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Pharmaceutics
Special Issues
Prodrugs
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Prodrugs

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (28 February 2013) | Viewed by 43694

Special Issue Editor

Prof. Dr. Barbara R. Conway

E-Mail Website
Guest Editor
Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, UK
Interests: biopharmaceutics; modified release; dissolution; infection prevention; biopolymers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This special issue will focus on prodrug strategies to address formulation, delivery, and toxicity limitations of drug molecules.
Prodrugs are pharmacological substances administered in an inactive (or less than fully active) form which are subsequently converted into active compounds through normal metabolic processes. The classical prodrug approach involves altering physico-chemical, biopharmaceutical or pharmacokinetic properties to maximize the amount of active drug reaching its site of action and this continues to be a useful strategy. Such approaches include increasing bioavailability (by optimization of aqueous solubility and lipophilicity) and influencing duration of pharmacological effects by increasing stability or decreasing first-pass effects. The prodrug approach can also be adopted to improve organoleptic properties and to improve how selectively the drug interacts with cells or processes that are not its intended target, reduces adverse or unintended side-effects.
Prodrug technologies are becoming more important for addressing undesirable properties associated with modern potential drugs and are being considered in the early stages of the drug development process. Computational approaches can consider using a design of linkers with drugs that have poor bioavailability to release the parental drugs in programmable manner and improve their bioavailability. Targeting approaches of coupling of low-molecular weight drugs to synthetic polymers such as PEG or serum proteins through a cleavable linker are also gaining popularity. Selective activation of prodrugs in tumour tissues can also be achieved using gene-directed enzyme prodrug therapy (GDEPT), virus-directed enzyme prodrug therapy (VDEPT), and antibody-directed enzyme prodrug therapy (ADEPT). Any of these aspects of prodrug design and application are welcome in this issue.

Prof. Dr. Barbara R. Conway
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug release
  • drug delivery
  • physicochemical characteristics
  • prodrug
  • drug targeting
  • oral administration
  • prodrug
  • tumour targeting
  • drug delivery
  • solubility
  • stability
  • poly (ethylene glycol) prodrugs
  • Monoclonal Antibody Drug Conjugates
  • ADPET
  • GDEPT
  • VDEPT

Related Special Issue

Published Papers (5 papers)

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Research

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210 KiB  
Communication
Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs
by Katalin Prokai-Tatrai, Vien Nguyen, Szabolcs Szarka, Krisztina Konya and Laszlo Prokai
Pharmaceutics 2013, 5(2), 318-328; https://doi.org/10.3390/pharmaceutics5020318 - 22 May 2013
Cited by 4 | Viewed by 7170
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Prodrugs)
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682 KiB  
Article
Encapsulation of Hydrocortisone and Mesalazine in Zein Microparticles
by Esther T. L. Lau, Steven J. Giddings, Salmaan G. Mohammed, Paul Dubois, Stuart K. Johnson, Roger A. Stanley, Peter J. Halley and Kathryn J. Steadman
Pharmaceutics 2013, 5(2), 277-293; https://doi.org/10.3390/pharmaceutics5020277 - 10 May 2013
Cited by 52 | Viewed by 9200
Abstract
Zein was investigated for use as an oral-drug delivery system by loading prednisolone into zein microparticles using coacervation. To investigate the adaptability of this method to other drugs, zein microparticles were loaded with hydrocortisone, which is structurally related to prednisolone; or mesalazine, which [...] Read more.
Zein was investigated for use as an oral-drug delivery system by loading prednisolone into zein microparticles using coacervation. To investigate the adaptability of this method to other drugs, zein microparticles were loaded with hydrocortisone, which is structurally related to prednisolone; or mesalazine, which is structurally different having a smaller LogP and ionizable functional groups. Investigations into the in vitro digestibility, and the electrophoretic profile of zein, and zein microparticles were conducted to shed further insight on using this protein as a drug delivery system. Hydrocortisone loading into zein microparticles was comparable with that reported for prednisolone, but mesalazine loading was highly variable. Depending on the starting quantities of hydrocortisone and zein, the average amount of microparticles equivalent to 4 mg hydrocortisone, (a clinically used dose), ranged from 60–115 mg, which is realistic and practical for oral dosing. Comparatively, an average of 2.5 g of microparticles was required to deliver 250 mg of mesalazine (a clinically used dose), so alternate encapsulation methods that can produce higher and more precise mesalazine loading are required. In vitro protein digestibility revealed that zein microparticles were more resistant to digestion compared to the zein raw material, and that individual zein peptides are not preferentially coacervated into the microparticles. In combination, these results suggest that there is potential to formulate a delivery system based on zein microparticles made using specific subunits of zein that is more resistant to digestion as starting material, to deliver drugs to the lower gastrointestinal tract. Full article
(This article belongs to the Special Issue Prodrugs)
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353 KiB  
Article
Preclinical Absorption, Distribution, Metabolism, and Excretion of an Oral Amide Prodrug of Gemcitabine Designed to Deliver Prolonged Systemic Exposure
by Enaksha Wickremsinhe, Jingqi Bao, Richard Smith, Richard Burton, Shannon Dow and Everett Perkins
Pharmaceutics 2013, 5(2), 261-276; https://doi.org/10.3390/pharmaceutics5020261 - 08 May 2013
Cited by 29 | Viewed by 9201
Abstract
Gemcitabine is an intravenously administered nucleoside analog chemotherapeutic agent. The ability to deliver this agent as an oral drug would allow greater flexibility of administration and patient convenience; however, attempts have been fraught with high first-pass metabolism and potential intestinal toxicity. Alternatively, an [...] Read more.
Gemcitabine is an intravenously administered nucleoside analog chemotherapeutic agent. The ability to deliver this agent as an oral drug would allow greater flexibility of administration and patient convenience; however, attempts have been fraught with high first-pass metabolism and potential intestinal toxicity. Alternatively, an amide prodrug of gemcitabine (LY2334737) was discovered, which is able to avoid the extensive first-pass metabolism that occurs following administration of gemcitabine. Preclinical in vitro and in vivo experiments were conducted to evaluate the hydrolysis and pharmacokinetics of LY2334737 and its downstream metabolites. In mice, rats, and dogs, the prodrug is absorbed largely intact across the intestinal epithelium and delivers LY2334737 to systemic circulation. The hydrolysis of LY2334737 is relatively slow, resulting in sustained release of gemcitabine in vivo. In vitro experiments identified carboxylesterase 2 (CES2) as a major enzyme involved in the hydrolysis of LY2334737, but with relatively low intrinsic clearance. Following hydrolysis of the prodrug, gemcitabine is cleared predominantly via the formation of its inactive metabolite dFdU. Both biliary and renal excretion was responsible for the elimination of LY2334737 and its metabolites in both mice and dogs. Full article
(This article belongs to the Special Issue Prodrugs)
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381 KiB  
Article
Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis
by Wing Man Lau, Charles M. Heard and Alex W. White
Pharmaceutics 2013, 5(2), 232-245; https://doi.org/10.3390/pharmaceutics5020232 - 17 Apr 2013
Cited by 9 | Viewed by 8902
Abstract
Psoriasis is a common, chronic and relapsing inflammatory skin disease. It affects approximately 2% of the western population and has no cure. Combination therapy for psoriasis often proves more efficacious and better tolerated than monotherapy with a single drug. Combination therapy could be [...] Read more.
Psoriasis is a common, chronic and relapsing inflammatory skin disease. It affects approximately 2% of the western population and has no cure. Combination therapy for psoriasis often proves more efficacious and better tolerated than monotherapy with a single drug. Combination therapy could be administered in the form of a co-drug, where two or more therapeutic compounds active against the same condition are linked by a cleavable covalent bond. Similar to the pro-drug approach, the liberation of parent moieties post-administration, by enzymatic and/or chemical mechanisms, is a pre-requisite for effective treatment. In this study, a series of co-drugs incorporating dithranol in combination with one of several non-steroidal anti-inflammatory drugs, both useful for the treatment of psoriasis, were designed, synthesized and evaluated. An ester co-drug comprising dithranol and naproxen in a 1:1 stoichiometric ratio was determined to possess the optimal physicochemical properties for topical delivery. The co-drug was fully hydrolyzed in vitro by porcine liver esterase within four hours. When incubated with homogenized porcine skin, 9.5% of the parent compounds were liberated after 24 h, suggesting in situ esterase-mediated cleavage of the co-drug would occur within the skin. The kinetics of the reaction revealed first order kinetics, Vmax = 10.3 μM·min−1 and Km = 65.1 μM. The co-drug contains a modified dithranol chromophore that was just 37% of the absorbance of dithranol at 375 nm and suggests reduced skin/clothes staining. Overall, these findings suggest that the dithranol-naproxen co-drug offers an attractive, novel approach for the treatment of psoriasis. Full article
(This article belongs to the Special Issue Prodrugs)
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Review

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417 KiB  
Review
Glutathione Transferase (GST)-Activated Prodrugs
by Paolo Ruzza and Andrea Calderan
Pharmaceutics 2013, 5(2), 220-231; https://doi.org/10.3390/pharmaceutics5020220 - 02 Apr 2013
Cited by 46 | Viewed by 8402
Abstract
Glutathione transferase (formerly GST) catalyzes the inactivation of various electrophile-producing anticancer agents via conjugation to the tripeptide glutathione. Moreover, several data link the overexpression of some GSTs, in particular GSTP1-1, to both natural and acquired resistance to various structurally unrelated anticancer drugs. Tumor [...] Read more.
Glutathione transferase (formerly GST) catalyzes the inactivation of various electrophile-producing anticancer agents via conjugation to the tripeptide glutathione. Moreover, several data link the overexpression of some GSTs, in particular GSTP1-1, to both natural and acquired resistance to various structurally unrelated anticancer drugs. Tumor overexpression of these proteins has provided a rationale for the search of GST inhibitors and GST activated cytotoxic prodrugs. In the present review we discuss the current structural and pharmacological knowledge of GST-activated cytotoxic compounds. Full article
(This article belongs to the Special Issue Prodrugs)
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