Targeting drugs to the brain by redox chemical delivery systems

Prókai, László; Prókai-Tátrai, Katalin; Bodor, Nicholas

doi:10.1002/1098-1128(200009)20:5<367::aid-med3>3.0.co;2-p

Cited by 115 publications

(69 citation statements)

References 216 publications

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“…Through prodrug strategies, some progress has been made recently in improving the BBB permeation characteristics of opioid peptides (Greene et al, 1996;Misicka et al, 1996;Patel et al, 1997;Prokai et al, 2000). For a prodrug strategy to be successful in delivering opioid peptides to the brain, the following criteria must be met: 1) the prodrug should have favorable physiochemical properties (e.g., hydrophobicity, low hydrogen-bonding potential, and no charge) for transcellular permeation across the BBB; 2) the prodrug should exhibit good "intrinsic" permeability across the BBB but not be a substrate for efflux transporters (e.g., P-gp); 3) the prodrug should be a good substrate for enzymes (e.g., esterases) in the brain that would catalyze its bioconversion to the opioid peptide but have less activity as a substrate for the same enzymes in other biological media/tissues or for other enzymes that could lead to nonproductive metabolism of the prodrug (e.g., endopeptidases); and 4) the prodrug should have a reasonable plasma half-life and not be rapidly metabolized in the blood compartment or cleared by the liver or kidney or be extensively protein-bound.…”

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confidence: 99%

In Vitro Stability and In Vivo Pharmacokinetic Studies of a Model Opioid Peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and Its Cyclic Prodrugs

Yang¹,

Chen²,

Borchardt³

2002

J Pharmacol Exp Ther

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In vitro stability and in vivo pharmacokinetic studies of a model opioid peptide, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE), and its cyclic prodrugs (acyloxyalkoxy-based cyclic prodrug of DADLE, coumarinic acid-based cyclic prodrug of DADLE, and oxymethyl-modified coumarinic acid-based cyclic prodrug of DADLE) were conducted. The enzymatic stability of DADLE and its prodrugs in various biological media was determined at 37°C in the presence and absence of paraoxon, a known esterase inhibitor. The prodrugs exhibited metabolic stability to exo-and endopeptidases, and esterase-catalyzed bioconversion of the prodrugs to DADLE was observed. For pharmacokinetic studies in rats, various biological samples (blood, bile, urine, and brain) were collected after i.v. administration of DADLE and its prodrugs. The samples were analyzed by highperformance liquid chromatography with tandem mass spectrometric detection, and the conversion from the prodrugs to intermediates to DADLE was monitored. The prodrugs exhibited similar pharmacokinetic properties and showed improved stability compared with DADLE in rat blood. This increased stability led to higher plasma concentrations of DADLE after i.v. administration of the prodrugs compared with i.v. administration of DADLE alone. In terms of elimination pathways, metabolism by endopeptidases was the major route for DADLE elimination, whereas rapid biliary excretion was the major route of elimination for the prodrugs. The rapid elimination of the prodrugs by the liver and the formation of stable intermediates after esterase hydrolysis limited the bioconversion efficiencies of the prodrugs to DADLE after i.v. administration. The substrate activity of the prodrugs for efflux transporters (e.g., Pglycoprotein) in the blood-brain barrier significantly restricted their access to the brain.The delivery of opioid peptides to the brain has presented significant challenges to pharmaceutical scientists due to the poor biopharmaceutical properties of the peptides. These include their lability to metabolism by exo-and endopeptidases and their low permeation across the blood-brain barrier (BBB) (Fricker and Drewe, 1996;Pauletti et al., 1996aPauletti et al., , 1997Prokai, 1998). The issue of metabolic lability has, for all practical purposes, been solved by medicinal chemists through the design of novel peptide bond bioisosteres to replace metabolically labile peptide bonds (Sawyer, 1995). Until recently, however, medicinal chemists have had less success in manipulating the structures of opioid peptides to achieve good BBB permeation while still retaining high affinity and selectivity for opioid receptors.Through prodrug strategies, some progress has been made recently in improving the BBB permeation characteristics of opioid peptides (Greene et al., 1996;Misicka et al., 1996;Patel et al., 1997;Prokai et al., 2000). For a prodrug strategy to be successful in delivering opioid peptides to the brain, the following criteria must be met: 1) the prodrug should have favorable physiochemical properties...

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mentioning

confidence: 99%

In Vitro Stability and In Vivo Pharmacokinetic Studies of a Model Opioid Peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and Its Cyclic Prodrugs

Yang¹,

Chen²,

Borchardt³

2002

J Pharmacol Exp Ther

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“…For example, the lipophilic dihydropyridine carrier readily crosses the BBB and has been shown to increase intracranial concentrations of a variety of drugs, including neurotransmitters, antibiotics, and antineoplastic agents [5]. Likewise, new transport vectors, such as a modified protein or receptor-specific monoclonal antibody, have also led to a successful delivery of a number of drugs across the BBB [6•].…”

Section: Rationale For Local Deliverymentioning

confidence: 99%

Drug delivery to tumors of the central nervous system

Lesniak

Langer

Brem

2001

Curr Neurol Neurosci Rep

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Contemporary treatment of malignant brain tumors has been hampered by problems with drug delivery to the tumor bed. Inherent boundaries of the central nervous system, such as the blood-brain barrier or the blood-cerebrospinal fluid barrier, and a general lack of response to many chemotherapeutic agents have led to alternative treatment modalities. In general, all these modalities have sought to either disrupt or bypass the physiologic brain barriers and deliver the drug directly to the tumor. This article reviews past, as well as current, methods of drug delivery to tumors of the central nervous system. Special emphasis is placed on biodegradable polymers that can release chemotherapeutic agents against malignant gliomas. A variety of other nonchemotherapeutic drugs, including antiangiogenesis and immunotherapeutic agents, are presented in the context of new polymer technology. Finally, future directions in drug delivery are discussed with an overview on new advances in emerging biotechnology.

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“…An additional rationale for replacing the central residue has been to abolish (or at least diminish) the endocrine effects seen with TRH [15,27]. Concurrently, the pyridinium moiety of the new central residue can easily be converted via chemical reduction to a dihydropyridine [2,3,4,28], and the resultant neutral peptides can serve as bioprecursor prodrugs of these TRH analogs [2,3]. The preferential activation of the prodrug to the permanently charged parent agent in the brain occurs via oxidation, analogously to that of the endogenous NADH → NAD + reaction [28].…”

Section: Introductionmentioning

confidence: 99%

“…At the same time, the “oxidized prodrugs” ( i.e. , the actual pyridinium-type TRH analogs) should quickly be eliminated from the periphery, due to their ionic nature [28], while oxidation of the prodrug in the brain actually prevents efflux from the BBB. Therefore, this particular prodrug approach is expected to result in brain-enhanced drug delivery.…”

Section: Introductionmentioning

confidence: 99%

Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs

et al. 2013

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Efforts to take advantage of the beneficial activities of thyrotropin-releasing hormone (TRH) in the brain are hampered by its poor metabolic stability and lack of adequate central nervous system bioavailability. We report here novel and metabolically stable analogs that we derived from TRH by replacing its amino-terminal pyroglutamyl (pGlu) residue with pyridinium-containing moieties. Exploratory studies have shown that the resultant compounds were successfully delivered into the mouse brain after systemic administration via their bioprecursor prodrugs, where they manifested neuropharmacological responses characteristic of the endogenous parent peptide. On the other hand, the loss of potency compared to TRH in a model testing antidepressant-like effect with a simultaneous preservation of analeptic activity has been observed, when pGlu was replaced with trigonelloyl residue. This finding may indicate an opportunity for designing TRH analogs with potential selectivity towards cholinergic effects.

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Targeting drugs to the brain by redox chemical delivery systems

Cited by 115 publications

References 216 publications

In Vitro Stability and In Vivo Pharmacokinetic Studies of a Model Opioid Peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and Its Cyclic Prodrugs

In Vitro Stability and In Vivo Pharmacokinetic Studies of a Model Opioid Peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and Its Cyclic Prodrugs

Drug delivery to tumors of the central nervous system

Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs

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