solutions and efficient Pt(iv) prodrug loading. Once injected into biological tissue, the Pt(iv) prodrug was easily reduced by physiological reductants (e.g. ascorbic acid or glutathione) into its cytotoxic and hydrophilic Pt(ii) form and released from the original nanocomposite, and the NIR laser irradiation could accelerate the release of Pt(ii) species. More importantly, Pd@Au-PEG-Pt has high tumor accumulation (29%ID per g), which makes excellent therapeutic efficiency at relatively low power density possible. The in vivo results suggested that, compared with single therapy the combined thermo-chemotherapy treatment with Pd@Au-PEG-Pt resulted in complete destruction of the tumor tissue without recurrence, while chemotherapy using Pd@Au-PEG-Pt without irradiation or photothermal treatment using Pd@Au-PEG alone did not. Our work highlights the prospects of a feasible drug delivery strategy of the Pt prodrug by using 2D Pd@Au nanoplates as drug delivery carriers for multimode cancer treatment.Owing to the excellent near infrared (NIR) light absorption and efficient passive targeting toward tumor tissue, two-dimensional (2D) core-shell PEGylated Pd@Au nanoplates have great potential in both photothermal therapy and drug delivery systems. In this work, we successfully conjugate Pd@Au nanoplates with a platinum(iv) prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)2] to obtain a nanocomposite (Pd@Au-PEG-Pt) for combined photothermal-chemotherapy. The

  3. A novel strategy for ADME screening of prodrugs: combined use of serum and hepatocytes to integrate bioactivation and clearance, and predict exposure to both active and prodrug to the systemic circulation.

    PubMed

    Hoppe, Edmund; Hewitt, Nicola J; Buchstaller, Hans-Peter; Eggenweiler, Hans-Michael; Sirrenberg, Christian; Zimmermann, Astrid; März, Joachim; Schwartz, Harry; Saal, Christoph; Meyring, Michael; Hecht, Stefan

    2014-05-01

    Common strategies to optimize prodrugs use either in vitro or rodent in vivo approaches, which do not consider elimination pathways that do not result in the generation of the desired product or might be misleading because of species differences, respectively. As a step forward, we have incorporated a novel application of hepatocytes into our prodrug optimization strategy to increase the bioavailability of a poorly soluble drug candidate by attaching a charged ester linker. The model involves the incubation of hepatocytes from multiple species in serum-containing medium to mimic formation as well as simultaneous metabolism of both prodrug and active drug. Using this strategy, a correlation between the in vitro AUC and the AUC after intravenous administration was obtained for active drug formation in several species. Moreover, hepatocytes correctly predicted the likelihood of undesired exposure with nonhydrolyzed prodrug. This novel approach enabled us to identify several prodrugs, which showed improved exposure over a wide dose range. Furthermore, a strategy was developed resulting in a decision tree that can be used to determine the applicability of the hepatocyte model in the screening process.

  4. The use of neoplastic donors to increase the donor pool.

    PubMed

    Fiaschetti, P; Pretagostini, R; Stabile, D; Peritore, D; Oliveti, A; Gabbrielli, F; Cenci, S; Ricci, A; Vespasiano, F; Grigioni, W F

    2012-09-01

    The aim of the study was to evaluate the experience of the Centre-Sud Transplant Organization (OCST) area using cadaveric donor with neoplastic diseases to evaluate the possibility of transmission to recipients. From January 1, 2003, to December 31, 2010, the neoplastic risk has been reported to be 5.4% (377/4654 referred donors). In 2003, the number of donors with a tumor and their mean age were respectively: 60 (10.3%) and 59.6 ± 19.9; 2004: 33 (5.2%) and 61.4 ± 15.9; 2005: 32 (6%) and 62.8 ± 15.5; 2006: 46 (7%) and 60.7 ± 19.1; 2007: 51 (7%) and 58.9 ± 16; in 2008: 58 (7%) and 59.7 ± 19.6; 2009: 47 (7%) and 57 ± 26; 2010: 49 (7%) and 64 ± 16. The organ most affected by tumor has been the central nervous system (18%). The tumor was diagnosed before in 325 (86%) cases, versus during organ retrieval in 48 (12.7%) donor operations but before, which four cases (1%) occured after transplantation. According to the histological types and grades, 28 evaluated donors (8.2%) were suitable for transplantation. The histological types were: thyroid carcinoma (n = 3); prostate carcinoma (n = 8), renal clear cell carcinoma (n = 7), oncocytoma (n = 1), meningiomas (n = 2), dermofibrosarcoma (n = 1); verrucous carcinoma of the vulva (n = 1), colon adenocarcinoma (n = 1), grade II astrocytoma (n = 1), adrenal gland tumor (n = 1), gastric GIST (n = 1), oligodendroglioma (n = 1). Forty-five organs were retrieved (22 livers, 19 kidneys, 3 hearts, and 1 pancreas) and transplanted into 44 recipients with 1 liver-kidney combined transplantation. Four recipients died due to causes not related to the tumor. No donor-transmitted tumor was detected among the recipients. Donation is absolutely not indicated in cases of tumors with high metastatic potential and high grades. Performing an accurate evaluation of the donor, taking into account the histological grade, currently can allow, organ retrieval and transplantation with an acceptable risk.

  5. Aqueous Nanomicellar Formulation for Topical Delivery of Biotinylated Lipid Prodrug of Acyclovir: Formulation Development and Ocular Biocompatibility

    PubMed Central

    Vadlapudi, Aswani Dutt; Cholkar, Kishore; Vadlapatla, Ramya Krishna

    2014-01-01

    Abstract Purpose: The objective of this study was to develop a clear, aqueous nanomicellar formulation and evaluate its in vitro ocular biocompatibility as a novel carrier for topical ocular delivery of biotinylated lipid prodrug for the treatment of herpetic keratitis. Methods: Micellar formulation of Biotin-12Hydroxystearic acid-acyclovir (B-12HS-ACV) was prepared by solvent evaporation/film hydration method with two nonionic surfactants, vitamin E TPGS and octoxynol-40. The optimized formulation was characterized for various parameters including micelle size, polydispersity index (PDI), and zeta-potential and in vitro prodrug release. Human corneal epithelial cells (HCECs) were employed for studying the cytotoxicity of the formulation. Further, mRNA expression levels of various cytokines were also studied with quantitative real-time PCR (qPCR). Results: Average size was 10.46±0.05 nm with a PDI of 0.086 for blank nanomicelles, and 10.78±0.09 nm with a PDI of 0.075 for prodrug-loaded nanomicelles. Both unloaded and prodrug-loaded nanomicelles had low negative zeta potential. Prodrug encapsulation efficiency of mixed nanomicelles was calculated to be ∼90%. Transmission electron microscopy analysis revealed that nanomicelles were spherical, homogenous, and devoid of aggregates. B-12HS-ACV release from nanomicelles was slow with no significant burst effect. Results show a sustained release of the prodrug from nanomicelles over a period of 4 days. Neither the blank formulation nor the prodrug-loaded micellar formulation demonstrated any cytotoxic effects. Further, incubation of HCECs with blank and prodrug-loaded nanomicellar groups did not significantly alter the expression levels of IL-1β, IL-6, IL-8, IL-17, TNF-α, and IFN-γ. Conclusions: In summary, a topical clear, aqueous nanomicellar formulation comprised of vitamin E TPGS and octoxynol-40 loaded with 0.1% B-12HS-ACV was successfully developed. B-12HS-ACV-loaded nanomicelles are small in size

  6. Targeted delivery of a model immunomodulator to the lymphatic system: comparison of alkyl ester versus triglyceride mimetic lipid prodrug strategies.

    PubMed

    Han, Sifei; Quach, Tim; Hu, Luojuan; Wahab, Anisa; Charman, William N; Stella, Valentino J; Trevaskis, Natalie L; Simpson, Jamie S; Porter, Christopher J H

    2014-03-10

    A lipophilic prodrug approach has been used to promote the delivery of a model immunomodulator, mycophenolic acid (MPA), to the lymphatic system after oral administration. Lymphatic transport was employed to facilitate enhanced drug uptake into lymphocytes, as recent studies demonstrate that targeted drug delivery to lymph resident lymphocytes may enhance immunomodulatory effects. Two classes of lymph-directing prodrugs were synthesised. Alkyl chain derivatives (octyl mycophenolate, MPA-C8E; octadecyl mycophenolate, MPA-C18E; and octadecyl mycophenolamide, MPA-C18AM), to promote passive partitioning into lipids in lymphatic transport pathways, and a triglyceride mimetic prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) to facilitate metabolic integration into triglyceride deacylation-reacylation pathways. Lymphatic transport, lymphocyte uptake and plasma pharmacokinetics were assessed in mesenteric lymph and carotid artery cannulated rats following intraduodenal infusion of lipid-based formulations containing MPA or MPA prodrugs. Patterns of prodrug hydrolysis in rat digestive fluid, and cellular re-esterification in vivo, were evaluated to examine the mechanisms responsible for lymphatic transport. Poor enzyme stability and low absorption appeared to limit lymphatic transport of the alkyl derivatives, although two of the three alkyl chain prodrugs - MPA-C18AM (6-fold) and MPA-C18E (13-fold) still increased lymphatic drug transport when compared to MPA. In contrast, 2-MPA-TG markedly increased lymphatic drug transport (80-fold) and drug concentrations in lymphocytes (103-fold), and this was achieved via biochemical incorporation into triglyceride deacylation-reacylation pathways. The prodrug was hydrolysed rapidly to 2-mycophenoloyl glycerol (2-MPA-MG) in the presence of rat digestive fluid, and 2-MPA-MG was subsequently re-esterified in the enterocyte with oleic acid (most likely originating from the co-administered formulation) prior to accessing the

  7. Self-immolative nitrogen mustards prodrugs cleavable by carboxypeptidase G2 (CPG2) showing large cytotoxicity differentials in GDEPT.

    PubMed

    Niculescu-Duvaz, Dan; Niculescu-Duvaz, Ion; Friedlos, Frank; Martin, Jan; Lehouritis, Panos; Marais, Richard; Springer, Caroline J

    2003-04-24

    Nineteen novel potential self-immolative prodrugs and their corresponding drugs have been synthesized for gene-directed enzyme prodrug therapy (GDEPT) with carboxypeptidase G2 (CPG2) as the activating enzyme. The compounds are derived from o- and p-amino and p-methylamino aniline nitrogen mustards. Their aqueous stability, kinetics of drug release by CPG2, and cytotoxicity in the colon carcinoma cell line WiDr, expressing either surface-tethered CPG2 (stCPG2(Q)3) or control beta-galactosidase, are assessed. The effect of various structural features on stability, kinetics of activation, and biological activity is discussed. The p-methylamino prodrugs are the most stable compounds from this series, with the largest cytotoxicity differentials between CPG2-expressing and nonexpressing cells. The most potent compounds in all series are prodrugs of bis-iodo nitrogen mustards. 4-[N-[4'-Bis(2' '-iodoethyl)aminophenyl]-N'-methylcarbamoyloxymethyl]phenylcarbamoyl-l-glutamic acid, compound 39b, is 124-fold more cytotoxic to WiDr cells expressing CPG2 than to cells expressing beta-galactosidase. An additional six compounds show better cytotoxicity differential than the published N-[4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl]-l-glutamic acid (CMDA) prodrug.

  8. Synthesis of novel pregnane-diosgenin prodrugs via Ring A and Ring A connection: A combined experimental and theoretical studies

    NASA Astrophysics Data System (ADS)

    Sethi, Arun; Singh, Ranvijay Pratap; Shukla, Dolly; Singh, Praveer

    2016-12-01

    Novel pregnane-diosgenin prodrugs have been synthesized. The route involved preparation of 3β-25R-spirost-5ene 3yl-benzoate-2-carboxylic acid (2) by the esterification of diosgenin (1) with phthalic anhydride. The pregnane-diosgenin prodrugs 5 &6 were synthesized by treating 3β-25R-spirost-5ene 3yl-benzoate-2-carboxylic acid (2) with 3β-hydroxy16α-methoxy pregn-5-ene-20-one (3) and 3β-hydroxypregn-5, 16-diene-20-one (4) respectively. The synthesized compounds have been characterized with the help of spectroscopic techniques like 1H, 13C NMR, FT-IR, UV-visible spectroscopy and mass spectrometry. Density functional theory (DFT) with B3LYP functional and 6-31G (d, p) basis set has been used for the Quantum chemical calculations. UV-Vis spectra of the synthesized compounds were also recorded and electronic properties such as frontier orbitals and band gap energies were calculated by TD-DFT approach. Intramolecular interactions have been identified by AIM approach and vibrational wavenumbers have been calculated using DFT method. The reactivity and reactive site within the synthesized prodrugs were examined with reactivity descriptors (global and local). Dipole moment, polarizability and first static hyperpolarizability were calculated to get a better insight of the properties of synthesized prodrugs. The probable reaction paths of prodrugs were calculated with molecular electrostatic potential (MEP) surface analysis.

  9. Pharmacokinetic studies and LC-MS/MS method development of ganciclovir and dipeptide monoester prodrugs in Sprague Dawley rats.

    PubMed

    Gunda, Sriram; Earla, Ravinder; Cholkar, Kishore; Mitra, Ashim K

    2015-09-01

    Ganciclovir (GCV) is utilized as an anti-herpetic agent. Reports from our laboratory have suggested that dipeptide ester prodrugs of GCV exhibit high affinity towards the oligopeptide transporter hPEPT1 and therefore seem to be promising candidates for the treatment of oral herpes virus infections. In this study, we have examined the bio-availability of a dipeptide prodrug of GCV after oral administration in jugular cannulated Sprague-Dawley rats. A new bio-analytical method was developed with Q-TRAP liquid chromatography tandem mass spectroscopy (LC-MS/MS) for simultaneous analysis of GCV, Valine-GCV (VGCV) and Tyrosine-Valine-GCV (YVGCV). Acyclovir (ACV) was used as an internal standard in the analysis. Area under plasma-concentration time curves for total concentration of GCV after oral administration of YVGCV was found to be approximately 200 % more than that of GCV following intestinal absorption. A complete conversion of the dipeptide prodrug (YVGCV) to parent compound, GCV, by hepatic first-pass metabolism was evident due to the absence of intermediate metabolite VGCV and administered prodrug YVGCV. The dipeptide prodrugs of GCV exhibit higher systemic availability of regenerated GCV upon oral administration and thus seem to be promising drug candidate in the treatment of systemic herpes infections.

  10. Design, Synthesis and Biological Evaluation of Brain-Targeted Thiamine Disulfide Prodrugs of Ampakine Compound LCX001.

    PubMed

    Xiao, Dian; Meng, Fan-Hua; Dai, Wei; Yong, Zheng; Liu, Jin-Qiu; Zhou, Xin-Bo; Li, Song

    2016-04-14

    Ampakine compounds have been shown to reverse opiate-induced respiratory depression by activation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. However, their pharmacological exploitations are hindered by low blood-brain barrier (BBB) permeability and limited brain distribution. Here, we explored whether thiamine disulfide prodrugs with the ability of "lock-in" can be used to solve these problems. A series of thiamine disulfide prodrugs 7a-7f of ampakine compound LCX001 was synthesized and evaluated. The trials in vitro showed that prodrugs 7e, 7d, 7f possessed a certain stability in plasma and quickly decomposed in brain homogenate by the disulfide reductase. In vivo, prodrug 7e decreased the peripheral distribution of LCX001 and significantly increased brain distribution of LCX001 after i.v. administration. This compound showed 2.23- and 3.29-fold greater increases in the AUC0-t and MRT0-t of LCX001 in brain, respectively, than did LCX001 itself. A preliminary pharmacodynamic study indicated that the required molar dose of prodrug 7e was only one eighth that of LCX001 required to achieve the same effect in mice. These findings provide an important reference to evaluate the clinical outlook of ampakine compounds.

  11. Single-Donor Leukophoretic Technique

    NASA Technical Reports Server (NTRS)

    Eberhardt, R. N.

    1977-01-01

    Leukocyte separation-and-retrieval device utilizes granulocyte and monocyte property of leukoadhesion to glass surfaces as basis of their separation from whole blood. Device is used with single donor technique and has application in biological and chemical processing, veterinary research and clinical care.

  12. The Meaning of the Sperm Donor for Heterosexual Couples: Confirming the Position of the Father.

    PubMed

    Wyverkens, Elia; Provoost, Veerle; Ravelingien, An; Pennings, Guido; De Sutter, Petra; Buysse, Ann

    2017-03-01

    In the literature, relatively little attention has been paid to the meaning of donor involvement in the intimate couple dyad. The current study aimed to enrich our understanding of couples' meaning-making regarding the anonymous sperm donor and how they dealt with the donor involvement. Semi-structured interviews were conducted with nine couples, who had at least one child conceived through sperm donation. Our thematic analysis showed that the donor conception was seen as a different path to create a normal family. Once the family was formed, most couples avoided talking about the donor because it was perceived as disrupting men's growing confidence in their position as father. Participants tried to confirm the position of the father to protect the family relationships. Uncertainties about how they were perceived as parents showed the continuing dominance of genetic ties within our social discourse. Participants also dealt with reminders of the donor in their daily life. Overall, they tried to manage the space taken up by the donor and to protect the position of the father. We relate our findings to literature on topic avoidance and shared obliviousness in families. For counseling practice, it could be useful to explore couples' meaning-making about the donor as this seemed to serve family functioning.

  13. Dipeptidyl-peptidase IV (DPP IV/CD26)-activated prodrugs: a successful strategy for improving water solubility and oral bioavailability.

    PubMed

    Velázquez, Sonsoles; de Castro, Sonia; Diez-Torrubia, Alberto; Balzarini, Jan; Camarasa, María-José

    2015-01-01

    In the search of novel enzyme-based prodrug approaches to improve pharmacological properties of therapeutic drugs such as solubility and bioavailability, dipeptidyl-peptidase IV (DPP IV, also termed as CD26) enzyme activity provides a previously unexplored successful prodrug strategy. This review covers key aspects of the enzyme useful for the design of CD26-directed prodrugs. The proof-of-concept of this prodrug technology is provided for amine-containing agents by directly linking appropriate di- (or oligo)peptide moieties to a free amino group of a non-peptidic drug through an amide bond which is specifically hydrolized by DPP IV/CD26. Special emphasis is also made in discussing the design and synthesis of more elaborated tripartite prodrug systems, for further extension of the strategy to hydroxy-containing drugs. The application of this technology to improve water solubility and oral bioavailability of prominent examples of antiviral nucleosides is highlighted.

  14. Facile Fabrication of Tumor Redox-Sensitive Nanoassemblies of Small-Molecule Oleate Prodrug as Potent Chemotherapeutic Nanomedicine.

    PubMed

    Luo, Cong; Sun, Jin; Sun, Bingjun; Liu, Dan; Miao, Lei; Goodwin, Tyler Jay; Huang, Leaf; He, Zhonggui

    2016-12-01

    The conjugate of paclitaxel (PTX) and docosahexaenoic acid has entered into clinical trials. However, the most recent clinical outcomes fell short of expectations, due to the extremely slow drug release from the hydrophobic conjugates. Herein, a novel prodrug-based nanoplatform self-assembled by the disulfide bond linked conjugates of PTX and oleic acid for rapid and differential release of PTX in tumor cells is reported. This redox-responsive prodrug-nanosystem demonstrates multiple therapeutic advantages, including one-step facile fabrication, high drug-loading efficiency (56%, w/w), on-demand drug release responding to redox stimuli, as well as favorable cellular uptake and biodistribution. These advantages result in significantly enhanced antitumor efficacy in vivo, with the tumor almost completely disappearing in mice. Such a uniquely engineered prodrug-nanosystem has great potential to be used as potent chemotherapeutic nanomedicine in clinical cancer therapy.

  15. Sodium N-(methylsulfonyl)-N-(4-nitro-2-phenoxyphenyl)sulfamate: a water-soluble nimesulide prodrug for parenteral use.

    PubMed

    Rapposelli, Simona; Digiacomo, Maria; Franchi, Silvia; Moretti, Sara; Pinza, Mario; Sacerdote, Paola; Balsamo, Aldo

    2010-10-04

    Several nimesulide preparations (i.e., tablet form, gels) have been marketed, but no parenteral solution has achieved the market because of their low wettability and unsatisfactory chemical-physical properties required for parenteral use. In this paper we describe the synthesis of the nimesulide prodrug 1 and its anti-inflammatory and antihyperalgesic properties. Pharmacological studies, carried out to evaluate the in vivo anti-inflammatory and analgesic activities of compound 1 and nimesulide, showed that sodium sulfamate 1 is an effective nimesulide prodrug that can be administered by parenteral route, undergoing a satisfactory absorption and an extensive transformation into the active nimesulide compound. Moreover, the evaluation of the plasma concentrations of nimesulide after rat treatment with compound 1 showed an increased and dose-dependent release of nimesulide. In contrast, the plasma concentrations of nimesulide, after "native" drug administration, still remain substantially unchanged. These preliminary results prompt further investigations on this prodrug as a possible candidate for parenteral use.

  16. Pyrazolo[3,4-d]pyrimidine Prodrugs: Strategic Optimization of the Aqueous Solubility of Dual Src/Abl Inhibitors

    PubMed Central

    2013-01-01

    Design and synthesis of prodrugs of promising drug candidates represents a valid strategy to overcome the lack of favorable ADME properties, in particular aqueous solubility and bioavailability. We report herein the successful application of this strategy with two representative pyrazolo[3,4-d]pyrimidine derivatives (1 and 2), which led to the development of the corresponding and highly water-soluble antitumor prodrugs (7 and 8). In vitro studies confirmed a significant improvement of aqueous solubility and, for compound 8, good plasma stability, suggesting superior in vivo bioavailability. As expected, the uncleaved water-soluble prodrugs 7 and 8 showed no activity toward the enzymatic targets (c-Src and c-Abl) but revealed promising antiproliferative activity in myeloid cell lines, as a consequence of the in vitro hydrolysis of the selected solubilizing moiety, followed by the release of the active compounds (1 and 2). PMID:24900720

  17. Synthesis and characterization of a novel chitosan based E. coli cytosine deaminase nanocomposite for potential application in prodrug enzyme therapy.

    PubMed

    Yata, Vinod Kumar; Ghosh, Siddhartha Sankar

    2011-01-01

    Cytosine deaminase is a non-mammalian enzyme of widespread interest for prodrug enzyme therapy due to its ability to convert prodrug 5-fluorocytosine into anticancer drug 5-fluorouracil. Cytosine deaminase enzyme has been purified to homogeneity from E. coli K-12 MTCC 1302 strain. K(m) values for cytosine and 5-fluorocytosine were found to be 0.26 mM and 1.82 mM, respectively. We developed a chitosan-entrapped cytosine deaminase nanocomposite. Atomic force microscopy and transmission electron microscopy images showed an elongated sphere shape nanocomposite with an average size of 80 nm diameter. Fourier transform infrared spectroscopy and X-ray diffraction results confirmed gel formation and entrapment of cytosine deaminase within the nanocomposite. Sustained release of cytosine deaminase from the nanocomposite up to one week depicted its potential implication in prodrug inducted enzyme therapy.

  18. Palladium-Mediated Dealkylation of N-Propargyl-Floxuridine as a Bioorthogonal Oxygen-Independent Prodrug Strategy

    NASA Astrophysics Data System (ADS)

    Weiss, Jason T.; Carragher, Neil O.; Unciti-Broceta, Asier

    2015-03-01

    Herein we report the development and biological screening of a bioorthogonal palladium-labile prodrug of the nucleoside analogue floxuridine, a potent antineoplastic drug used in the clinic to treat advanced cancers. N-propargylation of the N3 position of its uracil ring resulted in a vast reduction of its biological activity (~6,250-fold). Cytotoxic properties were bioorthogonally rescued in cancer cell culture by heterogeneous palladium chemistry both in normoxia and hypoxia. Within the same environment, the reported chemo-reversible prodrug exhibited up to 1,450-fold difference of cytotoxicity whether it was in the absence or presence of the extracellular palladium source, underlining the precise modulation of bioactivity enabled by this bioorthogonally-activated prodrug strategy.

  19. Calorimetry and Langmuir-Blodgett studies on the interaction of a lipophilic prodrug of LHRH with biomembrane models.

    PubMed

    Sarpietro, Maria G; Accolla, Maria L; Santoro, Nancy; Mansfeld, Friederike M; Pignatello, Rosario; Toth, Istvan; Castelli, Francesco

    2014-05-01

    The interaction between an amphiphilic luteinizing hormone-releasing hormone (LHRH) prodrug that incorporated a lipoamino acid moiety (C12-LAA) with biological membrane models that consisted of multilamellar liposomes (MLVs) and phospholipid monolayers, was studied using Differential Scanning Calorimetry (DSC) and Langmuir-Blodgett film techniques. The effect of the prodrug C12[Q1]LHRH on the lipid layers was compared with the results obtained with the pure precursors, LHRH and C12-LAA. Conjugation of LHRH with a LAA promoiety showed to improve the peptide interaction with biomembrane models. Basing on the calorimetric findings, the LAA moiety aided the transfer of the prodrug from an aqueous solution to the biomembrane model.

  20. Design of Fexofenadine Prodrugs Based on Tissue-Specific Esterase Activity and Their Dissimilar Recognition by P-Glycoprotein.

    PubMed

    Ohura, Kayoko; Nakada, Yuichiro; Kotani, Shunsuke; Imai, Teruko

    2015-09-01

    The aim of this study was to develop a suitable prodrug for fexofenadine (FXD), a model parent drug, that is resistant to intestinal esterase but converted to FXD by hepatic esterase. Carboxylesterases (CESs), human carboxylesterase 1 (hCE1) and human carboxylesterase 2 (hCE2), are the major esterases in human liver and intestine, respectively. These two CESs show quite different substrate specificities, and especially, hCE2 poorly hydrolyzes prodrugs with large acyl groups. FXD contains a carboxyl group and is poorly absorbed because of low membrane permeability and efflux by P-glycoprotein (P-gp). Therefore, two potential FXD prodrugs, ethyl-FXD and 2-hydroxyethyl-FXD, were synthesized by substitution of the carboxyl group in FXD. Both derivatives were resistant to intestinal hydrolysis, indicating their absorption as intact prodrugs. Ethyl-FXD was hydrolyzed by hepatic hCE1, but 2-hydroxyethyl-FXD was not. Both derivatives showed high membrane permeability in human P-gp-negative LLC-PK1 cells. In LLC-GA5-COL300 cells overexpressing human P-gp, ethyl-FXD was transported by P-gp, but its efflux was easily saturated. Whereas 2-hydroxyethyl-FXD showed more efficient P-gp-mediated transport than FXD. Although the structure of 2-hydroxyethyl-FXD only differs from ethyl-FXD by substitution of a hydroxyl group, 2-hydroxyethyl-FXD is unsuitable as a prodrug. However, ethyl-FXD is a good candidate prodrug because of good intestinal absorption and hepatic conversion by hCE1.

  1. Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy

    PubMed Central

    Ma, Xinpeng; Huang, Xiumei; Moore, Zachary; Huang, Gang; Kilgore, Jessica A.; Wang, Yiguang; Hammer, Suntrea; Williams, Noelle S.; Boothman, David A.; Gao, Jinming

    2016-01-01

    Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, β-lapachone (β-lap) was shown to be highly efficacious in killing non-small cell lung cancer (NSCLC) cells regardless of their p53, cell cycle and caspase status. Pre-clinical and clinical use of β-lap (clinical form, ARQ501 or 761) is hampered by poor pharmacokinetics and toxicity due to hemolytic anemia. Here, we report the development and preclinical evaluation of β-lap prodrug nanotherapeutics consisting of diester derivatives of β-lap encapsulated in biocompatible and biodegradable poly(ethylene glycol)-b-poly(d,l-lactic acid) (PEG-b-PLA) micelles. Compared to the parent drug, diester derivatives of β-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered β-lap-dC3 and -dC6 prodrugs were converted to β-lap. Cytotoxicity assays using A549 and H596 lung cancer cells showed that both micelle formulations maintained NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent cytotoxicity. However, antitumor efficacy study of β-lap-dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over β-lap-dC6 micelles or β-lap-HPβCD complexes. Improved therapeutic efficacy of β-lap-dC3 micelles correlated with higher area under the concentration-time curves of β-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γH2AX, and ATP depletion). β-Lap-dC3 prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy. PMID:25542645

  2. Facile synthesis of corticosteroids prodrugs from isolated hydrocortisone acetate and their quantum chemical calculations

    NASA Astrophysics Data System (ADS)

    Sethi, Arun; Singh, Ranvijay Pratap; Prakash, Rohit; Amandeep

    2017-02-01

    In the present research paper corticosteroids prodrugs of hydrocortisone acetate (1) have been synthesized, which was isolated from the flowers of Allamanda Violacea. The hydrocortisone acetate (1) was hydrolyzed to hydrocortisone (2) which was subsequently converted to prednisolone (3). Both the hydrocortisone (1) and prednisolone (2) underwent Steglich esterification with naproxen and Ibuprofen yielding compounds 11, 17 dihydroxy-21-(2-(6-methoxynaphthalene-2yl) propionoxy)-pregn-4-ene-3, 20-dione (4), 11, 17-dihydroxy-21-(2-(4-isobutylphenyl) propionoxy)-pregn-4-ene-3, 20-dione (5), 21-(2-(6-methoxynaphthalene-2-yl) propionoxy) 11,17-di-hydroxy-3,20-diketo-pregn-1,4-diene (6) and 11,17-di-hydroxy-3,20-diketo-pregn-1,4-diene-21-yl-2-(4-isobutylphenyl) propanoate (7). The synthesized compounds have been characterized with the help of spectroscopic techniques like 1H, 13C NMR, FT-IR spectroscopy and mass spectrometry. Density functional theory (DFT) with B3LYP functional and 6-31G (d, p) basis set has been used for the Quantum chemical calculations. The electronic properties such as frontier orbitals and band gap energies were calculated by TD-DFT approach. Intramolecular interactions have been identified by AIM (Atoms in Molecule) approach and vibrational wavenumbers have been calculated using DFT method. The reactivity and reactive site within the synthesized prodrugs have been examined with the help of reactivity descriptors. Dipole moment, polarizability and first static hyperpolarizability have been calculated to get a better insight of the properties of synthesized prodrugs. The molecular electrostatic potential (MEP) surface analysis has also been carried out.

  3. Metabolic Activation of the Anti-Hepatitis C Virus Nucleotide Prodrug PSI-352938

    PubMed Central

    Niu, Congrong; Tolstykh, Tatiana; Bao, Haiying; Park, Yeojin; Babusis, Darius; Lam, Angela M.; Bansal, Shalini; Du, Jinfa; Chang, Wonsuk; Reddy, P. Ganapati; Zhang, Hai-Ren; Woolley, Joseph; Wang, Li-Quan; Chao, Piyun B.; Ray, Adrian S.; Otto, Michael J.; Sofia, Michael J.

    2012-01-01

    PSI-352938 is a novel cyclic phosphate prodrug of β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylguanosine-5′-monophosphate with potent anti-HCV activity. In order to inhibit the NS5B RNA-dependent RNA polymerase, PSI-352938 must be metabolized to the active triphosphate form, PSI-352666. During in vitro incubations with PSI-352938, significantly larger amounts of PSI-352666 were formed in primary hepatocytes than in clone A hepatitis C virus (HCV) replicon cells. Metabolism and biochemical assays were performed to define the molecular mechanism of PSI-352938 activation. The first step, removal of the isopropyl group on the 3′,5′-cyclic phosphate moiety, was found to be cytochrome P450 (CYP) 3A4 dependent, with other CYP isoforms unable to catalyze the reaction. The second step, opening of the cyclic phosphate ring, was catalyzed by phosphodiesterases (PDEs) 2A1, 5A, 9A, and 11A4, all known to be expressed in the liver. The role of these enzymes in the activation of PSI-352938 was confirmed in primary human hepatocytes, where prodrug activation was reduced by inhibitors of CYP3A4 and PDEs. The third step, removal of the O6-ethyl group on the nucleobase, was shown to be catalyzed by adenosine deaminase-like protein 1. The resulting monophosphate was consecutively phosphorylated to the diphosphate and to the triphosphate PSI-352666 by guanylate kinase 1 and nucleoside diphosphate kinase, respectively. In addition, formation of nucleoside metabolites was observed in primary hepatocytes, and ecto-5′-nucleotidase was able to dephosphorylate the monophosphate metabolites. Since CYP3A4 is highly expressed in the liver, the CYP3A4-dependent metabolism of PSI-352938 makes it an effective liver-targeted prodrug, in part accounting for the potent antiviral activity observed clinically. PMID:22526308

  4. Boronic Prodrug of Endoxifen as an Effective Hormone Therapy for Breast Cancer

    PubMed Central

    Zhang, Changde; Zhong, Qiu; Zhang, Qiang; Zheng, Shilong; Miele, Lucio; Wang, Guangdi

    2015-01-01

    As a prodrug, tamoxifen is activated by the P450 enzyme CYP2D6 that is responsible for converting it to the active metabolites, 4-hydroxytamoxifen and endoxifen. Patients with genetic polymorphisms of CYP2D6 may not receive the full benefit of tamoxifen therapy. There is increasing evidence that poor metabolizer patients have lower plasma concentrations of endoxifen and suffer worse disease outcome, although some clinical studies reported no correlation between CYP2D6 polymorphism and tamoxifen therapy outcome. Endoxifen is currently undergoing clinical trials as a potentially improved and more potent SERM (Selective Estrogen Receptor Modulator) for endocrine therapy that is independent of CYP2D6 status in patients. However, direct administration of endoxifen may present the problem of low bioavailability due to its rapid first-pass metabolism via O-glucuronidation. We have designed and synthesized ZB483, a boronic prodrug of endoxifen suitable for oral administration with greatly enhanced bioavailability by increasing the concentration of endoxifen in mouse blood. Our study demonstrated that ZB483 potently inhibited growth of ER+ breast cancer cells in vitro and was efficiently converted to endoxifen in cell culture media by oxidative deboronation. In vivo this metabolic conversion is equally efficient as indicated in the pharmacokinetic study. Moreover, at the same dose, ZB483 afforded a 30-40 fold higher level endoxifen in mouse blood compared to unconjugated endoxifen administration. The significantly enhanced bioavailability of endoxifen conferred by the boronic prodrug was further validated in an in vivo efficacy study. ZB483 was demonstrated to be more efficacious than endoxifen in inhibiting xenograft tumor growth in mice at equal dosage but more so at lower dosage. Together, these preclinical studies demonstrate that ZB483 is a promising endocrine therapy agent with markedly enhanced bioavailability in systemic circulation and superior efficacy compared to

  5. Live donor transplantation--the incompetent donor: comparative law.

    PubMed

    Wolfman, Samuel; Shaked, Tali

    2008-12-01

    Informed consent of the patient to medical treatment is an essential prerequisite for any invasive medical procedure. However in emergency cases, when the patient is unable to sign a consent form due to unconsciousness or to psychotic state, than the primary medical consideration shall take place. In such a case, in order to save life or even prevent a major medical hazard to the patient, doctors are allowed, in certain cases and in accordance with well accepted medical practice, to perform invasive procedures, major surgery or risky pharmacological treatment, without the explicit consent of the patient. All the above refers to the cases when avoidance of such non-consented treatment may harm severely the health and wellbeing of the patient and there is no doubt that such treatment is for the ultimate benefit of the patient. The question, however, shall arise when such a medical procedure is not necessarily for the benefit of the patient, but rather for the benefit of somebody else. Such is the case in the transplantation area and the question of living donor-donee relationship. This paper shall analyze the legal situation in cases of non competent donors whose consent cannot be considered legal consent given in full understanding and out of free will. It will also compare three legal systems, the Israeli, the American and the traditional Jewish law, with regard to the different approaches to this human problem, where the autonomy of the donor may be sacrificed for the purpose of saving life of another person.

  6. Squalenoyl nucleoside monophosphate nanoassemblies: new prodrug strategy for the delivery of nucleotide analogues.

    PubMed

    Caron, Joachim; Reddy, L Harivardhan; Lepêtre-Mouelhi, Sinda; Wack, Séverine; Clayette, Pascal; Rogez-Kreuz, Christine; Yousfi, Rahima; Couvreur, Patrick; Desmaële, Didier

    2010-05-01

    4-(N)-1,1',2-trisnor-squalenoyldideoxycytidine monophosphate (SQddC-MP) and 4-(N)-1,1',2-trisnor-squalenoylgemcitabine monophosphate (SQdFdC-MP) were synthesized using phosphoramidite chemistry. These amphiphilic molecules self-assembled to about hundred nanometers size nanoassemblies in aqueous medium. Nanoassemblies of SQddC-MP displayed significant anti-HIV activity whereas SQdFdC-MP nanoassemblies displayed promising anticancer activity on leukemia cells. These results suggested that squalene conjugate of negatively charged nucleotide analogues efficiently penetrated within cells. Thus, we propose a new prodrug strategy for improved delivery of nucleoside analogues to ameliorate their biological efficacy.

  7. Controllable synthesis of polymerizable ester and amide prodrugs of acyclovir by enzyme in organic solvent.

    PubMed

    Li, Xia; Wu, Qi; Lv, De-shui; Lin, Xian-fu

    2006-05-15

    A facile control of the acylation position at the primary hydroxyl and amino of acyclovir, respectively, was achieved and five polymerizable acyclovir prodrugs were synthesized. Various reaction conditions were studied in detail. Thus, lipase acrylic resin from Candida antarctica (CAL-B) in pyridine or acetone showed high chemo-selectivity toward the primary hydroxyl of acyclovir. However, lipase PS 'Amano' (PS) in DMSO selectively acylated the amino group. The selectivity of PS could be adjusted by changing reaction solvents. The acyclovir vinyl derivatives obtained would be important monomers used for the preparation of macromolecular nucleoside drugs.

  8. Preparation of Conjugated Polymer Grafted with H2O2-Sensitive Prodrug for Cell Imaging and Tumor Cell Killing.

    PubMed

    Li, Meng; Li, Shengliang; Chen, Hui; Hu, Rong; Liu, Libing; Lv, Fengting; Wang, Shu

    2016-01-13

    In this work, a new conjugated polymer poly(fluorene-co-phenylene) derivative containing pendent quaternized chlormethine (PFP-Chl) was synthesized by covalent linking small molecular prodrug groups onto conjugated polymer side chains. H2O2-sensitive prodrug with an eight-member-cyclic boronate ester structure could suffer from H2O2-triggered nitrogen mustard release and further DNA cross-linking and alkylation. PFP-Chl combines therapeutic characteristic with excellent optical property of conjugated polymers. It is found that PFP-Chl could enter into cells by endocytosis to simultaneously exhibit abilities of fluorescent imaging and tumor cell inhibition.

  9. Amphiphilic NO-donor antioxidants.

    PubMed

    Chegaev, Konstantin; Lazzarato, Loretta; Rolando, Barbara; Marini, Elisabetta; Lopez, Gloria V; Bertinaria, Massimo; Di Stilo, Antonella; Fruttero, Roberta; Gasco, Alberto

    2007-02-01

    Models of amphiphilic NO-donor antioxidants 24-26 were designed and synthesized. The products were obtained by linking a lipophilic tail (C(6), C(8), C(10)) with a polar head constituted by the 2,6-dimethoxyphenol antioxidant joined to the NO-donor 3-furoxancarboxamide substructure through a bridge containing a quaternary ammonium group. Compound 23, containing the shortest C(2)-alkyl chain, was also studied as a reference. The antioxidant properties (TBARS and LDL oxidation assays) and the vasodilator properties of the compounds were studied in vitro. The ability of these products to interact with phospholipid vesicles was also investigated by NMR techniques. The results indicate that both activities are modulated by the ability of the compounds to accumulate on phospholipid layers.

  10. 21 CFR 630.6 - Donor notification.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Donor notification. 630.6 Section 630.6 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS GENERAL REQUIREMENTS FOR BLOOD, BLOOD COMPONENTS, AND BLOOD DERIVATIVES § 630.6 Donor notification. (a) Notification of donors. You, an...

  11. Designing shallow donors in diamond

    NASA Astrophysics Data System (ADS)

    Moussa, Jonathan

    2015-03-01

    The production of n-type semiconducting diamond has been a long-standing experimental challenge. The first-principles simulation of shallow dopants in semiconductors has been a long-standing theoretical challenge. A desirable theoretical goal is to identify impurities that will act as shallow donors in diamond and assess their experimental viability. I will discuss this identification process for the LiN4 donor complex. It builds a scientific argument from several models and computational results in the absence of computational tools that are both trustworthy and computationally tractable for this task. I will compare the theoretical assessment of viability with recent experimental efforts to co-dope diamond with lithium and nitrogen. Finally, I discuss the computational tools needed to facilitate future work on this problem and some preliminary simulations of donors near diamond surfaces. Sandia National Laboratories is a multi-program lab managed and operated by Sandia Corp., a wholly owned subsidiary of Lockheed Martin Corp., for the U.S. Department of Energy's National Nuclear Security Administration under Contract DE-AC04-94AL85000.

  12. Heteroaromatic donors in donor-acceptor-donor based fluorophores facilitate zinc ion sensing and cell imaging.

    PubMed

    Sreejith, Sivaramapanicker; Divya, Kizhumuri P; Jayamurthy, Purushothaman; Mathew, Jomon; Anupama, V N; Philips, Divya Susan; Anees, Palappuravan; Ajayaghosh, Ayyappanpillai

    2012-11-01

    The excited state intra molecular charge transfer (ICT) property of fluorophores has been extensively used for the design of fluorescent chemosensors. Herein, we report the synthesis and properties of three donor–π-acceptor–π-donor (D–π-A–π-D) based molecular probes BP, BT and BA. Two heteroaromatic rings, pyrrole (BP), and thiophene (BT) and a non-heteroaromatic ring N-alkoxy aniline (BA) were selected as donor moieties which were linked to a bipyridine binding site through a vinylic linkage. The heteroaromatic systems BP and BT perform selective and ratiometric emission signalling for zinc ions whereas the non-heteroaromatic probe BA does not. The advantages of the D–π-A–π-D design strategy in the design of ICT based probes for the selective fluorescent ratiometric signalling of zinc ions in biological media is discussed. Further, the use of BP, BT and BA for imaging Zn(2+) ions from MCF-7 cell lines is demonstrated.

  13. Synthesis and evaluation of sulfonylethyl-containing phosphotriesters of 3'-azido-3'-deoxythymidine as anticancer prodrugs.

    PubMed

    Wang, Jiang; Wang, Yi-Jun; Chen, Zhe-Sheng; Kwon, Chul-Hoon

    2014-11-01

    A series of bis(sulfonylethyl) and mono(sulfonylethyl) phenyl phosphotriesters of zidovudine (3'-azido-3'-deoxythymidine, AZT) were synthesized as potential anticancer prodrugs that liberate AZT monophosphate via nonenzymatic β-elimination mechanism. Stability studies demonstrated that all the synthesized prodrugs spontaneously liberate AZT monophosphate with half-lives in the range of 0.07-278.8h under model physiological conditions in 0.1M phosphate buffer at pH 7.4 and 37 °C. Analogous to aldophosphamide, the elimination rates were accelerated in the presence of reconstituted human plasma under the same conditions. Among the compounds, 3, 4, 8, and 10 were comparable or superior to AZT against five established human cancerous cell lines in vitro. Moreover, the selected compounds were equally sensitive to both the wild-type osteosarcoma 143 B and the thymidine kinase-deficient 143 B/TK(-) cell lines. The findings are consistent with that these compounds deliver AZT monophosphate intracellularly.

  14. Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug

    PubMed Central

    Sharpe, Martyn A.; Livingston, Andrew D.; Gist, Taylor L.; Ghosh, Pardip; Han, Junyan; Baskin, David S.

    2015-01-01

    The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P+-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models. PMID:26501110

  15. Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs.

    PubMed

    Phillips, Roger M

    2016-03-01

    The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high-priority target and one of the therapeutic strategies designed to eradicate hypoxic cells in tumours is a group of compounds known collectively as hypoxia-activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (1) the ability of oxygen to either reverse or inhibit the activation process and (2) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples.

  16. Polymeric prodrug-functionalized polypropylene films for sustained release of salicylic acid.

    PubMed

    Magaña, Hector; Palomino, Kenia; Cornejo-Bravo, Jose M; Díaz-Gómez, Luis; Concheiro, Angel; Zavala-Lagunes, Edgar; Alvarez-Lorenzo, Carmen; Bucio, Emilio

    2016-09-10

    Medical devices decorated with salicylic acid-based polymer chains (polymeric prodrug) that slowly release this anti-inflammatory and anti-biofilm drug at the implantation site were designed. A "grafting from" method was implemented to directly grow chains of a polymerizable derivative of salicylic acid (2-methacryloyloxy-benzoic acid, 2MBA) onto polypropylene (PP). PP was modified both at bulk and on the surface with poly(2MBA) by means of an oxidative pre-irradiation method ((60)Co source), in order to obtain a grafted polymer in which salicylic acid units were linked by means of labile ester bonds. The grafting percent depended on absorbed dose, reaction time, temperature and monomer concentration. The functionalized films were analyzed regarding structure (FTIR-ATR, SEM-EDX, fluorescence microscopy), temperature stability (TGA), interaction with aqueous medium (water contact angle and swelling), pH-responsive release and cytocompatibility (fibroblasts). In the obtained poly(2MBA)-grafted biomaterial, poly(2MBA) behaved as a polymeric prodrug that regulates salicylic acid release once in contact with aqueous medium, showing pH-dependent release rate.

  17. Synthesis and evaluation of sulfate conjugated metronidazole as a colon-specific prodrug of metronidazole.

    PubMed

    Kim, Hyunjeong; Lee, Yonghyun; Yoo, Hansun; Kim, Jihye; Kong, Hyesik; Yoon, Jeong-Hyun; Jung, Yunjin; Kim, Young Mi

    2012-04-01

    For an effort to improve therapeutic property of metronidazole (MTZ) which is a drug of choice for protozoal infections such as luminal amoebiasis, sulfate conjugated metronidazole (MTZS) was prepared and evaluated as a colon-specific prodrug of MTZ. The apparent partition coefficient of MTZ was greatly reduced by the sulfate conjugation. While (bio)chemically stable in the contents of the upper intestine, MTZS was rapidly cleaved to liberate MTZ on incubation with the cecal contents of rats. MTZ liberated from MTZS metabolized quickly at least partly by a microbial nitroreductase, suggesting the relevance of the metabolism to bioactivation of MTZ for antimicrobial action. Consistent with the hypothesis, MTZS elicited antibacterial activity in the cecal contents, which was as potent as free MTZ. The systemic absorption of MTZS was very low after oral administration of MTZS. In parallel with this, whereas MTZ disappeared mostly during the transit of the proximal small intestine, a substantial amount of MTZS remained in the small intestine, moving down to the large intestine where it metabolized rapidly. In addition to the efficient colonic delivery of MTZS, MTZS markedly reduced the systemic absorption of MTZ. Taken together, MTZS may be a potential colon-specific prodrug of MTZ which possesses improved therapeutic and toxicological properties.

  18. Magnetic nanoparticle hyperthermia induced cytosine deaminase expression in microencapsulated E. coli for enzyme-prodrug therapy.

    PubMed

    Nemani, Krishnamurthy V; Ennis, Riley C; Griswold, Karl E; Gimi, Barjor

    2015-06-10

    Engineered bacterial cells that are designed to express therapeutic enzymes under the transcriptional control of remotely inducible promoters can mediate the de novo conversion of non-toxic prodrugs to their cytotoxic forms. In situ cellular expression of enzymes provides increased stability and control of enzyme activity as compared to isolated enzymes. We have engineered Escherichia coli (E. coli), designed to express cytosine deaminase at elevated temperatures, under the transcriptional control of thermo-regulatory λpL-cI857 promoter cassette which provides a thermal switch to trigger enzyme synthesis. Enhanced cytosine deaminase expression was observed in cultures incubated at 42°C as compared to 30°C, and enzyme expression was further substantiated by spectrophotometric assays indicating enhanced conversion of 5-fluorocytosine to 5-fluorouracil. The engineered cells were subsequently co-encapsulated with magnetic iron oxide nanoparticles in immunoprotective alginate microcapsules, and cytosine deaminase expression was triggered remotely by alternating magnetic field-induced hyperthermia. The combination of 5-fluorocytosine with AMF-activated microcapsules demonstrated tumor cell cytotoxicity comparable to direct treatment with 5-fluorouracil chemotherapy. Such enzyme-prodrug therapy, based on engineered and immunoisolated E. coli, may ultimately yield an improved therapeutic index relative to monotherapy, as AMF mediated hyperthermia might be expected to pre-sensitize tumors to chemotherapy under appropriate conditions.

  19. Involvement of Carboxylesterase in Hydrolysis of Propranolol Prodrug during Permeation across Rat Skin

    PubMed Central

    Imai, Teruko; Takase, Yuko; Iwase, Harunobu; Hashimoto, Mitsuru

    2013-01-01

    The use of a prodrug, a conjugate of an active drug with a lipophilic substituent, is a good way of increasing the cutaneous absorption of a drug. However, the activity of dermal hydrolases has rarely been investigated in humans, or experimental animals. In the present study, we focused on the identification of rat dermal esterases and the hydrolysis of a prodrug during permeation across rat skin. We found that carboxylesterase (CES), especially the rat CES1 isozyme, Hydrolase A, is expressed in rat skin and that the hydrolysis of p-nitrophenyl acyl derivatives and caproyl-propranolol (PL) was 20-fold lower in the 9000g supernatant fraction of skin homogenate than in liver microsomes. A permeation study of caproyl-PL was performed in rat full-thickness and stripped skin using a flow-through diffusion cell. Caproyl-PL was easily partitioned into the stratum corneum and retained, not only in the stratum corneum, but also in viable epidermis and dermis. Caproyl-PL could barely be detected in the receptor fluid after application to either full-thickness or stripped skin. PL, derived from caproyl-PL, was, however, detected in receptor fluid after extensive hydrolysis of caproyl-PL in viable skin. Permeation of PL was markedly decreased under CES inhibition, indicating that the net flux of caproyl-PL is dependent on its conversion rate to PL. PMID:24300511

  20. Crystal Structure of the Geobacillus stearothermophilus Carboxylesterase Est55 and Its Activation of Prodrug CPT-11

    PubMed Central

    Liu, Ping; Ewis, Hosam E.; Tai, Phang C.; Lu, Chung-Dar; Weber, Irene T.

    2007-01-01

    Several mammalian carboxylesterases were shown to activate the prodrug irinotecan (CPT-11) to produce SN-38, a topoisomerase inhibitor used in cancer therapy. However, the potential use of bacterial carboxylesterases, which have the advantage of high stability, has not been explored. We present the crystal structure of the carboxyesterase Est55 from Geobacillus stearothermophilus and evaluation of its enzyme activity on CPT-11. Crystal structures were determined at pH 6.2 and 6.8 and resolution of 2.0 and 1.58 Å, respectively. Est55 folds into three domains, a catalytic domain, an α/β domain and a regulatory domain. The structure is in an inactive form; the side chain of His409, one of the catalytic triad residues, is directed away from the other catalytic residues Ser194 and Glu310. Moreover, the adjacent Cys408 is triply oxidized and lies in the oxyanion hole, which would block the binding of substrate, suggesting a regulatory role. However, Cys408 is not essential for enzyme activity. Mutation of Cys408 showed that hydrophobic side chains were favorable, while polar serine was unfavorable for enzyme activity. Est55 was shown to hydrolyze CPT-11 into the active form SN-38. The mutant C408V provided a more stable enzyme for activation of CPT-11. Therefore, engineered thermostable Est55 is a candidate for use with irinotecan in enzyme-prodrug cancer therapy. PMID:17239398

  1. Synthesis of Bisethylnorspermine Lipid Prodrug as Gene Delivery Vector Targeting Polyamine Metabolism in Breast Cancer

    PubMed Central

    Dong, Yanmei; Zhu, Yu; Li, Jing; Zhou, Qing-Hui; Wu, Chao; Oupický, David

    2013-01-01

    Progress in the development of nonviral gene delivery vectors continues to be hampered by low transfection activity and toxicity. Here we proposed to develop a lipid prodrug based on a polyamine analogue bisethylnorspermine (BSP) that can function dually as gene delivery vector and, after intracellular degradation, as active anticancer agent targeting dysregulated polyamine metabolism. We synthesized a prodrug of BSP (LS-BSP) capable of intracellular release of BSP using thiolytically sensitive dithiobenzyl carbamate linker. Biodegradability of LS-BSP contributed to decreased toxicity compared with nondegradable control L-BSP. BSP showed a strong synergistic enhancement of cytotoxic activity of TNF-related apoptosis-inducing ligand (TRAIL) in human breast cancer cells. Decreased enhancement of TRAIL activity was observed for LS-BSP when compared with BSP. LS-BSP formed complexes with plasmid DNA and mediated transfection activity comparable to DOTAP and L-BSP. Our results show that BSP-based vectors are promising candidates for combination drug/gene delivery. PMID:22545813

  2. Dissociable effects of the prodrug phendimetrazine and its metabolite phenmetrazine at dopamine transporters

    PubMed Central

    Solis, Ernesto; Suyama, Julie A.; Lazenka, Matthew F.; DeFelice, Louis J.; Negus, S. Stevens; Blough, Bruce E.; Banks, Matthew L.

    2016-01-01

    Phendimetrazine (PDM) is a clinically available anorectic and a candidate pharmacotherapy for cocaine addiction. PDM has been hypothesized to function as a prodrug that requires metabolism to the amphetamine-like monoamine transporter substrate phenmetrazine (PM) to produce its pharmacological effects; however, whether PDM functions as an inactive prodrug or has pharmacological activity on its own remains unclear. The study aim was to determine PDM pharmacological mechanisms using electrophysiological, neurochemical, and behavioral procedures. PDM blocked the endogenous basal hDAT (human dopamine transporter) current in voltage-clamped (−60 mV) oocytes consistent with a DAT inhibitor profile, whereas its metabolite PM induced an inward hDAT current consistent with a DAT substrate profile. PDM also attenuated the PM-induced inward current during co-application, providing further evidence that PDM functions as a DAT inhibitor. PDM increased nucleus accumbens dopamine levels and facilitated electrical brain stimulation reinforcement within 10 min in rats, providing in vivo evidence supporting PDM pharmacological activity. These results demonstrate that PDM functions as a DAT inhibitor that may also interact with the pharmacological effects of its metabolite PM. Overall, these results suggest a novel mechanism for PDM therapeutic effects via initial PDM DAT inhibition followed by PM DAT substrate-induced dopamine release. PMID:27514281

  3. May glutamine addiction drive the delivery of antitumor cisplatin-based Pt(IV) prodrugs?

    PubMed

    Ravera, Mauro; Gabano, Elisabetta; Tinello, Stefano; Zanellato, Ilaria; Osella, Domenico

    2017-02-01

    A small series of Pt(IV) prodrugs containing Gln-like (Gln=glutamine) axial ligands has been designed with the aim to take advantage of the increased demand of Gln showed by some cancer cells (glutamine addiction). In complex 4 the Gln, linked through the α-carboxylic group is recognized by the Gln transporters, in particular by the solute carrier transporter SLC1A5. All compounds showed cellular accumulation, as well as antiproliferative activity, related to their lipophilicity, as already demonstrated for the majority of Pt(IV) prodrugs, that enter cells mainly by passive diffusion. On the contrary, when the Gln concentration in cell medium is near or lower to the physiological value, complex 4 acts as a Trojan horse: it enters SLC1A5-overexpressing cells, where, upon reduction, it releases the active metabolite cisplatin and the Gln-containing ligand, thus preventing any possible extrusion by the L-type amino acid transporter LAT1. This selective mechanism could decrease off-target accumulation of 4 and, consequently, Pt-associated side-effects.

  4. Evaluation of carbohydrate-cysteamine thiazolidines as pro-drugs for the treatment of cystinosis.

    PubMed

    Ramazani, Yasaman; Levtchenko, Elena N; Van Den Heuvel, Lambertus; Van Schepdael, Ann; Paul, Prasanta; Ivanova, Ekaterina A; Pastore, Anna; Hartman, Trina M; Price, Neil P J

    2017-02-01

    Cystinosis is a genetic disorder caused by malfunction of cystinosin and is characterized by accumulation of cystine. Cysteamine, the medication used in cystinosis, causes halitosis resulting in poor patient compliance. Halitosis is mainly caused by the formation of dimethylsulfide as the final product in the cysteamine metabolism pathway. We have synthesized carbohydrate-cysteamine thiazolidines, and hypothesized that the hydrolytic breakdown of cysteamine-thiazolidines can result in free cysteamine being released in target organs. To examine our hypothesis, we tested these analogs in vitro in patient-derived fibroblasts. Cystinotic fibroblasts were treated with different concentrations of arabinose-cysteamine, glucose-cysteamine and maltose-cysteamine. We demonstrated that the analogs break down into cysteamine extracellularly and might therefore not be fully taken up by the cells under the form of the pro-drug. Potential modifications of the analogs that enable their intracellular rather than extracellular breakdown, is necessary to pursue the potential of these analogs as pro-drugs.

  5. The nitric oxide prodrug JS-K and its structural analogues as cancer therapeutic agents.

    PubMed

    Maciag, Anna E; Saavedra, Joseph E; Chakrapani, Harinath

    2009-09-01

    Nitric oxide (NO) prodrugs of the diazeniumdiolate class are routinely used as reliable sources of nitric oxide in chemical and biological laboratory settings. O(2)-(2,4-dinitrophenyl) diazeniumdiolates, which are derivatized forms of ionic diazeniumdiolates, have been found to show potent anti-proliferative activity in a variety of cancer cells, presumably through the effects of NO. One important member of this class of diazeniumdiolates, O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K), has shown promise as a novel cancer therapeutic agent in a number of animal models. This review describes the developments in chemical and biochemical characterization and structure-activity relationship of JS-K and its analogues. In addition, some molecular mechanistic insights into the observed anti-proliferative activity of JS-K are discussed. Finally, a structural motif is presented for O(2)-(aryl) diazeniumdiolate nitric oxide prodrugs that show potency comparable with that of JS-K.

  6. Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug.

    PubMed

    Sharpe, Martyn A; Livingston, Andrew D; Gist, Taylor L; Ghosh, Pardip; Han, Junyan; Baskin, David S

    2015-09-01

    The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

  7. Activation of adriamycin by the pH-dependent formaldehyde-releasing prodrug hexamethylenetetramine.

    PubMed

    Swift, Lonnie P; Cutts, Suzanne M; Rephaeli, Ada; Nudelman, Abraham; Phillips, Don R

    2003-02-01

    Previous studies have shown that Adriamycin can react with formaldehyde to yield an activated form of Adriamycin that can further react with DNA to yield Adriamycin-DNA adducts. Because hexamethylenetetramine (HMTA) is known to hydrolyze under cellular conditions and release six molecules of formaldehyde in a pH-dependent manner, we examined this clinical agent for its potential as a formaldehyde-releasing prodrug for the activation of Adriamycin. In IMR-32 neuroblastoma cells in culture, increasing levels of HMTA resulted in enhanced levels of Adriamycin-DNA adducts. These adducts were formed in a pH-dependent manner, with 4-fold more detected at pH 6.5 compared with pH 7.4, consistent with the known acid lability of HMTA. The resulting drug-DNA lesion was shown to be cytotoxic, with combined Adriamycin and prodrug treatment resulting in a 3-fold lower IC(50) value compared with that of Adriamycin alone. Given the acidic nature of solid tumors and the preferential release of formaldehyde from HMTA in acidic environments, HMTA therefore has some potential for localized activation of Adriamycin in solid tumors.

  8. [Serum ferritin in donors with regular plateletpheresis].

    PubMed

    Ma, Chun-Hui; Guo, Ru-Hua; Wu, Wei-Jian; Yan, Jun-Xiong; Yu, Jin-Lin; Zhu, Ye-Hua; He, Qi-Tong; Luo, Yi-Hong; Huang, Lu; Ye, Rui-Yun

    2011-04-01

    This study was aimed to evaluate the impact of regular donating platelets on serum ferritin (SF) of donors. A total of 93 male blood donors including 24 initial plateletpheresis donors and 69 regular plateletpheresis donors were selected randomly. Their SF level was measured by ELISA. The results showed that the SF level of initial plateletpheresis donors and regular plateletpheresis donors were 91.08 ± 23.38 µg/L and 57.16 ± 35.48 µg/L respectively, and all were in normal levels, but there was significant difference between the 2 groups (p < 0.05). The SF level decreased when the donation frequency increased, there were no significant differences between the groups with different donation frequency. Correlation with lifetime donations of platelets was not found. It is concluded that regular plateletpheresis donors may have lower SF level.

  9. Ester Prodrugs of Ketoprofen: Synthesis, In Vitro Stability, In Vivo Biological Evaluation and In Silico Comparative Docking Studies Against COX-1 and COX-2.

    PubMed

    Ahmed, Musa; Azam, Faizul; Gbaj, Abdul; Zetrini, Abdulmottaleb E; Abodlal, Amna Salem; Rghigh, Abir; Elmahdi, Eman; Hamza, Amel; Salama, Mabruk; Bensaber, Salah M

    2016-01-01

    Prompted by the ineptness of the currently used non-steroidal antiinflammatory drugs (NSAIDs) to control gastric mucosal and renal adverse reactions, several ester prodrugs of ketoprofen were synthesized and characterized by IR, 1H NMR and mass spectral data. Physicochemical properties such as aqueous solubility, octanol-water partition coefficient log P, chemical stability and enzymatic hydrolysis of the synthesized molecules have been studied to assess their potential as prodrugs. The obtained results confirmed that all ester prodrugs are chemically stable, possess increased lipophilicity compared to their parent compounds and converted to the active drugs in vivo. All of the tested ester prodrugs exhibited marked anti-inflammatory activity ranging from 91.8% to 113.3% in comparison with the parent drug, ketoprofen. A mutual prodrug obtained from two antiinflammatory molecules, ketoprofen and salicylic acid has been noted to potentiate the activity making it most active molecule of the series. The ulcerogenic index of the ester prodrugs was significantly lower than the parent drug, ketoprofen. Comparative docking studies against X-ray crystal structures of COX-1 and COX-2 further provided understanding of their interaction with the cyclooxygenases that will facilitate design of better inhibitors (or prodrugs) with sufficient specificity for COX-2 against COX-1. The study offers an innovative strategy for finding a molecule with safer therapeutic profile for longterm treatment of inflammatory diseases.

  10. Dipeptidyl peptidase IV-activated prodrugs of anti-varicella zoster virus bicyclic nucleoside analogues containing different self-cleavage spacer systems.

    PubMed

    Diez-Torrubia, Alberto; Cabrera, Silvia; De Meester, Ingrid; Camarasa, María-José; Balzarini, Jan; Velázquez, Sonsoles

    2012-09-01

    A new type of double prodrug of the antiviral family of bicyclic nucleoside analogues (BCNA) bearing cyclization self-cleavage spacers between the Val-Pro dipeptide sequence as well as the parent compound were synthesized and evaluated with regard to activation by the DPPIV/CD26 enzyme and for their stability in human and bovine serum. In buffer solution, carbamate and ester prodrugs were found to be chemically stable. Most prodrugs containing a dipeptidyl linker efficiently converted into the BCNA parent drug. In contrast, the Val-Pro alkyldiamino prodrugs converted predominantly into their alkyldiamino prodrug intermediates in the presence of CD26 and human serum. A marked increase in water solubility was observed for all prodrugs. In contrast to the parent compound, a tetrapeptide prodrug containing the Val-Val dipeptide as a self-cleavage spacer released substantial amounts of the BCNA parent drug at the basolateral side of Caco-2 cell cultures and exhibited 15- to 20-fold increased bioavailability in mice relative to the poorly bioavailable parent compound.

  11. Lipophilic prodrug conjugates allow facile and rapid synthesis of high loading capacity liposomes without the need for post-assembly purification

    PubMed Central

    Mikhalin, Alexander A.; Evdokimov, Nikolai M.; Frolova, Liliya V.; Magedov, Igor V.; Kornienko, Alexander; Johnston, Robert; Rogelj, Snezna; Tartis, Michaelann S.

    2014-01-01

    Dihydropyridopyrazoles are simplified synthetic analogues of podophyllotoxin that can effectively mimic its molecular scaffold and act as potent mitotic spindle poisons in dividing cancer cells. However, despite nanomolar potencies and ease of synthetic preparation, further clinical development of these promising anticancer agents is hampered due to their poor aqueous solubility. In this paper, we developed a prodrug strategy that enables incorporation of dihydropyridopyrazoles into liposome bilayers to overcome the solubility issues. The active drug was covalently connected to either myristic or palmitic acid anchor via carboxylesterase hydrolyzable linkage. The resulting prodrugs were self assembled into liposome bilayers from hydrated lipid films using ultrasound without the need for post-assembly purification. The average particle size of the prodrug-loaded liposomes was about 90 nm. The prodrug incorporation was verified by differential scanning calorimetry, spectrophotometry and gel filtration reaching maximum at 0.3 and 0.35 prodrug/lipid molar ratios for myristic and palmitic conjugates, respectively. However, the ratio of 0.2 was used in the particle size and biological activity experiments to maintain long-term stability of the prodrug-loaded liposomes against phase separation during storage. Antiproliferative activity was tested against HeLa and Jurkat cancer cell lines in vitro showing that the liposomal prodrug retained antitubulin activity of the parent drug and induced apoptosis mediated cancer cell death. Overall, the established data provide a powerful platform for further clinical development of dihydropyridopyrazoles using liposomes as the drug delivery system. PMID:25534989

  12. Simulation shows that HLA-matched stem cell donors can remain unidentified in donor searches

    PubMed Central

    Sauter, Jürgen; Solloch, Ute V.; Giani, Anette S.; Hofmann, Jan A.; Schmidt, Alexander H.

    2016-01-01

    The heterogeneous nature of HLA information in real-life stem cell donor registries may hamper unrelated donor searches. It is even possible that fully HLA-matched donors with incomplete HLA information are not identified. In our simulation study, we estimated the probability of these unnecessarily failed donor searches. For that purpose, we carried out donor searches in several virtual donor registries. The registries differed by size, composition with respect to HLA typing levels, and genetic diversity. When up to three virtual HLA typing requests were allowed within donor searches, the share of unnecessarily failed donor searches ranged from 1.19% to 4.13%, thus indicating that non-identification of completely HLA-matched stem cell donors is a problem of practical relevance. The following donor registry characteristics were positively correlated with the share of unnecessarily failed donor searches: large registry size, high genetic diversity, and, most strongly correlated, large fraction of registered donors with incomplete HLA typing. Increasing the number of virtual HLA typing requests within donor searches up to ten had a smaller effect. It follows that the problem of donor non-identification can be substantially reduced by complete high-resolution HLA typing of potential donors. PMID:26876789

  13. Brain death and care of the organ donor

    PubMed Central

    Kumar, Lakshmi

    2016-01-01

    Brain death has specific implications for organ donation with the potential for saving several lives. Awareness on maintenance of the brain dead has increased over the last decade with the progress in the field of transplant. The diagnosis of brain death is clinical and can be confirmed by apnea testing. Ancillary tests can be considered when the apnea test cannot be completed or is inconclusive. Reflexes of spinal origin may be present and should not be confused against the diagnosis of brain death. Adequate care for the donor targeting hemodynamic indices and lung protective ventilator strategies can improve graft quality for donation. Hormone supplementation using thyroxine, antidiuretic hormone, corticosteroid and insulin has shown to improve outcomes following transplant. India still ranks low compared to the rest of the world in deceased donation. The formation of organ sharing networks supported by state governments has shown a substantial increase in the numbers of deceased donors primarily by creating awareness and ensuring protocols in caring for the donor. This review describes the steps in the establishment of brain death and the management of the organ donor. Material for the review was collected through a Medline search, and the search terms included were brain death and organ donation. PMID:27275040

  14. Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors.

    PubMed

    Powell, Christine L; Bradford, Blair U; Craig, Christopher Patrick; Tsuchiya, Masato; Uehara, Takeki; O'Connell, Thomas M; Pogribny, Igor P; Melnyk, Stepan; Koop, Dennis R; Bleyle, Lisa; Threadgill, David W; Rusyn, Ivan

    2010-05-01

    Alcohol-induced liver injury (ALI) has been associated with, among other molecular changes, abnormal hepatic methionine metabolism, resulting in decreased levels of S-adenosylmethionine (SAM). Dietary methyl donor supplements such as SAM and betaine mitigate ALI in animal models; however, the mechanisms of protection remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress. We hypothesized that the protective action of methyl donors is mediated by an effect on the oxidative metabolism of alcohol in the liver. Male C57BL/6J mice were administered a control high-fat diet or diet enriched in methyl donors with or without alcohol for 4 weeks using the enteral alcohol feeding model. As expected, attenuation of ALI and an increase in reduced glutathione:oxidized glutathione ratio were achieved with methyl donor supplementation. Interestingly, methyl donors led to a 35% increase in blood alcohol elimination rate, and while there was no effect on alcohol metabolism in the stomach, a profound effect on liver alcohol metabolism was observed. The catalase-dependent pathway of alcohol metabolism was induced, yet the increase in CYP2E1 activity by alcohol was blunted, which may be mitigating production of oxidants. Additional factors contributing to the protective effects of methyl donors in ALI were increased activity of low- and high-K(m) aldehyde dehydrogenases leading to lower hepatic acetaldehyde, maintenance of the efficient mitochondrial energy metabolism, and promotion of peroxisomal beta-oxidation. Profound changes in alcohol metabolism represent additional important mechanism of the protective effect of methyl donors in ALI.

  15. Solid dispersions of the penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA): Formulation design and optimization studies

    PubMed Central

    Yang, Yu-Tsai; Di Pasqua, Anthony J.; Zhang, Yong; Sueda, Katsuhiko; Jay, Michael

    2015-01-01

    The penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was incorporated into a solid dispersion for oral administration by the solvent evaporation method using blends of polyvinylpyrrolidone (PVP), Eudragit® RL PO and α-tocopherol. D-optimal mixture design was used to optimize the formulation. Formulations that had a high concentration of both Eudragit® RL PO and α-tocopherol exhibited low water absorption and enhanced stability of the DTPA prodrug. Physicochemical properties of the optimal formulation were evaluated using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). In vitro release of the prodrug was evaluated using the USP Type II apparatus dissolution method. DSC studies indicated that the matrix had an amorphous structure, while FTIR spectrometry showed that DTPA penta-ethyl ester and excipients did not react with each other during formation of the solid dispersion.. Dissolution testing showed that the optimized solid dispersion exhibited a prolonged release profile, which could potentially result in a sustained delivery of DTPA penta-ethyl to enhance bioavailability. In conclusion, DTPA penta-ethyl ester was successfully incorporated into a solid matrix with high drug loading and improved stability compared to prodrug alone. PMID:24047113

  16. Targeting (cellular) lysosomal acid ceramidase by B13: Design, synthesis and evaluation of novel DMG-B13 ester prodrugs

    PubMed Central

    Bai, Aiping; Szulc, Zdzislaw, M.; Bielawski, Jacek; Pierce, Jason S.; Rembisa, Barbara; Terzieva, Silva; Mao, Cungui; Xu, Ruijuan; Wu, Bill; Clarke, Christopher J.; Newcomb, Benjamin; Liu, Xiang; Norris, James; Hannun, Yusuf A.; Bielawska, Alicja

    2015-01-01

    Acid ceramidase (ACDase) is being recognized as a therapeutic target for cancer. B13 represents a moderate inhibitor of ACDase. The present study concentrates on the lysosomal targeting of B13 via its N, N-dimethylglycine (DMG) esters (DMG-B13 prodrugs). Novel analogs, the isomeric mono-DMG-B13, LCL522 (3-O-DMG-B13•HCl) and LCL596 (1-O-DMG-B13•HCl) and di-DMG-B13, LCL521 (1,3-O, O-DMG-B13•2HCl) conjugates, were designed and synthesized through N, N-dimethyl glycine (DMG) esterification of the hydroxyl groups of B13. In MCF7 cells, DMG-B13 prodrugs were efficiently metabolized to B13. The early inhibitory effect of DMG-B13 prodrugs on cellular ceramidases was ACDase specific by their lysosomal targeting. The corresponding dramatic decrease of cellular Sph (80-97% Control/1h) by DMG-B13 prodrugs was mainly from the inhibition of the lysosomal ACDase. PMID:25456083

  17. Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer

    PubMed Central

    Zhang, Yumin; Yang, Cuihong; Wang, Weiwei; Liu, Jinjian; Liu, Qiang; Huang, Fan; Chu, Liping; Gao, Honglin; Li, Chen; Kong, Deling; Liu, Qian; Liu, Jianfeng

    2016-01-01

    Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff’s base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff’s base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy. PMID:26876480

  18. Contact-facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery

    PubMed Central

    Pan, Dipanjan; Pham, Christine TN; Weilbaecher, Katherine N; Tomasson, Michael H; Wickline, Samuel A; Lanza, Gregory M

    2016-01-01

    Sn2 lipase labile phospholipid prodrugs in conjunction with contact-facilitated drug delivery offer an important advancement in Nanomedicine. Many drugs incorporated into nanosystems, targeted or not, are substantially lost during circulation to the target. However, favorably altering the pharmacokinetics and volume of distribution of systemic drug delivery can offer greater efficacy with lower toxicity, leading to new prolonged-release nanoexcipients. However, the concept of achieving Paul Erhlich's inspired vision of a ‘magic bullet’ to treat disease has been largely unrealized due to unstable nanomedicines, nanosystems achieving low drug delivery to target cells, poor intracellular bioavailability of endocytosed nanoparticle payloads, and the substantial biological barriers of extravascular particle penetration into pathological sites. As shown here, Sn2 phospholipid prodrugs in conjunction with contact-facilitated drug delivery prevent premature drug diffusional loss during circulation and increase target cell bioavailability. The Sn2 phospholipid prodrug approach applies equally well for vascular constrained lipid-encapsulated particles and micelles the size of proteins that penetrate through naturally fenestrated endothelium in the bone marrow or thin-walled venules of an inflamed microcirculation. At one time Nanomedicine was considered a ‘Grail Quest’ by its loyal opposition and even many in the field adsorbing the pains of a long-learning curve about human biology and particles. However, Nanomedicine with innovations like Sn2 phospholipid prodrugs has finally made ‘made the turn’ toward meaningful translational success. PMID:26296541

  19. Utilization of peptide carrier system to improve intestinal absorption: targeting prolidase as a prodrug-converting enzyme

    NASA Technical Reports Server (NTRS)

    Bai, J. P.; Hu, M.; Subramanian, P.; Mosberg, H. I.; Amidon, G. L.

    1992-01-01

    The feasibility of targeting prolidase as a peptide prodrug-converting enzyme has been examined. The enzymatic hydrolysis by prolidase of substrates for the peptide transporter L-alpha-methyldopa-pro and several dipeptide analogues without an N-terminal alpha-amino group (phenylpropionylproline, phenylacetylproline, N-benzoylproline, and N-acetylproline) was investigated. The Michaelis-Menten parameters Km and Vmax for L-alpha-methyldopa-pro are 0.09 +/- 0.02 mM and 3.98 +/- 0.25 mumol/min/mg protein, respectively. However, no hydrolysis of the dipeptide analogues without an N-terminal alpha-amino group is observed, suggesting that an N-terminal alpha-amino group is required for prolidase activity. These results demonstrate that prolidase may serve as a prodrug-converting enzyme for the dipeptide-type prodrugs, utilizing the peptide carrier for transport of prodrugs into the mucosal cells and prolidase, a cytosolic enzyme, to release the drug. However, a free alpha-amino group appears to be necessary for prolidase hydrolysis.

  20. Amino Acid Derivatives as Palmitoylethanolamide Prodrugs: Synthesis, In Vitro Metabolism and In Vivo Plasma Profile in Rats.

    PubMed

    Vacondio, Federica; Bassi, Michele; Silva, Claudia; Castelli, Riccardo; Carmi, Caterina; Scalvini, Laura; Lodola, Alessio; Vivo, Valentina; Flammini, Lisa; Barocelli, Elisabetta; Mor, Marco; Rivara, Silvia

    2015-01-01

    Palmitoylethanolamide (PEA) has antinflammatory and antinociceptive properties widely exploited in veterinary and human medicine, despite its poor pharmacokinetics. Looking for prodrugs that could progressively release PEA to maintain effective plasma concentrations, we prepared carbonates, esters and carbamates at the hydroxyl group of PEA. Chemical stability (pH 7.4) and stability in rat plasma and liver homogenate were evaluated by in vitro assays. Carbonates and carbamates resulted too labile and too resistant in plasma, respectively. Ester derivatives, prepared by conjugating PEA with various amino acids, allowed to modulate the kinetics of PEA release in plasma and stability in liver homogenate. L-Val-PEA, with suitable PEA release in plasma, and D-Val-PEA, with high resistance to hepatic degradation, were orally administered to rats and plasma levels of prodrugs and PEA were measured at different time points. Both prodrugs showed significant release of PEA, but provided lower plasma concentrations than those obtained with equimolar doses of PEA. Amino-acid esters of PEA are a promising class to develop prodrugs, even if they need further chemical optimization.

  1. Amino Acid Derivatives as Palmitoylethanolamide Prodrugs: Synthesis, In Vitro Metabolism and In Vivo Plasma Profile in Rats

    PubMed Central

    Vacondio, Federica; Bassi, Michele; Silva, Claudia; Castelli, Riccardo; Carmi, Caterina; Scalvini, Laura; Lodola, Alessio; Vivo, Valentina; Flammini, Lisa; Barocelli, Elisabetta; Mor, Marco; Rivara, Silvia

    2015-01-01

    Palmitoylethanolamide (PEA) has antinflammatory and antinociceptive properties widely exploited in veterinary and human medicine, despite its poor pharmacokinetics. Looking for prodrugs that could progressively release PEA to maintain effective plasma concentrations, we prepared carbonates, esters and carbamates at the hydroxyl group of PEA. Chemical stability (pH 7.4) and stability in rat plasma and liver homogenate were evaluated by in vitro assays. Carbonates and carbamates resulted too labile and too resistant in plasma, respectively. Ester derivatives, prepared by conjugating PEA with various amino acids, allowed to modulate the kinetics of PEA release in plasma and stability in liver homogenate. L-Val-PEA, with suitable PEA release in plasma, and D-Val-PEA, with high resistance to hepatic degradation, were orally administered to rats and plasma levels of prodrugs and PEA were measured at different time points. Both prodrugs showed significant release of PEA, but provided lower plasma concentrations than those obtained with equimolar doses of PEA. Amino-acid esters of PEA are a promising class to develop prodrugs, even if they need further chemical optimization. PMID:26053855

  2. Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts

    PubMed Central

    2015-01-01

    A disodium phosphonooxymethyl prodrug of the antitumor agent triptolide was prepared from the natural product in three steps (39% yield) and displayed excellent aqueous solubility at pH 7.4 (61 mg/mL) compared to the natural product (17 μg/mL). The estimated shelf life (t90) for hydrolysis of the prodrug at 4 °C and pH 7.4 was found to be two years. In a mouse model of human colon adenocarcinoma (HT-29), the prodrug administered intraperitoneally was effective in reducing or eliminating xenograft tumors at dose levels as low as 0.3 mg/kg when given daily and at 0.9 mg/kg when given less frequently. When given via intraperitoneal and oral routes at daily doses of 0.6 and 0.9 mg/kg, the prodrug was also effective and well tolerated in a mouse model of human ovarian cancer (A2780). PMID:26596892

  3. Expression of Carboxylesterase Isozymes and Their Role in the Behavior of a Fexofenadine Prodrug in Rat Skin.

    PubMed

    Imai, Teruko; Ariyoshi, Satomi; Ohura, Kayoko; Sawada, Takashi; Nakada, Yuichiro

    2016-02-01

    The expression of carboxylesterase (CES) and the transdermal movement of an ester prodrug were studied in rat skin. Ethyl-fexofenadine (ethyl-FXD) was used as a model lipophilic prodrug that is slowly hydrolyzed to its parent drug, FXD (MW 502). Among the CES1 and CES2 isozymes, Hydrolase A is predominant in rat skin and this enzyme was involved in 65% of the cutaneous hydrolysis of ethyl-FXD. The similarity of the permeation behavior of ethyl-FXD in full thickness and stripped skin indicated that the stratum corneum was not a barrier to penetration. However, only FXD was observed in receptor fluid, not ethyl-FXD, presumably because of the high degree of binding of ethyl-FXD in viable skin. The rate of hydrolysis of ethyl-FXD was much faster than steady-state flux, such that the influx rate was the rate-limiting process for transdermal permeation. Although Hydrolase A levels gradually increased in skin taken from rats aged from 8 to 90 weeks, variations in the expression levels of the esterase hardly affected the conversion of prodrug. The present data suggest that the slow hydrolysis of the prodrug of an active ingredient in viable skin followed by slow diffusion of active drug may provide a useful approach to topical application.

  4. Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer

    NASA Astrophysics Data System (ADS)

    Zhang, Yumin; Yang, Cuihong; Wang, Weiwei; Liu, Jinjian; Liu, Qiang; Huang, Fan; Chu, Liping; Gao, Honglin; Li, Chen; Kong, Deling; Liu, Qian; Liu, Jianfeng

    2016-02-01

    Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff’s base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff’s base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy.

  5. Evaluation of physicochemical properties, skin permeation and accumulation profiles of salicylic acid amide prodrugs as sunscreen agent.

    PubMed

    Yan, Yi-Dong; Sung, Jun Ho; Lee, Dong Won; Kim, Jung Sun; Jeon, Eun-Mi; Kim, Dae-Duk; Kim, Dong Wuk; Kim, Jong Oh; Piao, Ming Guan; Li, Dong Xun; Yong, Chul Soon; Choi, Han Gon

    2011-10-31

    Various amide prodrugs of salicylic acid were synthesised, and their physicochemical properties including lipophilicity, chemical stability and enzymatic hydrolysis were investigated. In vivo skin permeation and accumulation profiles were also evaluated using a combination of common permeation enhancing techniques such as the use of a supersaturated solution of permeants in an enhancer vehicle, a lipophilic receptor solution, removal of the stratum corneum and delipidisation of skin. Their capacity factor values were proportional to the degree of carbon-carbon saturation in the side chain. All these amides were highly stable in acetonitrile and glycerine. Amide prodrugs were converted to salicylic acid both in hairless mouse liver and skin homogenates. N-dodecyl salicylamide (C12SM) showed the lowest permeation of salicylic acid in skin compared to the other prodrugs, probably due to its low aqueous solubility. It had a high affinity for the stratum corneum and its accumulation was restricted to only the uppermost layer of skin. Thus, this amide prodrug could be a safer topical sunscreen agent with minimum potential for systemic absorption.

  6. Synthesis, Chemical and Enzymatic Hydrolysis, and Aqueous Solubility of Amino Acid Ester Prodrugs of 3-Carboranyl Thymidine Analogues for Boron Neutron Capture Therapy of Brain Tumors

    PubMed Central

    Hasabelnaby, Sherifa; Goudah, Ayman; Agarwal, Hitesh K.; Abd alla, Mosaad S. M.; Tjarks, Werner

    2012-01-01

    Various water-soluble L-valine-, L-glutamate-, and glycine ester prodrugs of two 3-Carboranyl Thymidine Analogues (3-CTAs), designated N5 and N5-2OH, were synthesized for Boron Neutron Capture Therapy (BNCT) of brain tumors since the water solubilities of the parental compounds proved to be insufficient in preclinical studies. The amino acid ester prodrugs were prepared and stored as hydrochloride salts. The water solubilities of these amino acid ester prodrugs, evaluated in phosphate buffered saline (PBS) at pH 5, pH 6 and pH 7.4, improved 48 to 6600 times compared with parental N5 and N5-2OH. The stability of the amino acid ester prodrugs was evaluated in PBS at pH 7.4, Bovine serum, and Bovine cerebrospinal fluid (CSF). The rate of the hydrolysis in all three incubation media depended primarily on the amino acid promoiety and, to a lesser extend, on the site of esterification at the deoxyribose portion of the 3-CTAs. In general, 3'-amino acid ester prodrugs were less sensitive to chemical and enzymatic hydrolysis than 5'-amino acid ester prodrugs and the stabilities of the latter decreased in the following order: 5'-valine > 5'-glutamate > 5'-glycine. The rate of the hydrolysis of the 5'-amino acid ester prodrugs in Bovine CSF was overall higher than in PBS and somewhat lower than in Bovine serum. Overall, 5'-glutamate ester prodrug of N5 and the 5'-glycine ester prodrugs of N5 and N5-2OH appeared to be the most promising candidates for preclinical BNCT studies. PMID:22889558

  7. Formulating a new basis for the treatment against botulinum neurotoxin intoxication: 3,4-diaminopyridine prodrug design and characterization

    PubMed Central

    Zakhari, Joseph S.; Kinoyama, Isao; Hixon, Mark S.; Di Mola, Antonia; Globisch, Daniel; Janda, Kim D.

    2011-01-01

    Botulism is a disease characterized by neuromuscular paralysis and is produced from botulinum neurotoxins (BoNTs) found within the Gram positive bacterium Clostridium botulinum. This bacteria produces the most deadliest toxin known, with lethal doses as low as 1 ng/kg. Due to the relative ease of production and transport, the use of these agents as potential bioterrorist weapons has become of utmost concern. No small molecule therapies against BoNT intoxication have been approved to date. However, 3,4-diaminopyridine, (3,4-DAP), a potent reversible inhibitor of voltage-gated potassium channels, is an effective cholinergic agonist used in the treatment of neuromuscular degenerative disorders that require cholinergic enhancement. 3,4-DAP has also been shown to facilitate recovery of neuromuscular action potential post botulinum intoxication by blocking K+ channels. Unfortunately, 3,4-DAP displays toxicity largely due to blood-brain-barrier (BBB) penetration. As a dual-action prodrug approach to cholinergic enhancement we have designed carbamate and amide conjugates of 3,4-DAP. The carbamate prodrug is intended to be a slowly reversible inhibitor of acetylcholinesterase (AChE) along the lines of the stigmines thereby allowing increased persistence of released acetylcholine within the synaptic cleft. As a secondary activity, cleavage of the carbamate prodrug by AChE will afford the localized release of 3,4-DAP, which in turn, will enhance the pre-synaptic release of additional acetylcholine. Being a competitive inhibitor with respect to acetylcholine, the activity of the prodrug will be greatest at the synaptic junctions most depleted of acetylcholine. Here we report upon the synthesis and biochemical characterization of three new classes of prodrugs intended to limit previously reported stability and toxicity issues. Of the prodrugs examined, compound 32, demonstrated the most clinically relevant half-life of 2.76 h, while selectively inhibiting AChE over

  8. Donor free radical explosive composition

    DOEpatents

    Walker, Franklin E. [15 Way Points Rd., Danville, CA 94526; Wasley, Richard J. [4290 Colgate Way, Livermore, CA 94550

    1980-04-01

    An improved explosive composition is disclosed and comprises a major portion of an explosive having a detonation velocity between about 1500 and 10,000 meters per second and a minor amount of a donor additive comprising an organic compound or mixture of organic compounds capable of releasing low molecular weight free radicals or ions under mechanical or electrical shock conditions and which is not an explosive, or an inorganic compound or mixture of inorganic compounds capable of releasing low molecular weight free radicals or ions under mechanical or electrical shock conditions and selected from ammonium or alkali metal persulfates.

  9. Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF1) receptor antagonist BMS-665053 leading to improved oral bioavailability.

    PubMed

    Hartz, Richard A; Vrudhula, Vivekananda M; Ahuja, Vijay T; Grace, James E; Lodge, Nicholas J; Bronson, Joanne J; Macor, John E

    2017-03-15

    A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies.

  10. Pyrrolo[2,1-c][1,4]benzodiazepine-beta-glucuronide prodrugs with a potential for selective therapy of solid tumors by PMT and ADEPT strategies.

    PubMed

    Kamal, Ahmed; Tekumalla, Venkatesh; Raju, P; Naidu, V G M; Diwan, Prakash V; Sistla, Ramakrishna

    2008-07-01

    Pyrrolo[2,1-c][1,4]benzodiazepine-beta-glucuronide prodrugs 15a-b, with a potential for selective therapy of solid tumors by PMT and ADEPT have been designed, synthesized and evaluated for selective cytotoxicity in the presence of the enzyme beta-glucuronidase. The prodrugs have been found to possess reduced cytotoxicity compared to the parent moieties, and are excellent substrates for the enzyme, exhibiting cytotoxicity selectively in the presence of the enzyme. Enhanced water solubility and improved stability are the other important outcomes upon modifying these molecules as their prodrugs.

  11. BLISS: A Computer Program for the Protection of Blood Donors

    DTIC Science & Technology

    1982-06-28

    34 KEYBORD KEYS ’STOP’ AND THEN ’RUN’." 910 PRINT 920 IF Hardcopy,$="Y" THEN 980 930 PRINT "PRESS ’CONT’ TO GO 04" 940 PAUSE". 950 PRINT PAGE 960 PRINT 970

  12. Design, synthesis and in vitro kinetic study of tranexamic acid prodrugs for the treatment of bleeding conditions

    NASA Astrophysics Data System (ADS)

    Karaman, Rafik; Ghareeb, Hiba; Dajani, Khuloud Kamal; Scrano, Laura; Hallak, Hussein; Abu-Lafi, Saleh; Mecca, Gennaro; Bufo, Sabino A.

    2013-07-01

    Based on density functional theory (DFT) calculations for the acid-catalyzed hydrolysis of several maleamic acid amide derivatives four tranexamic acid prodrugs were designed. The DFT results on the acid catalyzed hydrolysis revealed that the reaction rate-limiting step is determined on the nature of the amine leaving group. When the amine leaving group was a primary amine or tranexamic acid moiety, the tetrahedral intermediate collapse was the rate-limiting step, whereas in the cases by which the amine leaving group was aciclovir or cefuroxime the rate-limiting step was the tetrahedral intermediate formation. The linear correlation between the calculated DFT and experimental rates for N-methylmaleamic acids 1- 7 provided a credible basis for designing tranexamic acid prodrugs that have the potential to release the parent drug in a sustained release fashion. For example, based on the calculated B3LYP/6-31G(d,p) rates the predicted t1/2 (a time needed for 50 % of the prodrug to be converted into drug) values for tranexamic acid prodrugs ProD 1- ProD 4 at pH 2 were 556 h [50.5 h as calculated by B3LYP/311+G(d,p)] and 6.2 h as calculated by GGA: MPW1K), 253 h, 70 s and 1.7 h, respectively. Kinetic study on the interconversion of the newly synthesized tranexamic acid prodrug ProD 1 revealed that the t1/2 for its conversion to the parent drug was largely affected by the pH of the medium. The experimental t1/2 values in 1 N HCl, buffer pH 2 and buffer pH 5 were 54 min, 23.9 and 270 h, respectively.

  13. Lipid nanoparticles with different oil/fatty ester ratios as carriers of buprenorphine and its prodrugs for injection.

    PubMed

    Wang, Jhi-Joung; Liu, Kuo-Sheng; Sung, K C; Tsai, Chia-Yin; Fang, Jia-You

    2009-09-10

    Buprenorphine is a promising drug for the treatment of chronic pain and opioid dependence. The aim of the present work was to evaluate the feasibility of lipid nanoparticles with different oil/fatty ester ratios for injection of buprenorphine. To improve the release properties and analgesic duration of the drug, ester prodrugs were also incorporated into the nanoparticles for evaluation. Linseed oil and cetyl palmitate were respectively chosen as the liquid lipid and solid lipid in the inner phase of the nanoparticulate systems. Differential scanning calorimetry (DSC) was performed, and the particle size, zeta potential, molecular environment, and lipid/water partitioning were determined to characterize the state of the drug/prodrug and lipid modification. The in vitro release kinetics were measured by a Franz assembly. DSC showed that systems without oil (solid lipid nanoparticles, SLNs) had a more ordered crystalline lattice in the inner matrix compared to those with oil (nanostructured lipid carriers, NLCs and lipid emulsion, LE). The mean diameter of the nanoparticles ranged between 180 and 200nm. The in vitro drug/prodrug release occurred in a delayed manner in decreasing order as follows: SLN>NLC>LE. It was found that the release rate was reduced following an increase in alkyl ester chains in the prodrugs. The in vivo antinociception was examined by a cold ethanol tail-flick test in rats. Compared to an aqueous solution, a prolonged analgesic duration was detected after an intravenous injection of buprenorphine-loaded SLNs and buprenorphine propionate (Bu-C3)-loaded NLCs (with 10% linseed oil in the lipid phase). The Bu-C3 in NLCs even showed a maximum antinociceptive activity for 10h. In vitro erythrocyte hemolysis and lactate dehydrogenase (LDH) release from neutrophils demonstrated a negligible toxicity of these carriers. Our results indicate the feasibility of using lipid nanoparticles, especially SLNs and NLCs, as parenteral delivery systems for

  14. Interaction of dipeptide prodrugs of saquinavir with multidrug resistance protein-2 (MRP-2): evasion of MRP-2 mediated efflux.

    PubMed

    Jain, Ritesh; Agarwal, Sheetal; Mandava, Nanda Kishore; Sheng, Ye; Mitra, Ashim K

    2008-10-01

    Saquinavir (SQV), the first protease inhibitor approved by FDA to treat HIV-1 infection. This drug is a well-known substrate for multidrug resistance protein-2 (MRP-2). The objective of this study was to investigate whether derivatization of SQV to dipeptide prodrugs, valine-valine-saquinavir (Val-Val-SQV) and glycine-valine-saquinavir (Gly-Val-SQV), targeting peptide transporter can circumvent MRP-2 mediated efflux. Uptake and transport studies were carried out across MDCKII-MRP2 cell monolayers to investigate the interaction of SQV and its prodrugs with MRP-2. In situ single pass intestinal perfusion experiments in rat jejunum were performed to calculate intestinal absorption rate constants and permeabilities of SQV, Val-Val-SQV and Gly-Val-SQV. Uptake studies demonstrated that the prodrugs have significantly lower interaction with MRP-2 relative to SQV. Transepithelial transport of Val-Val-SQV and Gly-Val-SQV across MDCKII-MRP2 cells exhibited an enhanced absorptive flux and reduced secretory flux as compared to SQV. Intestinal perfusion studies revealed that synthesized prodrugs have higher intestinal permeabilities relative to SQV. Enhanced absorption of Val-Val-SQV and Gly-Val-SQV relative to SQV can be attributed to their translocation by the peptide transporter in the jejunum. In the presence of MK-571, a MRP family inhibitor, there was a significant increase in the permeabilities of SQV and Gly-Val-SQV indicating that these compounds are probably substrates for MRP-2. However, there was no change in the permeability of Val-Val-SQV with MK-571 indicating lack of any interaction of Val-Val-SQV with MRP-2. In conclusion, peptide transporter targeted prodrug modification of MRP-2 substrates may lead to shielding of these drug molecules from MRP-2 efflux pumps.

  15. Simultaneous modulation of transport and metabolism of acyclovir prodrugs across rabbit cornea: An approach involving enzyme inhibitors.

    PubMed

    Katragadda, Suresh; Talluri, Ravi S; Mitra, Ashim K

    2006-08-31

    The aim of this study is to identify the class of enzymes responsible for the hydrolysis of amino acid and dipeptide prodrugs of acyclovir (ACV) and to modulate transport and metabolism of amino acid and dipeptide prodrugs of acyclovir by enzyme inhibitors across rabbit cornea. l-Valine ester of acyclovir, valacyclovir (VACV) and l-glycine-valine ester of acyclovir, gly-val-acyclovir (GVACV) were used as model compounds. Hydrolysis studies of VACV and GVACV in corneal homogenate were conducted in presence of various enzyme inhibitors. IC(50) values were determined for the enzyme inhibitors. Transport studies were conducted with isolated rabbit corneas at 34 degrees C. Complete inhibition of VACV hydrolysis was observed in the presence of Pefabloc SC (4-(2-aminoethyl)-benzenesulfonyl-fluoride) and PCMB (p-chloromercuribenzoic acid). Similar trend was also observed with GVACV in the presence of bestatin. IC(50) values of PCMB and bestatin for VACV and GVACV were found to be 3.81+/-0.94 and 0.34+/-0.08muM respectively. Eserine, tetraethyl pyrophosphate (TEPP) and diisopropyl fluorophosphate (DFP) also produced significant inhibition of VACV hydrolysis. Transport of VACV and GVACV across cornea showed decreased metabolic rate and modulation of transport in presence of PCMB and bestain respectively. The principle enzyme classes responsible for the hydrolysis of VACV and GVACV were carboxylesterases and aminopeptidases respectively. Enzyme inhibitors modulated the transport and metabolism of prodrugs simultaneously even though their affinity towards prodrugs was distinct. In conclusion, utility of enzyme inhibitors to modulate transport and metabolism of prodrugs appears to be promising strategy for enhancing drug transport across cornea.

  16. Laparoscopic donor nephrectomy versus open donor nephrectomy: recipient's perspective.

    PubMed

    Jamale, Tukaram E; Hase, Niwrutti K; Iqbal, Anwar M

    2012-11-01

    Effects of laparoscopic donor nephrectomy (LDN) on graft function, especially early post-transplant, have been controversial. To assess and compare early and late graft function in kidneys procured by open and laparoscopic methods, a retrospective observational study was carried out on 37 recipients-donors who underwent LDN after introduction of this technique in February 2007 at our center, a tertiary care nephrology referral center. Demographic, immunological and intraoperative variables as well as immunosuppressive protocols and number of human leukocyte antigen (HLA) mismatches were noted. Early graft function was assessed by serum creatinine on Days two, five, seven, 14 and 28 and at the time of discharge. Serum creatinine values at three months and at one year post-transplant were considered as the surrogates of late graft function. Data obtained were compared with the data from 33 randomly selected kidney transplants performed after January 2000 by the same surgical team, in whom open donor nephrectomy was used. Pearson's chi square test, Student's t test and Mann-Whitney U test were used for statistical analysis. Early graft function (serum creatinine on Day five 2.15 mg/dL vs 1.49 mg/dL, P = 0.027) was poorer in the LDN group. Late graft function as assessed by serum creatinine at three months (1.45 mg/dL vs 1.31 mg/dL, P = 0.335) and one year (1.56 mg/dL vs 1.34 mg/dL, P = 0.275) was equivalent in the two groups. Episodes of early acute graft dysfunction due to acute tubular necrosis were significantly higher in the LDN group (37.8% vs 12.1%, Z score 2.457, P = 0.014). Warm ischemia time was significantly prolonged in the LDN group (255 s vs 132.5 s, P = 0.002). LDN is associated with slower recovery of graft function and higher incidence of early acute graft dysfunction due to acute tubular necrosis. Late graft function at one year is however comparable.

  17. Hydroperoxides as Hydrogen Bond Donors

    NASA Astrophysics Data System (ADS)

    Møller, Kristian H.; Tram, Camilla M.; Hansen, Anne S.; Kjaergaard, Henrik G.

    2016-06-01

    Hydroperoxides are formed in the atmosphere following autooxidation of a wide variety of volatile organics emitted from both natural and anthropogenic sources. This raises the question of whether they can form hydrogen bonds that facilitate aerosol formation and growth. Using a combination of Fourier transform infrared spectroscopy, FT-IR, and ab initio calculations, we have compared the gas phase hydrogen bonding ability of tert-butylhydroperoxide (tBuOOH) to that of tert-butanol (tBuOH) for a series of bimolecular complexes with different acceptors. The hydrogen bond acceptor atoms studied are nitrogen, oxygen, phosphorus and sulphur. Both in terms of calculated redshifts and binding energies (BE), our results suggest that hydroperoxides are better hydrogen bond donors than the corresponding alcohols. In terms of hydrogen bond acceptor ability, we find that nitrogen is a significantly better acceptor than the other three atoms, which are of similar strength. We observe a similar trend in hydrogen bond acceptor ability with other hydrogen bond donors including methanol and dimethylamine.

  18. [Clinical selection of blood donors].

    PubMed

    Danic, B

    2003-06-01

    For 20 years, the organization set up to insure the blood transfusion safety has never stopped strengthening. It is based on clinical and epidemiological selection of the blood donation candidates, biologic selection of blood donations and different physico-chemical techniques for pathogens reduction or inactivation in blood products. In France, this organization is optimized by the assertion of the voluntary and non-remunerated character of blood donation registered in the law of January 4th, 1993. The blood donors selection is structured in three successive stages. The first stage is the pre-donation information. The second stage begins with reading and filling out an info-questionnaire which prepare for an interview with a physician. This interview is specially directed to prevention of transfusion-transmitted infections and the prevention of adverse reactions after a 400 to 600 mL collection of whole blood or components. Finally, the third stage is the delivery of a post-donation information which invites the donor to contact the "établissement français du sang" (EFS) in case of a new event arisen after the donation or in case of reviewing of its own answers during the medical interview.

  19. Azido- and chlorido-cobalt complex as carrier-prototypes for antitumoral prodrugs.

    PubMed

    Pires, Bianca M; Giacomin, Letícia C; Castro, Frederico A V; Cavalcanti, Amanda dos S; Pereira, Marcos D; Bortoluzzi, Adailton J; Faria, Roberto B; Scarpellini, Marciela

    2016-04-01

    Cobalt(III) complexes are well-suited systems for cytotoxic drug release under hypoxic conditions. Here, we investigate the effect of cytotoxic azide release by cobalt-containing carrier-prototypes for antitumoral prodrugs. In addition, we study the species formed after reduction of Co(3+) → Co(2+) in the proposed models for these prodrugs. Three new complexes, [Co(III)(L)(N3)2]BF4(1), [{Co(II)(L)(N3)}2](ClO4)2(2), and [Co(II)(L)Cl]PF6(3), L=[(bis(1-methylimidazol-2-yl)methyl)(2-(pyridyl-2-yl)ethyl)amine], were synthesized and studied by several spectroscopic, spectrometric, electrochemical, and crystallographic methods. Reactivity and spectroscopic data reveal that complex 1 is able to release N3(-) either after reduction with ascorbic acid, or by ambient light irradiation, in aqueous phosphate buffer (pH6.2, 7.0 and 7.4) and acetonitrile solutions. The antitumoral activities of compounds 1-3 were tested in normoxia on MCF-7 (human breast adenocarcinoma), PC-3 (human prostate) and A-549 (human lung adenocarcinoma epithelial) cell lines, after 24h of exposure. Either complexes or NaN3 presented IC50 values higher than 200 μM, showing lower cytotoxicity than the clinical standard antitumoral complex cisplatin, under the same conditions. Complexes 1-3 were also evaluated in hypoxia on A-549 and results indicate high IC50 data (>200 μM) after 24h of exposure. However, an increase of cancer cell susceptibility to 1 and 2 was observed at 300 μM. Regarding complex 3, no cytotoxic activity was observed in the same conditions. The data presented here indicate that the tridentate ligand L is able to stabilize both oxidation states of cobalt (+3 and +2). In addition, the cobalt(III) complex generates the low cytotoxic cobalt(II) species after reduction, which supports their use as as carrier prototypes for antitumoral prodrugs.

  20. Development of a Δ9-Tetrahydrocannabinol Amino Acid-Dicarboxylate Prodrug With Improved Ocular Bioavailability

    PubMed Central

    Adelli, Goutham R.; Bhagav, Prakash; Taskar, Pranjal; Hingorani, Tushar; Pettaway, Sara; Gul, Waseem; ElSohly, Mahmoud A.; Repka, Michael A.; Majumdar, Soumyajit

    2017-01-01

    Purpose The aim of the present study was to evaluate the utility of the relatively hydrophilic Δ9-tetrahydrocannabinol (THC) prodrugs, mono and di-valine esters (THC-Val and THC-Val-Val) and the amino acid (valine)-dicarboxylic acid (hemisuccinate) ester (THC-Val-HS), with respect to ocular penetration and intraocular pressure (IOP) lowering activity. THC, timolol, and pilocarpine eye drops were used as controls. Methods THC-Val, THC-Val-Val, and THC-Val-HS were synthesized and chemically characterized. Aqueous solubility and in vitro transcorneal permeability of THC and the prodrugs, in the presence of various surfactants and cyclodextrins, were determined. Two formulations were evaluated for therapeutic activity in the α-chymotrypsin induced rabbit glaucoma model, and the results were compared against controls comprising of THC emulsion and marketed timolol maleate and pilocarpine eye drops. Results THC-Val-HS demonstrated markedly improved solubility (96-fold) and in vitro permeability compared to THC. Selected formulations containing THC-Val-HS effectively delivered THC to the anterior segment ocular tissues in the anesthetized rabbits: 62.1 ng/100 μL of aqueous humor (AH) and 51.4 ng/50 mg of iris ciliary bodies (IC) (total THC). The duration and extent of IOP lowering induced by THC-Val-HS was 1 hour longer and 10% greater, respectively, than that obtained with THC and was comparable with the pilocarpine eye drops. Timolol ophthalmic drops, however, exhibited a longer duration of activity. Both THC and THC-Val-HS were detected in the ocular tissues following multiple dosing of THC-Val-HS in conscious animals. The concentration of THC in the iris-ciliary bodies at the 60- and 120-minute time points (53 and 57.4 ng/50 mg) were significantly greater than that of THC-Val-HS (24.2 and 11.3 ng/50 mg). Moreover, at the two time points studied, the concentration of THC was observed to increase or stay relatively constant, whereas THC-Val-HS concentration decreased

  1. Role of glutamate 64 in the activation of the prodrug 5-fluorocytosine by yeast cytosine deaminase.

    PubMed

    Wang, Jifeng; Sklenak, Stepan; Liu, Aizhuo; Felczak, Krzysztof; Wu, Yan; Li, Yue; Yan, Honggao

    2012-01-10

    Yeast cytosine deaminase (yCD) catalyzes the hydrolytic deamination of cytosine to uracil as well as the deamination of the prodrug 5-fluorocytosine (5FC) to the anticancer drug 5-fluorouracil. In this study, the role of Glu64 in the activation of the prodrug 5FC was investigated by site-directed mutagenesis, biochemical, nuclear magnetic resonance (NMR), and computational studies. Steady-state kinetics studies showed that the mutation of Glu64 causes a dramatic decrease in k(cat) and a dramatic increase in K(m), indicating Glu64 is important for both binding and catalysis in the activation of 5FC. (19)F NMR experiments showed that binding of the inhibitor 5-fluoro-1H-pyrimidin-2-one (5FPy) to the wild-type yCD causes an upfield shift, indicating that the bound inhibitor is in the hydrated form, mimicking the transition state or the tetrahedral intermediate in the activation of 5FC. However, binding of 5FPy to the E64A mutant enzyme causes a downfield shift, indicating that the bound 5FPy remains in an unhydrated form in the complex with the mutant enzyme. (1)H and (15)N NMR analysis revealed trans-hydrogen bond D/H isotope effects on the hydrogen of the amide of Glu64, indicating that the carboxylate of Glu64 forms two hydrogen bonds with the hydrated 5FPy. ONIOM calculations showed that the wild-type yCD complex with the hydrated form of the inhibitor 1H-pyrimidin-2-one is more stable than the initial binding complex, and in contrast, with the E64A mutant enzyme, the hydrated inhibitor is no longer favored and the conversion has a higher activation energy, as well. The hydrated inhibitor is stabilized in the wild-type yCD by two hydrogen bonds between it and the carboxylate of Glu64 as revealed by (1)H and (15)N NMR analysis. To explore the functional role of Glu64 in catalysis, we investigated the deamination of cytosine catalyzed by the E64A mutant by ONIOM calculations. The results showed that without the assistance of Glu64, both proton transfers before and

  2. Aromatic nitrogen mustard-based prodrugs: activity, selectivity, and the mechanism of DNA cross-linking.

    PubMed

    Chen, Wenbing; Han, Yanyan; Peng, Xiaohua

    2014-06-10

    Three novel H2O2-activated aromatic nitrogen mustard prodrugs (6-8) are reported. These compounds contain a DNA alkylating agent connected to a H2O2-responsive trigger by different electron-withdrawing linkers so that they are inactive towards DNA but can be triggered by H2O2 to release active species. The activity and selectivity of these compounds towards DNA were investigated by measuring DNA interstrand cross-link (ICL) formation in the presence or absence of H2O2. An electron-withdrawing linker unit, such as a quaternary ammonia salt (6), a carboxyamide (7), and a carbonate group (8), is sufficient to deactivate the aromatic nitrogen mustard resulting in less than 1.5 % cross-linking formation. However, H2O2 can restore the activity of the effectors by converting a withdrawing group to a donating group, therefore increasing the cross-linking efficiency (>20 %). The stability and reaction sites of the ICL products were determined, which revealed that alkylation induced by 7 and 8 not only occurred at the purine sites but also at the pyrimidine site. For the first time, we isolated and characterized the monomer adducts formed between the canonical nucleosides and the aromatic nitrogen mustard (15) which supported that nitrogen mustards reacted with dG, dA, and dC. The activation mechanism was studied by NMR spectroscopic analysis. An in vitro cytotoxicity assay demonstrated that compound 7 with a carboxyamide linker dramatically inhibited the growth of various cancer cells with a GI50 of less than 1 μM, whereas compound 6 with a charged linker did not show any obvious toxicity in all cell lines tested. These data indicated that a neutral carboxyamide linker is preferable for developing nitrogen mustard prodrugs. Our results showed that 7 is a potent anticancer prodrug that can serve as a model compound for further development. We believe these novel aromatic nitrogen mustards will inspire further and effective applications.

  3. Gamete donors' expectations and experiences of contact with their donor offspring

    PubMed Central

    Kirkman, Maggie; Bourne, Kate; Fisher, Jane; Johnson, Louise; Hammarberg, Karin

    2014-01-01

    STUDY QUESTION What are the expectations and experiences of anonymous gamete donors about contact with their donor offspring? SUMMARY ANSWER Rather than consistently wanting to remain distant from their donor offspring, donors' expectations and experiences of contact with donor offspring ranged from none to a close personal relationship. WHAT IS KNOWN ALREADY Donor conception is part of assisted reproduction in many countries, but little is known about its continuing influence on gamete donors' lives. STUDY DESIGN, SIZE, DURATION A qualitative research model appropriate for understanding participants' views was employed; semi-structured interviews were conducted during January–March 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS Before 1998, gamete donors in Victoria, Australia, were subject to evolving legislation that allowed them to remain anonymous or (from 1988) to consent to the release of identifying information. An opportunity to increase knowledge of donors' expectations and experiences of contact with their donor offspring recently arose in Victoria when a recommendation was made to introduce mandatory identification of donors on request from their donor offspring, with retrospective effect. Pre-1998 donors were invited through an advertising campaign to be interviewed about their views, experiences and expectations; 36 sperm donors and 6 egg donors participated. MAIN RESULTS AND THE ROLE OF CHANCE This research is unusual in achieving participation by donors who would not normally identify themselves to researchers or government inquiries. Qualitative thematic analysis revealed that most donors did not characterize themselves as parents of their donor offspring. Donors' expectations and experiences of contact with donor offspring ranged from none to a close personal relationship. LIMITATIONS, REASONS FOR CAUTION It is not possible to establish whether participants were representative of all pre-1998 donors. WIDER IMPLICATIONS OF THE FINDINGS Anonymous

  4. Extended Criteria Donors in Liver Transplantation.

    PubMed

    Vodkin, Irine; Kuo, Alexander

    2017-05-01

    Mortality rates on the liver transplant waiting list are increasing. The shortage of organs has resulted in higher utilization of extended criteria donors (ECDs), with centers pushing the limits of what is acceptable for transplantation. Donor quality is more appropriately represented as a continuum of risk, and careful selection and matching of ECD grafts with recipients may lead to excellent outcomes. Although there is no precise definition for what constitutes an ECD liver, this review focuses on frequently cited characteristics, including donor age, steatosis, donation after cardiac death, and donors with increased risk of disease transmission.

  5. Novel guidelines for organ donor cancer screening.

    PubMed

    Hassanain, Mazen

    2014-05-20

    Donor transmitted malignancy is a real disastrous risk when dealing with expanded criteria donors. As donor age is increasing, guidelines for cancer screening of the elderly brain dead organ donors must be evidence-based but systematic review of such is sparse. Based on a review of published literature and our 20 years' experience, we propose a new series of guidelines concerning screening for the four most common malignancies: breast colon, lung and prostate cancer. Prospective testing of the efficacy of such protocol will then follow.

  6. Nitrogen related shallow thermal donors in silicon

    NASA Astrophysics Data System (ADS)

    Fujita, N.; Jones, R.; Öberg, S.; Briddon, P. R.

    2007-07-01

    In this letter, the authors investigate the electrical properties of nitrogen related shallow thermal donor (STD) candidates and their concentrations under different doping conditions by means of density functional theory. Experimentally, the existence of STDs containing one nitrogen atom and both even and odd numbers of oxygen atoms has been proposed. However, so far first principles studies have not presented a candidate for the latter. Here, they show that the NO defect possesses a shallow donor level. Adding one or two more oxygen atoms results in the donor level to become shallower. The fraction of shallow nitrogen related donors to N dimers increases in material with low concentration of nitrogen.

  7. Gastroprotective [6]-Gingerol Aspirinate as a Novel Chemopreventive Prodrug of Aspirin for Colon Cancer

    PubMed Central

    Zhu, Yingdong; Wang, Fang; Zhao, Yantao; Wang, Pei; Sang, Shengmin

    2017-01-01

    A growing body of research suggests daily low-dose aspirin (ASA) reduces heart diseases and colorectal cancers. However, the major limitation to the use of aspirin is its side effect to cause ulceration and bleeding in the gastrointestinal tract. Preclinical studies have shown that ginger constituents ameliorate ASA-induced gastric ulceration. We here report the design and synthesis of a novel prodrug of aspirin, [6]-gingerol aspirinate (GAS). Our data show that GAS exerts enhanced anti-cancer properties in vitro and superior gastroprotective effects in mice. GAS was also able to survive stomach acid and decomposed in intestinal linings or after absorption to simultaneously release ASA and [6]-gingerol. We further present that GAS inactivates both COX-1 and COX-2 equally. Our results demonstrate the enhanced anticancer properties along with gastroprotective effects of GAS, suggesting that GAS can be a therapeutic equivalent for ASA in inflammatory and proliferative diseases without the deleterious effects on stomach mucosa. PMID:28067282

  8. Discovery of an L-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100.

    PubMed

    Kim, Se-Ho; Tangallapally, Rajendra; Kim, In Chul; Trovato, Richard; Parker, Daniel; Patton, J Scott; Reeves, Leslie; Bradford, Chad; Wettstein, Daniel; Baichwal, Vijay; Papac, Damon; Bajji, Ashok; Carlson, Robert; Yager, Kraig M

    2015-11-15

    Various types of Hsp90 inhibitors have been and continue to undergo clinical investigation. One development candidate is the purine-based, synthetic Hsp90 inhibitor 1 (MPC-3100), which successfully completed a phase I clinical study. However, further clinical development of 1 was hindered by poor solubility and consequent formulation issues and promoted development of a more water soluble prodrug. Towards this end, numerous pro-moieties were explored in vitro and in vivo. These studies resulted in identification of L-alanine ester mesylate, 2i (MPC-0767), which exhibited improved aqueous solubility, adequate chemical stability, and rapid bioconversion without the need for solubilizing excipients. Based on improved physical characteristics and favorable PK and PD profiles, 2i mesylate was selected for further development. A convergent, scalable, chromatography-free synthesis for 2i mesylate was developed to support further clinical evaluation.

  9. Ether lipid-ester prodrugs of acyclic nucleoside phosphonates: activity against adenovirus replication in vitro.

    PubMed

    Hartline, Caroll B; Gustin, Kortney M; Wan, William B; Ciesla, Stephanie L; Beadle, James R; Hostetler, Karl Y; Kern, Earl R

    2005-02-01

    The acyclic nucleoside phosphonate cidofovir (CDV) and its closely related analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-adenine ([S]-HPMPA) have been reported to have activity against many adenovirus (AdV) serotypes. A new series of orally active ether lipid-ester prodrugs of CDV and of (S)-HPMPA that have slight differences in the structure of their lipid esters were evaluated, in tissue-culture cells, for activity against 5 AdV serotypes. The results indicated that, against several AdV serotypes, the most active compounds were 15-2500-fold more active than the unmodified parent compounds and should be evaluated further for their potential to treat AdV infections in humans.

  10. N-Acyl-phosphoramidates as potential novel form of gemcitabine prodrugs.

    PubMed

    Baraniak, Janina; Pietkiewicz, Aleksandra; Kaczmarek, Renata; Radzikowska, Ewa; Kulik, Katarzyna; Krolewska, Karolina; Cieslak, Marcin; Krakowiak, Agnieszka; Nawrot, Barbara

    2014-04-01

    Gemcitabine (dFdC) is a cytidine analog remarkably active against a wide range of solid tumors. Inside a cell, gemcitabine is phosphorylated by deoxycytidine kinase to yield gemcitabine monophosphate, further converted to gemcitabine di- and triphosphate. The most frequent form of acquired resistance to gemcitabine in vitro is the deoxycytidine kinase deficiency. Thus, proper prodrugs carrying the 5'-pdFdC moiety may help to overcome this problem. A series of new derivatives of gemcitabine possessing N-acyl(thio)phosphoramidate moieties were prepared and their cytotoxic properties were determined. N-Acyl-phosphoramidate derivatives of gemcitabine have similar cytotoxicity as gemcitabine itself, and have been found accessible to the cellular enzymes. The nicotinic carboxamide derivative of gemcitabine 5'-O-phosphorothioate occurred to be the best inhibitor of bacterial DNA polymerase I and human DNA polymerase α.

  11. Lipase-catalyzed synthesis of (S)-naproxen ester prodrug by transesterification in organic solvents.

    PubMed

    Tsai, S W; Tsai, C S; Chang, C S

    1999-06-01

    A lipase-catalyzed enantioselective transesterification process was developed for the synthesis of (S)-naproxen 2-N-morpholinoethyl ester prodrug from racemic 2,2,2-trifluoroethyl naproxen ester in organic solvents. By selecting isooctane and 37 degrees C as the best solvent and temperature, the apparent fits of the initial conversion rates for transesterification and hydrolysis side reaction suggest a ping-pong Bi-Bi enzymatic mechanism with the alcohol as a competitive enzyme inhibitor. Improvements in the initial conversion rate and the productivity for the desired (S)-ester product were obtained after comparing with the result of an enantioselective esterification process. Studies of water content in isooctane and alcohol containing various N,N-dialkylamino groups on the enzyme activity and enantioselectivity, as well as the recovery of (S)-ester product by using extraction, were also reported.

  12. Novel triclabendazole prodrug: A highly water soluble alternative for the treatment of fasciolosis.

    PubMed

    Flores-Ramos, Miguel; Ibarra-Velarde, Froylán; Jung-Cook, Helgi; Hernández-Campos, Alicia; Vera-Montenegro, Yolanda; Castillo, Rafael

    2017-02-01

    In this work we present the synthesis, aqueous solubility and stability, hydrolysis by alkaline phosphatase, and in vivo fasciolicidal activity in sheep of a highly water soluble phosphate salt prodrug of triclabendazole (MFR-5). The aqueous solubility of MFR-5 at pH 7 was 88,000-fold that of triclabendazole. MFR-5 showed excellent aqueous stability (>95% after 26h) at pH 7, making it ideal for developing pharmaceutical compositions in the form of solutions that can easily be hydrolyzed by the enzyme alkaline phosphatase (t=13.6s) to liberate the precursor compound. An aqueous solution of MFR-5 administered intramuscularly to sheep at concentrations of 4, 6 and 8mg/kg presented a fasciolicidal efficiency of 96.5%, 98.4% and 99.2%, respectively. In the in vivo experiments, MFR-5 reduced 100% the excretion of eggs in all of the above concentrations.

  13. Imaging of doxorubicin release from theranostic macromolecular prodrugs via fluorescence resonance energy transfer.

    PubMed

    Krüger, Harald R; Schütz, Irene; Justies, Aileen; Licha, Kai; Welker, Pia; Haucke, Volker; Calderón, Marcelo

    2014-11-28

    Herein we present a FRET-based theranostic macromolecular prodrug (TMP) composed of (a) dendritic polyglycerol (PG) as polymeric nanocarrier, (b) doxorubicin (Dox) linked via a pH-sensitive hydrazone to (c) a tri-functional linker, and (d) an indodicarbocyanine dye (IDCC) attached in close proximity to Dox. The drug fluorescence is quenched via intramolecular FRET until the pH-sensitive hydrazone bond between the TMP and Dox is cleaved at acidic pH. By measuring its fluorescence, we characterized the TMP cleavage kinetics at different pH values in vitro. The intracellular release of Dox from the carrier was monitored in real time in intact cancer cells, giving more insight into the mode of action of a polymer drug conjugate.

  14. Excited‐State Dynamics of a Two‐Photon‐Activatable Ruthenium Prodrug

    PubMed Central

    Greenough, Simon E.; Horbury, Michael D.; Smith, Nichola A.; Sadler, Peter J.; Paterson, Martin J.

    2016-01-01

    Abstract We present a new approach to investigate how the photodynamics of an octahedral ruthenium(II) complex activated through two‐photon absorption (TPA) differ from the equivalent complex activated through one‐photon absorption (OPA). We photoactivated a RuII polypyridyl complex containing bioactive monodentate ligands in the photodynamic therapy window (620–1000 nm) by using TPA and used transient UV/Vis absorption spectroscopy to elucidate its reaction pathways. Density functional calculations allowed us to identify the nature of the initially populated states and kinetic analysis recovers a photoactivation lifetime of approximately 100 ps. The dynamics displayed following TPA or OPA are identical, showing that TPA prodrug design may use knowledge gathered from the more numerous and easily conducted OPA studies. PMID:26632426

  15. Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals

    PubMed Central

    Gollnest, Tristan; de Oliveira, Thiago Dinis; Schols, Dominique; Balzarini, Jan; Meier, Chris

    2015-01-01

    The antiviral activity of nucleoside reverse transcriptase inhibitors is often limited by ineffective phosphorylation. We report on a nucleoside triphosphate (NTP) prodrug approach in which the γ-phosphate of NTPs is bioreversibly modified. A series of TriPPPro-compounds bearing two lipophilic masking units at the γ-phosphate and d4T as a nucleoside analogue are synthesized. Successful delivery of d4TTP is demonstrated in human CD4+ T-lymphocyte cell extracts by an enzyme-triggered mechanism with high selectivity. In antiviral assays, the compounds are potent inhibitors of HIV-1 and HIV-2 in CD4+ T-cell (CEM) cultures. Highly lipophilic acyl residues lead to higher membrane permeability that results in intracellular delivery of phosphorylated metabolites in thymidine kinase-deficient CEM/TK− cells with higher antiviral activity than the parent nucleoside. PMID:26503889

  16. Carbapenem-based prodrugs. Design, synthesis, and biological evaluation of carbapenems.

    PubMed

    Hakimelahi, Gholam Hossein; Moosavi-Movahedi, Ali Akbar; Saboury, Ali Akbar; Osetrov, Valeriy; Khodarahmi, Ghadam Ali; Shia, Kak-Shan

    2005-04-01

    Syntheses of racemic trans-3-hydroxycarbonyl-6-(phenylacetamido)carbapenem (13), trans-3-phosphono-6-(phenylacetamido)carbapenem (17), and beta-lactam based prodrugs 19 and 22 were accomplished. Carbapenem 13 was found to possess antibacterial activity, comparable with imipenem (+)-3, against Staphylococcus aureus FDA 209P, S. aureus 95, Escherichia coli ATCC 39188, Klebsiella pneumoniae NCTC 418, Pseudomonas aeruginosa 1101-75, P. aeruginosa 18S-H, and Xanthomonas maltophilia GN 12873. Like imipenem ((+)-3), carbapenem 13 was not stable to X. maltophilia oxyiminocephalosporinase type II. Its phosphonate analog 17, however, was neither a significant antibacterial agent nor a good beta-lactamase inhibitor. Chemical combinations of trans carbapenem 13 with cis carbapenem 6 (compound 19) as well as clavulanic acid (20) with cis carbapenem 6 (compound 22) via a tetrachloroethane linker exhibited remarkable activity against beta-lactamase producing microorganisms in vitro.

  17. Far-Red Light-Activatable Prodrug of Paclitaxel for the Combined Effects of Photodynamic Therapy and Site-Specific Paclitaxel Chemotherapy.

    PubMed

    Thapa, Pritam; Li, Mengjie; Bio, Moses; Rajaputra, Pallavi; Nkepang, Gregory; Sun, Yajing; Woo, Sukyung; You, Youngjae

    2016-04-14

    Paclitaxel (PTX) is one of the most useful chemotherapeutic agents approved for several cancers, including ovarian, breast, pancreatic, and nonsmall cell lung cancer. However, it causes systemic side effects when administered parenterally. Photodynamic therapy (PDT) is a new strategy for treating local cancers using light and photosensitizer. Unfortunately, PDT is often followed by recurrence due to incomplete ablation of tumors. To overcome these problems, we prepared the far-red light-activatable prodrug of PTX by conjugating photosensitizer via singlet oxygen-cleavable aminoacrylate linker. Tubulin polymerization enhancement and cytotoxicity of prodrugs were dramatically reduced. However, once illuminated with far-red light, the prodrug effectively killed SKOV-3 ovarian cancer cells through the combined effects of PDT and locally released PTX. Ours is the first PTX prodrug that can be activated by singlet oxygen using tissue penetrable and clinically useful far-red light, which kills the cancer cells through the combined effects of PDT and site-specific PTX chemotherapy.

  18. Sulforaphane Preconditioning Sensitizes Human Colon Cancer Cells towards the Bioreductive Anticancer Prodrug PR-104A

    PubMed Central

    Erzinger, Melanie M.; Bovet, Cédric; Hecht, Katrin M.; Senger, Sabine; Winiker, Pascale; Sobotzki, Nadine; Cristea, Simona; Beerenwinkel, Niko; Shay, Jerry W.; Marra, Giancarlo; Wollscheid, Bernd; Sturla, Shana J.

    2016-01-01

    The chemoprotective properties of sulforaphane (SF), derived from cruciferous vegetables, are widely acknowledged to arise from its potent induction of xenobiotic-metabolizing and antioxidant enzymes. However, much less is known about the impact of SF on the efficacy of cancer therapy through the modulation of drug-metabolizing enzymes. To identify proteins modulated by a low concentration of SF, we treated HT29 colon cancer cells with 2.5 μM SF. Protein abundance changes were detected by stable isotope labeling of amino acids in cell culture. Among 18 proteins found to be significantly up-regulated, aldo-keto reductase 1C3 (AKR1C3), bioactivating the DNA cross-linking prodrug PR-104A, was further characterized. Preconditioning HT29 cells with SF reduced the EC50 of PR-104A 3.6-fold. The increase in PR-104A cytotoxicity was linked to AKR1C3 abundance and activity, both induced by SF in a dose-dependent manner. This effect was reproducible in a second colon cancer cell line, SW620, but not in other colon cancer cell lines where AKR1C3 abundance and activity were absent or barely detectable and could not be induced by SF. Interestingly, SF had no significant influence on PR-104A cytotoxicity in non-cancerous, immortalized human colonic epithelial cell lines expressing either low or high levels of AKR1C3. In conclusion, the enhanced response of PR-104A after preconditioning with SF was apparent only in cancer cells provided that AKR1C3 is expressed, while its expression in non-cancerous cells did not elicit such a response. Therefore, a subset of cancers may be susceptible to combined food-derived component and prodrug treatments with no harm to normal tissues. PMID:26950072

  19. Oncolytic herpes simplex virus expressing yeast cytosine deaminase: relationship between viral replication, transgene expression, prodrug bioactivation.

    PubMed

    Yamada, S; Kuroda, T; Fuchs, B C; He, X; Supko, J G; Schmitt, A; McGinn, C M; Lanuti, M; Tanabe, K K

    2012-03-01

    Yeast cytosine deaminase (yCD) is a well-characterized prodrug/enzyme system that converts 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU), and has been combined with oncolytic viruses. However, in vivo studies of the interactions between 5-FC bioactivation and viral replication have not been previously reported, nor have the kinetics of transgene expression and the pharmacokinetics of 5-FC and 5-FU. We constructed a replication-conditional Herpes simplex virus 1 (HSV-1) expressing yCD and examined cytotoxicity when 5-FC was initiated at different times after viral infection, and observed that earlier 5-FC administration led to greater cytotoxicity than later 5-FC administration in vitro and in vivo. In animal models, 12 days of 5-FC administration was superior to 6 days, but dosing beyond 12 days did not further enhance efficacy. Consistent with the dosing-schedule results, both viral genomic DNA copy number and viral titers were observed to peak on Day 3 after viral injection and gradually decrease thereafter. The virus is replication-conditional and was detected in tumors for as long as 2 weeks after viral injection. The maximum relative extent of yCD conversion of 5-FC to 5-FU in tumors was observed on Day 6 after viral injection and it decreased progressively thereafter. The observation that 5-FU generation within tumors did not lead to appreciable levels of systemic 5-FU (<10 ng ml⁻¹) is important and has not been previously reported. The approaches used in these studies of the relationship between the viral replication kinetics, transgene expression, prodrug administration and anti-tumor efficacy are useful in the design of clinical trials of armed, oncolytic viruses.

  20. Colistin Methanesulfonate Is an Inactive Prodrug of Colistin against Pseudomonas aeruginosa

    PubMed Central

    Bergen, Phillip J.; Li, Jian; Rayner, Craig R.; Nation, Roger L.

    2006-01-01

    There is a dearth of information on the pharmacodynamics of “colistin,” despite its increasing use as a last line of defense for treatment of infections caused by multidrug-resistant gram-negative organisms. The antimicrobial activities of colistin and colistin methanesulfonate (CMS) were investigated by studying the time-kill kinetics of each against a type culture of Pseudomonas aeruginosa in cation-adjusted Mueller-Hinton broth. The appearance of colistin from CMS spiked at 8.0 and 32 mg/liter was measured by high-performance liquid chromatography, which generated colistin concentration-time profiles. These concentration-time profiles were subsequently mimicked in other incubations, independent of CMS, by incrementally spiking colistin. When the cultures were spiked with CMS at either concentration, there was a substantial delay in the onset of the killing effect which was not evident until the concentrations of colistin generated from the hydrolysis of CMS had reached approximately 0.5 to 1 mg/liter (i.e., ∼0.5 to 1 times the MIC for colistin). The time course of the killing effect was similar when colistin was added incrementally to achieve the same colistin concentration-time course observed from the hydrolysis of CMS. Given that the killing kinetics of CMS can be accounted for by the appearance of colistin, CMS is an inactive prodrug of colistin with activity against P. aeruginosa. This is the first study to demonstrate the formation of colistin in microbiological media containing CMS and to demonstrate that CMS is an inactive prodrug of colistin. These findings have important implications for susceptibility testing involving “colistin,” in particular, for MIC measurement and for microbiological assays and pharmacokinetic and pharmacodynamic studies. PMID:16723551

  1. Differences in social representation of blood donation between donors and non-donors: an empirical study

    PubMed Central

    Guarnaccia, Cinzia; Giannone, Francesca; Falgares, Giorgio; Caligaris, Aldo Ozino; Sales-Wuillemin, Edith

    2016-01-01

    Background Both donors and non-donors have a positive image of blood donation, so donors and non-donors do not differ regarding their views on donation but do differ in converting their opinion into an active deed of donation. Several studies have identified altruism and empathy as the main factors underlying blood donation. However, a mixture of various motivational factors mould the complex behaviour of donation. This paper presents an exploratory study on differences of social representations of blood donation between blood donors and non-donors, in order to understand the reasons that bring someone to take the decision to become a blood donor. Materials and methods Participants filled in the Adapted Self-Report Altruism Scale, Toronto Empathy Questionnaire and answered a test of verbal association. Descriptive and correlation analyses were carried out on quantitative data, while a prototypic analysis was used for qualitative data. Results The study was carried out on a convenience sample of 786 individuals, 583 donors (mean age: 35.40 years, SD: 13.01 years; 39.3% female) and 203 non-donors (mean age: 35.10 years, SD: 13.30 years; 67.5% female). Social representations of donors seem to be more complex and articulated than those of non-donors. The terms that appear to be central were more specific in donors (life, needle, blood, help, altruism were the words most associated by non-donors; life, aid, altruism, solidarity, health, love, gift, generosity, voluntary, control, needed, useful, needle were the words most associated by donors). Furthermore, non-donors associated a larger number of terms referring to negative aspects of blood donation. Discussion Aspects related to training and the accuracy of any information on blood donation seem to be important in the decision to become a donor and stabilise the behaviour of donation over time, thus ensuring the highest levels of quality and safety in blood establishments. PMID:26674814

  2. CH-01 is a Hypoxia-Activated Prodrug That Sensitizes Cells to Hypoxia/Reoxygenation Through Inhibition of Chk1 and Aurora A

    PubMed Central

    2013-01-01

    The increased resistance of hypoxic cells to all forms of cancer therapy presents a major barrier to the successful treatment of most solid tumors. Inhibition of the essential kinase Checkpoint kinase 1 (Chk1) has been described as a promising cancer therapy for tumors with high levels of hypoxia-induced replication stress. However, as inhibition of Chk1 affects normal replication and induces DNA damage, these agents also have the potential to induce genomic instability and contribute to tumorigenesis. To overcome this problem, we have developed a bioreductive prodrug, which functions as a Chk1/Aurora A inhibitor specifically in hypoxic conditions. To achieve this activity, a key functionality on the Chk1 inhibitor (CH-01) is masked by a bioreductive group, rendering the compound inactive as a Chk1/Aurora A inhibitor. Reduction of the bioreductive group nitro moiety, under hypoxic conditions, reveals an electron-donating substituent that leads to fragmentation of the molecule, affording the active inhibitor. Most importantly, we show a significant loss of viability in cancer cell lines exposed to hypoxia in the presence of CH-01. This novel approach targets the most aggressive and therapy-resistant tumor fraction while protecting normal tissue from therapy-induced genomic instability. PMID:23597309

  3. Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity.

    PubMed

    Liu, Yi; Piao, Hongyu; Gao, Ying; Xu, Caihong; Tian, Ye; Wang, Lihong; Liu, Jinwen; Tang, Bo; Zou, Meijuan; Cheng, Gang

    2015-01-01

    7-Ethyl-10-hydroxycamptothecin (SN38), an active metabolite of irinotecan (CPT-11), is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C10-OH)SN38 and chitosan-(C20-OH)SN38) to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C10-OH)SN38 (CS-(10s)SN38) and chitosan-(C20-OH) SN38 (CS-(20s)SN38) were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC)0-24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P<0.01). A larger AUC0-24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 (P<0.05). Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20s)SN38 exhibited better in vivo antitumor activity than CS-(10s)SN38 at a dose of 2.5 mg/kg (P<0.05). In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C20-OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.

  4. Donor pretreatment with carbon monoxide prevents ischemia/reperfusion injury following heart transplantation in rats

    PubMed Central

    Fujisaki, Noritomo; Kohama, Keisuke; Nishimura, Takeshi; Yamashita, Hayato; Ishikawa, Michiko; Kanematsu, Akihiro; Yamada, Taihei; Lee, Sungsoo; Yumoto, Tetsuya; Tsukahara, Kohei; Kotani, Joji; Nakao, Atsunori

    2016-01-01

    Because inhaled carbon monoxide (CO) provides potent anti-inflammatory and antioxidant effects against ischemia reperfusion injury, we hypothesized that treatment of organ donors with inhaled CO would decrease graft injury after heart transplantation. Hearts were heterotopically transplanted into syngeneic Lewis rats after 8 hours of cold preservation in University of Wisconsin solution. Donor rats were exposed to CO at a concentration of 250 parts per million for 24 hours via a gas-exposure chamber. Severity of myocardial injury was determined by total serum creatine phosphokinase and troponin I levels at three hours after reperfusion. In addition, Affymetrix gene array analysis of mRNA transcripts was performed on the heart graft tissue prior to implantation. Recipients of grafts from CO-exposed donors had lower levels of serum troponin I and creatine phosphokinase; less upregulation of mRNA for interleukin-6, intercellular adhesion molecule-1, and tumor necrosis factor-α; and fewer infiltrating cells. Although donor pretreatment with CO altered the expression of 49 genes expressly represented on the array, we could not obtain meaningful data to explain the mechanisms by which CO potentiated the protective effects. Pretreatment with CO gas before organ procurement effectively protected cardiac grafts from ischemia reperfusion-induced injury in a rat heterotopic cardiac transplant model. A clinical report review indicated that CO-poisoned organ donors may be comparable to non-poisoned donors. PMID:27867479

  5. Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest

    PubMed Central

    Zhao, Yong; Tu, Mei-Juan; Wang, Wei-Peng; Qiu, Jing-Xin; Yu, Ai-Xi; Yu, Ai-Ming

    2016-01-01

    Osteosarcoma (OS) is the most common primary malignant bone tumor in children, and microRNA-34a (miR-34a) replacement therapy represents a new treatment strategy. This study was to define the effectiveness and safety profiles of a novel bioengineered miR-34a prodrug in orthotopic OS xenograft tumor mouse model. Highly purified pre-miR-34a prodrug significantly inhibited the proliferation of human 143B and MG-63 cells in a dose dependent manner and to much greater degrees than controls, which was attributed to induction of apoptosis and G2 cell cycle arrest. Inhibition of OS cell growth and invasion were associated with release of high levels of mature miR-34a from pre-miR-34a prodrug and consequently reduction of protein levels of many miR-34a target genes including SIRT1, BCL2, c-MET, and CDK6. Furthermore, intravenous administration of in vivo-jetPEI formulated miR-34a prodrug significantly reduced OS tumor growth in orthotopic xenograft mouse models. In addition, mouse blood chemistry profiles indicated that therapeutic doses of bioengineered miR-34a prodrug were well tolerated in these animals. The results demonstrated that bioengineered miR-34a prodrug was effective to control OS tumor growth which involved the induction of apoptosis and cell cycle arrest, supporting the development of bioengineered RNAs as a novel class of large molecule therapeutic agents. PMID:27216562

  6. In Vitro and Clinical Evaluations of the Drug-Drug Interaction Potential of a Metabotropic Glutamate 2/3 Receptor Agonist Prodrug with Intestinal Peptide Transporter 1

    PubMed Central

    Long, Amanda J.; Annes, William F.; Witcher, Jennifer W.; Knadler, Mary Pat; Ayan-Oshodi, Mosun A.; Mitchell, Malcolm I.; Leese, Phillip; Hillgren, Kathleen M.

    2017-01-01

    Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with Km value of approximately 30 µM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC50 = 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter. PMID:27895114

  7. Synthesis and Evaluation of a CBZ-AAN-Dox Prodrug and its in vitro Effects on SiHa Cervical Cancer Cells Under Hypoxic Conditions.

    PubMed

    Chen, Hongyuan; Liu, Xiao; Clayman, Eric S; Shao, Fangyuan; Xiao, Manshan; Tian, Xuyan; Fu, Wuyu; Zhang, Caiyun; Ruan, Bibo; Zhou, Pengjun; Liu, Zhong; Wang, Yifei; Rui, Wen

    2015-10-01

    Although doxorubicin (Dox) is widely used in clinical treatment for solid tumors, it causes many side-effects such as heart and kidney damage, bone marrow suppression, and drug resistance. Legumain is a lysosomal protease that is elevated and associated with an invasive and metastatic phenotype in a number of solid tumors. In this study, we designed and synthesized a Dox prodrug, N-benzyloxycarbonyl-Ala-Ala-Asn-Doxorubicin (CBZ-AAN-Dox), with 94% purity. Single substrate kinetic assays demonstrated hLegumain-specific enzymatic cleavage and activation of the prodrug in vitro, and this enzymatic cleavage of the prodrug substrate was more sensitive in acidic conditions, releasing more than 70% of Dox after 24 h. Treatment of tumor cells with our prodrug demonstrated a much higher IC50 value, significantly enhanced uptake of the prodrug, and considerably less cellular toxicity compared to Dox treatment alone. Our study presents a novel prodrug, CBZ-AAN-Dox, to potentially increase both the safety and efficacy of clinical treatment of tumors by exploiting the tumor's innate expression of legumain.

  8. 21 CFR 630.6 - Donor notification.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... the reason for that decision; (ii) Where appropriate, the types of donation of blood or blood... GENERAL REQUIREMENTS FOR BLOOD, BLOOD COMPONENTS, AND BLOOD DERIVATIVES § 630.6 Donor notification. (a) Notification of donors. You, an establishment that collects blood or blood components, must make...

  9. 21 CFR 630.6 - Donor notification.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... the reason for that decision; (ii) Where appropriate, the types of donation of blood or blood... GENERAL REQUIREMENTS FOR BLOOD, BLOOD COMPONENTS, AND BLOOD DERIVATIVES § 630.6 Donor notification. (a) Notification of donors. You, an establishment that collects blood or blood components, must make...

  10. 21 CFR 630.6 - Donor notification.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... the reason for that decision; (ii) Where appropriate, the types of donation of blood or blood... GENERAL REQUIREMENTS FOR BLOOD, BLOOD COMPONENTS, AND BLOOD DERIVATIVES § 630.6 Donor notification. (a) Notification of donors. You, an establishment that collects blood or blood components, must make...

  11. Fecal microbiota transplantation and donor standardization.

    PubMed

    Owens, Casey; Broussard, Elizabeth; Surawicz, Christina

    2013-09-01

    Clostridium difficile diarrhea is a common and severe infectious disease. Antibiotics, which are standard initial treatment, are less effective for treating refractory or recurrent infection. Fecal microbiota transplantation, where healthy donor stool is transplanted into a patient, is an alternative to antibiotic therapy that requires standardization for donors and patients.

  12. Payment for donor kidneys: pros and cons.

    PubMed

    Friedman, E A; Friedman, A L

    2006-03-01

    Continuous growth of the end stage renal disease population treated by dialysis, outpaces deceased donor kidneys available, lengthens the waiting time for a deceased donor transplant. As estimated by the United States Department of Health & Human Services: '17 people die each day waiting for transplants that can't take place because of the shortage of donated organs.' Strategies to expand the donor pool--public relations campaigns and Drivers' license designation--have been mainly unsuccessful. Although illegal in most nations, and viewed as unethical by professional medical organizations, the voluntary sale of purchased donor kidneys now accounts for thousands of black market transplants. The case for legalizing kidney purchase hinges on the key premise that individuals are entitled to control of their body parts even to the point of inducing risk of life. One approach to expanding the pool of kidney donors is to legalize payment of a fair market price of about 40,000 dollars to donors. Establishing a federal agency to manage marketing and purchase of donor kidneys in collaboration with the United Network for Organ Sharing might be financially self-sustaining as reduction in costs of dialysis balances the expense of payment to donors.

  13. Negotiating boundaries: Accessing donor gametes in India

    PubMed Central

    Widge, A.; Cleland, J.

    2011-01-01

    Background: This paper documents how couples and providers access donor materials for conception in the Indian context and perceptions about using them. The objective is to facilitate understanding of critical issues and relevant concerns. Methods: A postal survey was conducted with a sample of 6000 gynaecologists and in-depth interviews were conducted with 39 gynaecologists in four cities. Results: Donor gametes are relatively more acceptable than a few years ago, especially if confidentiality can be maintained, though lack of availability of donor materials is sometimes an impediment to infertility treatment. Donor sperms are usually accessed from in-house or commercial sperm banks, pathology laboratories, IVF centres, professional donors, relatives or friends. There is scepticism about screening procedures of sperm banks. Donor eggs are usually accessed from voluntary donors, friends, relatives, egg sharing programmes, donation from other patients, advertising and commercial donors. There are several concerns regarding informed consent for using donated gametes, using relatives and friends gametes, the unregulated use of gametes and embryos, record keeping and documentation, unethical and corrupt practices and commercialisation. Conclusion: These issues need to be addressed by patients, providers and regulatory authorities by providing information, counselling, ensuring informed consent, addressing exploitation and commercialisation, ensuring monitoring, proper documentation and transparency. PMID:24753849

  14. 21 CFR 630.6 - Donor notification.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... of donation of blood or blood components that the donor should not donate in the future; (3) Where... the reason for that decision; (ii) Where appropriate, the types of donation of blood or blood... GENERAL REQUIREMENTS FOR BLOOD, BLOOD COMPONENTS, AND BLOOD DERIVATIVES § 630.6 Donor notification....

  15. 42 CFR 35.64 - Donors.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Donors. 35.64 Section 35.64 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT Contributions for the Benefit of Patients § 35.64 Donors. Authorized contributions...

  16. 42 CFR 35.64 - Donors.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Donors. 35.64 Section 35.64 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT Contributions for the Benefit of Patients § 35.64 Donors. Authorized contributions...

  17. 42 CFR 35.64 - Donors.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Donors. 35.64 Section 35.64 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT Contributions for the Benefit of Patients § 35.64 Donors. Authorized contributions...

  18. The Experience of Living Kidney Donors

    ERIC Educational Resources Information Center

    Brown, Judith Belle; Karley, Mary Lou; Boudville, Neil; Bullas, Ruth; Garg, Amit X.; Muirhead, Norman

    2008-01-01

    This article describes the experiences, feelings, and ideas of living kidney donors. Using a phenomenological, qualitative research approach, the authors interviewed 12 purposefully selected living kidney donors (eight men and four women), who were between four and 29 years since donation. Interviews were audiotaped, and transcribed verbatim, and…

  19. Organ donors: deceased or alive? Quo vadis?

    PubMed

    Rozental, R

    2006-01-01

    Irrespectively of universal shortage of donor organs there is a tendency of increasing the number of transplantations from living and deceased donors. Each of these two methods has positive and negative features. The main obstacles using living donors are health hazard, necessity to solve certain donor's social and psychological problems, possibility of organ trade and moving. The main problems connected with organ retrieval from deceased donors are possible conflicts with public opinion: difficulties in interpretation of brain death, legislation, obtaining of informed consent from donor's relatives, etc. Future progress in organ transplantation may take place through activation of organ retrieval from deceased donors. The most perspective ways are change to presumed consent in all countries, establishing of centralized system of donor detection and registration, intensification of transplant coordination, active contacts with mass-media, etc. It is necessary to increase (enhance) participation of the members of the public in organ donation process, to develop solidarity among the public members and to involve public authorities to deal with this problem. Bioethical standards should be put in accordance with common progress and some ethical traditions should be changed.

  20. Non Heart-Beating Donors in England

    PubMed Central

    Chaib, Eleazar

    2008-01-01

    When transplantation started all organs were retrieved from patients immediately after cardio-respiratory arrest, i.e. from non-heart-beating donors. After the recognition that death resulted from irreversible damage to the brainstem, organ retrieval rapidly switched to patients certified dead after brainstem testing. These heart-beating-donors have become the principal source of organs for transplantation for the last 30 years. The number of heart-beating-donors are declining and this is likely to continue, therefore cadaveric organs from non-heart-beating donor offers a large potential of resources for organ transplantation. The aim of this study is to examine clinical outcomes of non-heart-beating donors in the past 10 years in the UK as an way of decreasing pressure in the huge waiting list for organs transplantation. PMID:18297216

  1. Kinetics of thermal donor generation in silicon

    NASA Technical Reports Server (NTRS)

    Mao, B.-Y.; Lagowski, J.; Gatos, H. C.

    1984-01-01

    The generation kinetics of thermal donors at 450 C in Czochralski-grown silicon was found to be altered by high-temperature preannealing (e.g., 1100 C for 30 min). Thus, when compared with as-grown Si, high-temperature preannealed material exhibits a smaller concentration of generated thermal donors and a faster thermal donor saturation. A unified mechanism of nucleation and oxygen diffusion-controlled growth (based on solid-state plate transformation theory) is proposed to account for generation kinetics of thermal donors at 450 C, in as-grown and high-temperature preannealed Czochralski silicon crystals. This mechanism is consistent with the main features of the models which have been proposed to explain the formation of oxygen thermal donors in silicon.

  2. Reduction of in-source collision-induced dissociation and thermolysis of sulopenem prodrugs for quantitative liquid chromatography/electrospray ionization mass spectrometric analysis by promoting sodium adduct formation.

    PubMed

    Wujcik, Chad E; Kadar, Eugene P

    2008-10-01

    Six chromatographically resolved sulopenem prodrugs were monitored for their potential to undergo both in-source collision-induced dissociation (CID) and thermolysis. Initial Q1 scans for each prodrug revealed the formation of intense [Prodrug2 + H]+, [Prodrug2 + Na]+, [Prodrug + Na]+, and [Sulopenem + Na]+ ions. Non-adduct-associated sulopenem ([Sulopenem + H]+) along with several additional lower mass ions were also observed. Product ion scans of [Prodrug3 + Na]+ showed the retention of the sodium adduct in the collision cell continuing down to opening of the beta-lactam ring. In-source CID and temperature experiments were conducted under chromatographic conditions while monitoring several of the latter ion transitions (i.e., adducts, dimers and degradants/fragments) for a given prodrug. The resulting ion profiles indicated the regions of greatest stability for temperature and declustering potential (DP) that provided the highest signal intensity for each prodrug and minimized in-source degradation. The heightened stability of adduct ions, relative to their appropriate counterpart (i.e., dimer to dimer adduct and prodrug to prodrug adduct ions), was observed under elevated temperature and DP conditions. The addition of 100 microM sodium to the mobile phase further enhanced the formation of these more stable adduct ions, yielding an optimal [Prodrug + Na]+ ion signal at temperatures from 400 to 600 degrees C. A clinical liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay for sulopenem prodrug PF-04064900 in buffered whole blood was successfully validated using sodium-fortified mobile phase and the [PF-04064900 + Na]+ ion for quantitation. A conservative five-fold increase in sensitivity from previously validated preclinical assays using the [PF-04064900 + H]+ precursor ion was achieved.

  3. Clinical potential of gene-directed enzyme prodrug therapy to improve radiation therapy in prostate cancer patients.

    PubMed

    Vajda, Alice; Marignol, Laure; Foley, Ruth; Lynch, Thomas H; Lawler, Mark; Hollywood, Donal

    2011-12-01

    Despite the advances in prostate cancer diagnosis and treatment, current therapies are not curative in a significant proportion of patients. Gene-directed enzyme prodrug therapy (GDEPT), when combined with radiation therapy, could improve the outcome of treatment for prostate cancer, the second leading cause of cancer death in the western world. GDEPT involves the introduction of a therapeutic transgene, which can be targeted to the tumour cells. A prodrug is administered systemically and is converted to its toxic form only in those cells containing the transgene, resulting in cell kill. This review will discuss the clinical trials which have investigated the potential of GDEPT at various stages of prostate cancer progression. The advantages of using GDEPT in combination with radiotherapy will be examined, as well as some of the recent advances which enhance the potential utility of GDEPT.

  4. Synthesis, spectral studies and anti-inflammatory activity of glycolamide esters of niflumic acid as potential prodrugs.

    PubMed

    Gadad, Andanappa K; Bhat, Shailija; Tegeli, Varsha S; Redasani, Vivek V

    2002-01-01

    In order to reduce the gastric irritation caused by direct contact mechanism of the carboxylic acid group, a series of glycolamide esters of niflumic acid (CAS 4394-00-7) (1) have been prepared as bio-labile prodrugs by reacting appropriate 2-chloroacetamides with niflumic acid. The required 2-chloroacetamides were obtained by the condensation of chloroacetyl chloride and corresponding amine. Their structures were confirmed by UV, IR and 1H NMR spectra. Selected compounds were evaluated for anti-inflammatory activity in carrageenan induced paw oedema in rats at the doses of 45, 90 and 150 mg/kg b.w. Prodrugs showed comparable anti-inflammatory activity (67.1-79.4%) at 150 mg/kg b.w. with respect to niflumic acid (70.3%) at 45 mg/kg b.w., indicating moderate release of niflumic acid in vivo. The highest activity was observed with diethylamine (4) and pyrrolidine (9) derivatives.

  5. Synthesis and evaluation of the anti-inflammatory effects of niflumic acid lipophilic prodrugs in brain edema.

    PubMed

    el Kihel, L; Bourass, J; Richomme, P; Petit, J Y; Letourneux, Y

    1996-11-01

    Five new lipophilic prodrugs of the non-steroidal anti-inflammatory drug, niflumic acid (Nifluril, CAS 4394-00-7), were synthetized and evaluated on the experimental brain edema (injection of phospholipase A2). The effect of these drugs in comparison with dexamethasone which elicits a marked effect on clinical and experimental brain edema was evaluated. Niflumic acid was vectorised by cholesterol, hexadecanol and by three 1,3-diacylglycerols. The anti-inflammatory activity of these compounds on experimental brain edema was evaluated by determination of the prostaglandin E2 (PGE2) brain tissue concentration. Niflumic acid reduced the prostaglandin E2 production more significantly than dexamethasone. Niflumic acid prodrug forms (1,3-dihexadecanoyl-2-[2-[3-(trifluoromethyl)anilino]nicotinoyl] glycerol and 1,3-dihexadecanoyl-2-[2-[3-(trifluoromethyl)anilino]nicotinoyloxybuta noyl] glycerol also showed a marked anti-inflammatory activity at low concentrations.

  6. Strong enhancement of recombinant cytosine deaminase activity in Bifidobacterium longum for tumor-targeting enzyme/prodrug therapy.

    PubMed

    Hamaji, Yoshinori; Fujimori, Minoru; Sasaki, Takayuki; Matsuhashi, Hitomi; Matsui-Seki, Keiichi; Shimatani-Shibata, Yuko; Kano, Yasunobu; Amano, Jun; Taniguchi, Shun'ichiro

    2007-04-01

    In our previous studies, a strain of the nonpathogenic, anaerobic, intestinal bacterium, Bifidobacterium longum (B. longum), was found to be localized selectively and to proliferate within solid tumors after systemic administration. In addition, B. longum transformed with the shuttle-plasmid encoding the cytosine deaminase (CD) gene expressed active CD, which deaminated the prodrug 5-fluorocytosine (5-FC) to the anticancer agent 5-fluorouracil (5-FU). We also reported antitumor efficacy with the same plasmid in several animal experiments. In this study, we constructed a novel shuttle-plasmid, pAV001-HU-eCD-M968, which included the mutant CD gene with a mutation at the active site to increase the enzymatic activity. In addition, the plasmid-transformed B. longum produces mutant CD and strongly increased (by 10-fold) its 5-FC to 5-FU enzymatic activity. The use of B. longum harboring the new shuttle-plasmid increases the effectiveness of our enzyme/prodrug strategy.

  7. A prodrug approach to improve the physico-chemical properties and decrease the genotoxicity of nitro compounds.

    PubMed

    Chung, Man Chin; Bosquesi, Priscila Longhin; dos Santos, Jean Leandro

    2011-01-01

    In therapeutics research, the nitro compounds are part of an important group of drugs with multiple pharmacological activities. However, in drug design, the inclusion of a nitro group in a molecule changes the physico-chemical and electronic properties and is associated with increased mutagenicity and carcinogenicity. In addition, several studies have related the relationship between the antimicrobial and/or anti-protozoal activity and the mutagenic effect to reduction of the nitro group. This work reviews the toxicity of nitro compounds and shows how the use of prodrugs can increase the biological activity and decrease the genotoxicity of nitro compounds, without any modification in nitro reduction behavior, but rather by physico-chemical improvement. Examples are given of metronidazole and nitrofurazone prodrugs.

  8. Donor Conception and "Passing," or; Why Australian Parents of Donor-Conceived Children Want Donors Who Look Like Them.

    PubMed

    Wong, Karen-Anne

    2017-03-01

    This article explores the processes through which Australian recipients select unknown donors for use in assisted reproductive technologies and speculates on how those processes may affect the future life of the donor-conceived person. I will suggest that trust is an integral part of the exchange between donors, recipients, and gamete agencies in donor conception and heavily informs concepts of relatedness, race, ethnicity, kinship, class, and visibility. The decision to be transparent (or not) about a child's genetic parentage affects recipient parents' choices of donor, about who is allowed to "know" children's genetic backgrounds, and how important it is to be able to "pass" as an unassisted conception. In this way, recipients must trust the process, institutions, and individuals involved in their treatment, as well as place trust in the future they imagine for their child. The current market for donor gametes reproduces normative conceptions of the nuclear family, kinship, and relatedness by facilitating "matching" donors to recipients by phenotype and cultural affinities. Recipient parents who choose not to prioritize "matching," and actively disclose the process of children's conceptions, may embark on a project of queering heteronormative family structures and place great trust in both their own children and changing social attitudes to reduce stigma and generate acceptance for non-traditional families.

  9. Human artificial insemination by donor and the Australian community.

    PubMed

    Rawson, G

    1985-03-01

    Findings from a national sample of 989 persons and an 'Opinion Leader' survey of 279 executive and ordinary members of 40 organizations identified as having an interest in AID showed that Australians overall approved of the procedure for helping infertile married couples, only 17% of the national sample unequivocally disapproving. Key variables in determining opinions on AID included age, education, country of origin, family status, religion and exposure to infertility. However only 15% of national respondents accepted that AID should be made available to any unmarried women on request although opinions were more evenly spread on its provision to unmarried women in a long-term relationship with a man. Over one-third of 'Opinion Leaders' believed that children should never be told of their AID conception, 13% that they should be given identifying and one third non-identifying information on the donor. A majority believed that AID should be directly carried out or supervised by doctors in hospital clinics. There was strong opposition to business or voluntary organization involvement. Suggestions for changes in the law, while emphasizing protection of donors, recipients, children, persons who ran AID programs and control over futuristic research activities, often showed a misunderstanding of the legal process. The major reasons for exclusion of donors were genetic defects and medical problems although many behavioural characteristics were mentioned. Views on recipients' rights to choose the sex of the AID child were marginally against the proposition.

  10. Donor, dad, or…? Young adults with lesbian parents' experiences with known donors.

    PubMed

    Goldberg, Abbie E; Allen, Katherine R

    2013-06-01

    In this exploratory qualitative study of 11 young adults, ages 19-29 years, we examine how young people who were raised by lesbian parents make meaning out of and construct their relationships with known donors. In-depth interviews were conducted to examine how participants defined their family composition, how they perceived the role of their donors in their lives, and how they negotiated their relationships with their donors. Findings indicate that mothers typically chose known donors who were family friends, that the majority of participants always knew who their donors were, and that their contact with donors ranged from minimal to involved. Further, participants perceived their donors in one of three ways: as strictly donors and not members of their family; as extended family members but not as parents; and as fathers. The more limited role of donors in participants' construction of family relationships sheds light on how children raised in lesbian, gay, and bisexual families are contributing to the redefinition and reconstruction of complex kinship arrangements. Our findings hold implications for clinicians who work with lesbian-mother families, and suggest that young adulthood is an important developmental phase during which interest in and contact with the donor may shift, warranting a transfer of responsibility from mother to offspring in terms of managing the donor-child relationship.

  11. The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders

    PubMed Central

    Prokai, Laszlo; Nguyen, Vien; Szarka, Szabolcs; Garg, Puja; Sabnis, Gauri; Bimonte-Nelson, Heather A.; McLaughlin, Katie J.; Talboom, Joshua S.; Conrad, Cheryl D.; Shughrue, Paul J.; Gould, Todd D.; Brodie, Angela; Merchenthaler, Istvan; Koulen, Peter; Prokai-Tatrai, Katalin

    2015-01-01

    Many neurological and psychiatric maladies originate from the deprivation of the human brain from estrogens. However, current hormone therapies cannot be used safely to treat these conditions commonly associated with menopause because of detrimental side-effects in the periphery. The latter also prevents the use of the hormone for neuroprotection. Here we show that a small-molecule bioprecursor prodrug, 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), converts to 17β-estradiol in the brain after systemic administration, but remains inert in the rest of the body. The localized and rapid formation of estrogen from the prodrug was revealed by a series of in vivo bioanalytical assays and through in vivo imaging in rodents. DHED treatment efficiently alleviated symptoms originated from brain estrogen deficiency in animal models of surgical menopause and provided neuroprotection in a rat stroke model. Concomitantly, we determined that 17β-estradiol formed in the brain from DHED elicited changes in gene expression and neuronal morphology identical to those obtained after direct 17β-estradiol treatment. Altogether, complementary functional and mechanistic data show that our approach is highly relevant therapeutically, because administration of the prodrug selectively produces estrogen in the brain independently from the route of administration and treatment regimen. Therefore, peripheral responses associated with the use of systemic estrogens, such as stimulation of the uterus and estrogen-responsive tumor growth, were absent. Collectively, our brain-selective prodrug approach may safely provide estrogen neuroprotection and medicate neurological and psychiatric symptoms developing from estrogen deficiency, particularly those encountered after surgical menopause, without the adverse side-effects of current hormone therapies. PMID:26203081

  12. Transcorneal Permeation of L - and D - Aspartate Ester Prodrugs of Acyclovir: Delineation of Passive Diffusion versus Transporter Involvement

    PubMed Central

    Majumdar, Soumyajit; Hingorani, Tushar; Srirangam, Ramesh; Gadepalli, Rama Sarma; Rimoldi, John M; Repka, Michael A

    2008-01-01

    Purpose The aim of this study was to evaluate the contribution of amino acid transporters in the transcorneal permeation of the aspartate (Asp) ester acyclovir (ACV) prodrug. Methods Physicochemical characterization, solubility and stability of acyclovir L-aspartate (L-Asp-ACV) and acyclovir D-aspartate (D-Asp-ACV) were studied. Transcorneal permeability was evaluated across excised rabbit cornea. Results Solubility of L-Asp-ACV and D-Asp-ACV were about 2-fold higher than that of ACV. The prodrugs demonstrated greater stability under acidic conditions. Calculated pKa and logP values for both prodrugs were identical. Transcorneal permeability of L-Asp-ACV (12.1±1.48×10−6 cm/s) was 4-fold higher than D-Asp-ACV (3.12±0.36×10−6 cm/s) and ACV (3.25±0.56×10−6 cm/s). ACV generation during the transport process was minimal. L-Asp-ACV transport was sodium and energy dependent but was not inhibited by glutamic acid. Addition of BCH, a specific Bo,+ and L amino acid transporter inhibitor, decreased transcorneal L-Asp-ACV permeability to 2.66±0.21×10−6 cm/s. L-Asp-ACV and D-Asp-ACV did not demonstrate significant difference in stability in ocular tissue homogenates. Conclusion The results demonstrate that enhanced transport of L-Asp-ACV is as a result of corneal transporter involvement (probably amino acid transporter B0,+) and not as a result of changes in physicochemical properties due to prodrug derivatization (permeability of D-Asp-ACV and ACV were not significantly different). PMID:18839288

  13. Nanoassemblies containing a fluorouracil/zidovudine glyceryl prodrug with phospholipase A2-triggered drug release for cancer treatment.

    PubMed

    Jin, Yiguang; Yang, Fang; Du, Lina

    2013-12-01

    Secretory phospholipase A2 (sPLA2), which is overexpressed in many tumors, cleaves ester bonds at the sn-2 position of phospholipids. A PLA2-sensitive amphiphilic prodrug, 1-O-octadecyl-2-(5-fluorouracil)-N-acetyl-3-zidovudine-phosphorylglycerol (OFZG), was synthesized and used to prepare nanoassemblies through the injection of a mixture of OFZG/cholesterol/Tween 80 (2:1:0.1, mol:mol:mol) into water. Cholesterol and Tween 80 was incorporated into the OFZG monolayers at the air/water interface to yield nanoassemblies. The resulting nanoassemblies exhibited a narrow size distribution with a mean size of 77.8nm and were stable due to their high surface charges. The in vitro experiments showed that PLA2 degraded OFZG. The nanoassemblies exhibited higher anticancer activity than the parent drug 5-fluorouracil (5-FU) in COLO205, HT-28, and HCT-116 cells. The intravenous (i.v.) administration of the nanoassemblies into mice resulted in the rapid elimination of OFZG from the circulation and its distribution mainly in the liver, lung, spleen, and kidney. After their injection into tumor-bearing mice, the nanoassemblies exhibited anticancer efficiency comparable to that of 5-FU, even though the nanoassemblies contained concentrations of only 1/10 of the molar amount of 5-FU. The lessons learned from the study and methods for the design of PLA2-sensitive amphiphilic prodrugs are also discussed. Enzyme-sensitive amphiphilic combinatorial prodrugs and prodrug-loaded nanoassemblies may represent a new strategy for anticancer drug design.

  14. New Enzyme Prodrug and Methionine-Depletion Combination Therapy of Breast Cancer Designed for Effective Delivery to the Tumor

    DTIC Science & Technology

    2011-10-01

    the prodrug. Annexin V is known to bind with high affinity to phosphatidylserine (PS) in phospholipids bilayers. PS has recently been shown to be...We have tested a procedure to quantify the exposure of phosphatidylserine on the surface of the tumor vasculature in nude mice with MDA-MB-231... Phosphatidylserine is a marker of t umor vasculature and a potential target for cancer imaging and ttherapy, Int. J. Radiat. Oncol. Bioi. Phys. 54

  15. Bright Solid-State Emission of Disilane-Bridged Donor-Acceptor-Donor and Acceptor-Donor-Acceptor Chromophores.

    PubMed

    Shimada, Masaki; Tsuchiya, Mizuho; Sakamoto, Ryota; Yamanoi, Yoshinori; Nishibori, Eiji; Sugimoto, Kunihisa; Nishihara, Hiroshi

    2016-02-24

    The development of disilane-bridged donor-acceptor-donor (D-Si-Si-A-Si-Si-D) and acceptor-donor-acceptor (A-Si-Si-D-Si-Si-A) compounds is described. Both types of compound showed strong emission (λem =ca. 500 and ca. 400 nm, respectively) in the solid state with high quantum yields (Φ: up to 0.85). Compound 4 exhibited aggregation-induced emission enhancement in solution. X-ray diffraction revealed that the crystal structures of 2, 4, and 12 had no intermolecular π-π interactions to suppress the nonradiative transition in the solid state.

  16. Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue

    PubMed Central

    Incecayir, Tuba; Sun, Jing; Tsume, Yasuhiro; Xu, Hao; Gose, Tomoka; Nakanishi, Takeo; Tamai, Ikumi; Hilfinger, John; Lipka, Elke; Amidon, Gordon L.

    2016-01-01

    The goal of this study was to improve the intestinal mucosal cell membrane permeability of the poorly absorbed guanidino analogue of a neuraminidase inhibitor, oseltamivir carboxylate (GOC) using a carrier mediated strategy. Valyl amino acid prodrug of GOC with isopropyl-methylenedioxy linker (GOC-ISP-Val) was evaluated as the potential substrate for intestinal oligopeptide transporter, hPEPT1 in Xenopus laevis oocytes heterologously expressing hPEPT1 and an intestinal mouse perfusion system. The diastereomers of GOC-ISP-Val were assessed for chemical and metabolic stability. Permeability of GOC-ISP-Val was determined in Caco-2 cells and mice. Diastereomer 2 was about two times more stable than diastereomer 1 in simulated intestinal fluid and rapidly hydrolyzed to the parent drug in cell homogenates. The prodrug had a nine times enhanced apparent permeability (Papp) in Caco-2 cells compared to the parent drug. Both diastereomer exhibited high effective permeability (Peff ) in mice, 6.32±3.12 and 5.20±2.81 x10−5 cm/s for diastereomer 1 and 2, respectively. GOC-ISP-Val was found to be a substrate of hPEPT1. Overall, this study indicates that the prodrug, GOC-ISP-Val seems to be a promising oral anti-influenza agent that has sufficient stability at physiologically relevant pHs prior to absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells. PMID:26869437

  17. PSMA-Specific Theranostic Nanoplex for Combination of TRAIL Gene and 5-FC Prodrug Therapy of Prostate Cancer

    PubMed Central

    Chen, Zhihang; Penet, Marie-France; Krishnamachary, Balaji; Banerjee, Sangeeta R.; Pomper, Martin G.; Bhujwalla, Zaver M.

    2015-01-01

    Metastatic prostate cancer causes significant morbidity and mortality and there is a critical unmet need for effective treatments. We have developed a theranostic nanoplex platform for combined imaging and therapy of prostate cancer. Our prostate-specific membrane antigen (PSMA) targeted nanoplex is designed to deliver plasmid DNA encoding tumor necrosis factor related apoptosis-inducing ligand (TRAIL), together with bacterial cytosine deaminase (bCD) as a prodrug enzyme. Nanoplex specificity was tested using two variants of human PC3 prostate cancer cells in culture and in tumor xenografts, one with high PSMA expression and the other with negligible expression levels. The expression of EGFP-TRAIL was demonstrated by fluorescence optical imaging and real-time PCR. Noninvasive 19F MR spectroscopy detected the conversion of the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU) by bCD. The combination strategy of TRAIL gene and 5-FC/bCD therapy showed significant inhibition of the growth of prostate cancer cells and tumors. These data demonstrate that the PSMA-specific theranostic nanoplex can deliver gene therapy and prodrug enzyme therapy concurrently for precision medicine in metastatic prostate cancer. PMID:26706476

  18. Gelatin-encapsulated iron oxide nanoparticles for platinum (IV) prodrug delivery, enzyme-stimulated release and MRI.

    PubMed

    Cheng, Ziyong; Dai, Yunlu; Kang, Xiaojiao; Li, Chunxia; Huang, Shanshan; Lian, Hongzhou; Hou, Zhiyao; Ma, Pingan; Lin, Jun

    2014-08-01

    A facile method for transferring hydrophobic iron oxide nanoparticles (IONPs) from chloroform to aqueous solution via encapsulation of FITC-modified gelatin based on the hydrophobic-hydrophobic interaction is described in this report. Due to the existence of large amount of active groups such as amine groups in gelatin, the fluorescent labeling molecules of fluorescein isothiocyanate (FITC) and platinum (IV) prodrug functionalized with carboxylic groups can be conveniently conjugated on the IONPs. The nanoparticles carrying Pt(IV) prodrug exhibit good anticancer activities when the Pt(IV) complexes are reduced to Pt(II) in the intracellular environment, while the pure Pt(IV) prodrug only presents lower cytotoxicity on cancer cells. Meanwhile, fluorescence of FITC on the surface of nanoparticles was completely quenched due to the possible Förster Resonance Energy Transfer (FRET) mechanism and showed a fluorescence recovery after gelatin release and detachment from IONPs. Therefore FITC as a fluorescence probe can be used for identification, tracking and monitoring the drug release. In addition, adding pancreatic enzyme can effectively promote the gelatin release from IONPs owing to the degradation of gelatin. Noticeable darkening in magnetic resonance image (MRI) was observed at the tumor site after in situ injection of nanoparticles, indicating the IONPs-enhanced T2-weighted imaging. Our results suggest that the gelatin encapsulated Fe3O4 nanoparticles have potential applications in multi-functional drug delivery system for disease therapy, MR imaging and fluorescence sensor.

  19. Enzyme-Sensitive and Amphiphilic PEGylated Dendrimer-Paclitaxel Prodrug-Based Nanoparticles for Enhanced Stability and Anticancer Efficacy.

    PubMed

    Li, Ning; Cai, Hao; Jiang, Lei; Hu, Jiani; Bains, Ashika; Hu, Jesse; Gong, Qiyong; Luo, Kui; Gu, Zhongwei

    2017-03-01

    In this study, we prepared a smart polymeric vehicle for the hydrophobic drug paclitaxel (PTX) that allowed a maximum steady-state circulation and a fast intracellular release in tumors. PTX was linked to the Janus PEGylated (PEG = poly(ethylene glycol)) peptide dendrimer via an enzyme-sensitive linker glycylphenylalanylleucylglycine tetrapeptide by efficient click reaction, resulting in Janus dendritic prodrug with 20.9% PTX content. The prodrug self-assembled into nanoscale particles with appropriate nanosizes, compact morphology, and negative surface charge. In addition to high stability during circulation, as demonstrated by protein adsorption assays and drug release studies in the cancer's intracellular environment, the nanoparticles were able to quickly release the drug intact in its original molecular structure, as verified via high-performance liquid chromatography and mass spectrometry analyses. Compared to free PTX, the enzyme-responsive feature of nanoparticles promoted higher cytotoxicity against 4T1 cancer cells and much lower cytotoxicity against normal cells. The nanoparticles accumulated in the tumor and were retained for an extended period of time, as confirmed by fluorescence imaging. Therefore, these nanoparticles exhibited significantly enhanced antitumor efficiency in the 4T1 breast cancer model as indicated by the observed inhibition of angiogenesis and proliferation as well as induction of apoptosis. Moreover, the nanoparticles reduced the occurrence of side effects, particularly dose-limited toxicities, as monitored by body weight and hematological features. Hence, our Janus PEGylated dendrimer-PTX prodrug-based nanoparticles may potentially serve as nanoscale vehicles for breast cancer therapy.

  20. Lipophilic prodrugs of a triazole-containing colchicine analogue in liposomes: biological effects on human tumor cells.

    PubMed

    Kuznetsova, N R; Svirshchevskaya, E V; Sitnikov, N S; Abodo, L; Sutorius, H; Zapke, J; Velder, J; Thomopoulou, P; Oschkinat, H; Prokop, A; Schmalz, H G; Fedorov, A Yu; Vodovozova, E L

    2013-01-01

    Colchicine site binders--blockers of tubulin polymerization--are potential antimitotic agents for anticancer therapy. To reduce their systemic toxicity and improve biodistribution, encapsulation in nanosized liposomes may be employed. Liposomes present a convenient means for preparation of injectable formulations of hydrophobic compounds, however colchicine as such is known to leak through the lipid bilayer. In this study, newly synthesized triazole-containing analogues of colchicine and allocolchicine, and their palmitic and oleic esters (lipophilic prodrugs) were tested for anti-proliferative activity and apoptosis-inducing potential. In contrast to colchicine conjugates, whose activities ranged with those of colchicine, allocolchicine derivatives exhibited drastically lower effects and were discarded. Liposomes of about 100 nm in diameter composed of egg phosphatidylcholine--yeast phosphatidylinositol--palmitic or oleic prodrug, 8 : 1: 1, by mol, were prepared by standard extrusion technique and tested in a panel of four human tumor cell lines. Liposome formulations preserved the biological activities of the parent colchicinoid the most towards human epithelial tumor cells. Moreover, liposomal form of the oleoyl bearing colchicinoid inhibited cell proliferation more efficiently than free lipophilic prodrug. Due to substantial loading capacity of the liposomes, the dispersions contain sufficient concentration of the active agent to test wide dose range in experiments on systemic administration to animals.

  1. Influence of bromoethyl group on biological activity of 5-fluorouracil prodrug: Insights from X-ray crystallography and molecular docking

    NASA Astrophysics Data System (ADS)

    Li, Xian-Chuan; Liu, Kuan-Guan; Qin, Da-An; Cheng, Chen-Chen; Chen, Bing-Xiong; Hu, Mao-Lin

    2012-11-01

    To develop alkyl halides for a promising prodrug system, a 5-fluorouracil prodrug containing a bromoethyl group (5-FUBr) was synthesized and its hydrophobicity, cytotoxicity and DNA-bonding ability were investigated in detail. Compare with 5-fluorouracil, 5-FUBr exhibits a great advantage of hydrophobicity and shows significant reduction in toxic side effect. To explore the mechanism of action of 5-FUBr at the molecular level, X-ray crystallography and molecular docking were exploited to make a more detailed analysis of the bromoethyl contribution to the construction of meaningful structure-activity relationship. Details of X-ray crystal structure of 5-FUBr suggest that 5-fluorouracil may be more apt to be released from 5-FUBr. The appearance of the bromoethyl group in 5-FUBr makes a remarkable impact on inhibition of thymidylate synthase (TS), and the impact of subtle structural variation between 5-fluorouracil and 5-FUBr should be taken into account in the process of developing this family of 5-fluorouracil prodrugs.

  2. Antibody-directed enzyme prodrug therapy with the T268G mutant of human carboxypeptidase A1: in vitro and in vivo studies with prodrugs of methotrexate and the thymidylate synthase inhibitors GW1031 and GW1843.

    PubMed

    Wolfe, L A; Mullin, R J; Laethem, R; Blumenkopf, T A; Cory, M; Miller, J F; Keith, B R; Humphreys, J; Smith, G K

    1999-01-01

    Antibody-directed enzyme prodrug therapy (ADEPT) is a technique to increase antitumor selectivity in cancer chemotherapy. Our approach to this technology has been to design a mutant of human carboxypeptidase A (hCPA1-T268G) which is capable of hydrolyzing in vivo stable prodrugs of MTX and targeting this enzyme to tumors on an Ep-CAM1-specific antibody, ING1. Through the use of this >99% human enzyme which is capable of catalyzing a completely nonhuman reaction, we hope to increase ADEPT selectivity while decreasing overall immunogenicity of the enzyme-antibody conjugate. In the current report, prodrugs of the thymidylate synthase inhibitors GW1031 and GW1843 and the dihydrofolate reductase inhibitor methotrexate were studied for their wild-type and mutant hCPA enzyme hydrolysis, their in vivo stability, and their use in therapy. Prodrugs with high kcat/Km ratios for mutated versus wild-type hCPA1 were examined in vitro for their stability in human pancreatic juice, and in vivo for their stability in mouse plasma and tissues. In addition, targeting and in vivo enzyme activity studies were performed with an ING1 antibody conjugate of the mutant enzyme (ING1-hCPA1-T268G). Finally, in vivo therapy studies were performed with LS174T tumors to demonstrate proof of principle. Results indicate that prodrugs can be synthesized that are selective and efficient substrates of hCPA1-T268G and not substrates of the endogenous CPA activities; this leads to excellent in vivo stability for these compounds. In vivo conjugate targeting studies showed that the antibody-enzyme conjugate was targeted to the tumor and enzyme was initially active in vivo at the site. Unfortunately therapeutic studies did not demonstrate tumor reduction. Experiments to determine reasons for the lack of antitumor activity showed that the enzyme activity decreased as a result of enzyme instability. The results offer encouragement for additional novel mutant enzyme improvements and additional in vivo studies

  3. Living donor liver transplantation in Egypt

    PubMed Central

    Marwan, Ibrahim

    2016-01-01

    In Egypt there is no doubt that chronic liver diseases are a major health concern. Hepatitis C virus (HCV) prevalence among the 15−59 years age group is estimated to be 14.7%. The high prevalence of chronic liver diseases has led to increasing numbers of Egyptian patients suffering from end stage liver disease (ESLD), necessitating liver transplantation (LT). We reviewed the evolution of LT in Egypt and the current status. A single center was chosen as an example to review the survival and mortality rates. To date, deceased donor liver transplantation (DDLT) has not been implemented in any program though Egyptian Parliament approved the law in 2010. Living donor liver transplantation (LDLT) seemed to be the only logical choice to save many patients who are in desperate need for LT. By that time, there was increase in number of centers doing LDLT (13 centers) and increase in number of LDLT cases [2,400] with improvement of the results. Donor mortality rate is 1.66 per 1,000 donors; this comprised four donors in the Egyptian series. The exact recipient survival is not accurately known however, and the one-year, three-year and five-year survival were 73.17%, 70.83% and 64.16% respectively in the International Medical Center (IMC) in a series of 145 adult to adult living donor liver transplantation (AALDLT) cases. There was no donor mortality in this series. LDLT are now routinely and successfully performed in Egypt with reasonable donor and recipient outcomes. Organ shortage remains the biggest hurdle facing the increasing need for LT. Although LDLT had reasonable outcomes, it carries considerable risks to healthy donors. For example, it lacks cadaveric back up, and is not feasible for all patients. The initial success in LDLT should drive efforts to increase the people awareness about deceased organ donation in Egypt. PMID:27115003

  4. Living donor liver transplantation in Egypt.

    PubMed

    Amer, Khaled E; Marwan, Ibrahim

    2016-04-01

    In Egypt there is no doubt that chronic liver diseases are a major health concern. Hepatitis C virus (HCV) prevalence among the 15-59 years age group is estimated to be 14.7%. The high prevalence of chronic liver diseases has led to increasing numbers of Egyptian patients suffering from end stage liver disease (ESLD), necessitating liver transplantation (LT). We reviewed the evolution of LT in Egypt and the current status. A single center was chosen as an example to review the survival and mortality rates. To date, deceased donor liver transplantation (DDLT) has not been implemented in any program though Egyptian Parliament approved the law in 2010. Living donor liver transplantation (LDLT) seemed to be the only logical choice to save many patients who are in desperate need for LT. By that time, there was increase in number of centers doing LDLT (13 centers) and increase in number of LDLT cases [2,400] with improvement of the results. Donor mortality rate is 1.66 per 1,000 donors; this comprised four donors in the Egyptian series. The exact recipient survival is not accurately known however, and the one-year, three-year and five-year survival were 73.17%, 70.83% and 64.16% respectively in the International Medical Center (IMC) in a series of 145 adult to adult living donor liver transplantation (AALDLT) cases. There was no donor mortality in this series. LDLT are now routinely and successfully performed in Egypt with reasonable donor and recipient outcomes. Organ shortage remains the biggest hurdle facing the increasing need for LT. Although LDLT had reasonable outcomes, it carries considerable risks to healthy donors. For example, it lacks cadaveric back up, and is not feasible for all patients. The initial success in LDLT should drive efforts to increase the people awareness about deceased organ donation in Egypt.

  5. Platelets regulate vascular endothelial stability: assessing the storage lesion and donor variability of apheresis platelets

    PubMed Central

    Baimukanova, Gyulnar; Miyazawa, Byron; Potter, Daniel R.; Muench, Marcus O.; Bruhn, Roberta; Gibb, Stuart L.; Spinella, Philip C.; Cap, Andrew P.; Cohen, Mitchell J.; Pati, Shibani

    2016-01-01

    BACKGROUND In current blood banking practices, platelets (PLTs) are stored in plasma at 22°C, with gentle agitation for up to 5 days. To date, the effects of storage and donor variability on PLT regulation of vascular integrity are not known. STUDY DESIGN AND METHODS In this study, we examined the donor variability of leukoreduced fresh (Day 1) or stored (Day 5) PLTs on vascular endothelial barrier function in vitro and in vivo. In vitro, PLT effects on endothelial cell (EC) monolayer permeability were assessed by analyzing transendothelial electrical resistances (TEER). PLT aggregation, a measure of hemostatic potential, was analyzed by impedance aggregometry. In vivo, PLTs were investigated in a vascular endothelial growth factor A (VEGF-A)-induced vascular permeability model in NSG mice, and PLT circulation was measured by flow cytometry. RESULTS Treatment of endothelial monolayers with fresh Day 1 PLTs resulted in an increase in EC barrier resistance and decreased permeability in a dose-dependent manner. Subsequent treatment of EC monolayers with Day 5 PLTs demonstrated diminished vasculoprotective effects. Donor variability was noted in all measures of PLT function. Day 1 PLT donors were more variable in their effects on TEER than Day 5 PLTs. In mice, while all PLTs regardless of storage time demonstrated significant protection against VEGF-A–induced vascular leakage, Day 5 PLTs exhibited reduced protection when compared to Day 1 PLTs. Day 1 PLTs demonstrated significant donor variability against VEGF-A–challenged vascular leakage in vivo. Systemic circulating levels of Day 1 PLTs were higher than those of Day 5 PLTs CONCLUSIONS In vitro and in vivo, Day 1 PLTs are protective in measures of vascular endothelial permeability. Donor variability is most prominent in Day 1 PLTs. A decrease in the protective effects is found with storage of the PLT units between Day 1 and Day 5 at 22°C, thereby suggesting that Day 5 PLTs are diminished in their ability to

  6. Interventional radiology in living donor liver transplant.

    PubMed

    Cheng, Yu-Fan; Ou, Hsin-You; Yu, Chun-Yen; Tsang, Leo Leung-Chit; Huang, Tung-Liang; Chen, Tai-Yi; Hsu, Hsien-Wen; Concerjero, Allan M; Wang, Chih-Chi; Wang, Shih-Ho; Lin, Tsan-Shiun; Liu, Yueh-Wei; Yong, Chee-Chien; Lin, Yu-Hung; Lin, Chih-Che; Chiu, King-Wah; Jawan, Bruno; Eng, Hock-Liew; Chen, Chao-Long

    2014-05-28

    The shortage of deceased donor liver grafts led to the use of living donor liver transplant (LDLT). Patients who undergo LDLT have a higher risk of complications than those who undergo deceased donor liver transplantation (LT). Interventional radiology has acquired a key role in every LT program by treating the majority of vascular and non-vascular post-transplant complications, improving graft and patient survival and avoiding, in the majority of cases, surgical revision and/or re-transplant. The aim of this paper is to review indications, diagnostic modalities, technical considerations, achievements and potential complications of interventional radiology procedures after LDLT.

  7. Biotransformations of Antidiabetic Vanadium Prodrugs in Mammalian Cells and Cell Culture Media: A XANES Spectroscopic Study

    PubMed Central

    2016-01-01

    The antidiabetic activities of vanadium(V) and -(IV) prodrugs are determined by their ability to release active species upon interactions with com