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Pharmaceutics, Volume 5, Issue 2 (June 2013), Pages 220-370

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Research

Jump to: Review

Open AccessArticle Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis
Pharmaceutics 2013, 5(2), 232-245; doi:10.3390/pharmaceutics5020232
Received: 1 February 2013 / Revised: 1 April 2013 / Accepted: 10 April 2013 / Published: 17 April 2013
Cited by 7 | PDF Full-text (381 KB) | HTML Full-text | XML Full-text
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 [...] 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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Open AccessArticle Development of a Novel Lipophilic, Magnetic Nanoparticle for in Vivo Drug Delivery
Pharmaceutics 2013, 5(2), 246-260; doi:10.3390/pharmaceutics5020246
Received: 25 February 2013 / Revised: 2 April 2013 / Accepted: 12 April 2013 / Published: 23 April 2013
Cited by 3 | PDF Full-text (4609 KB) | HTML Full-text | XML Full-text
Abstract
The aim of the present study was to evaluate the transfection potential of chitosan-coated, green-fluorescent magnetic nanoparticles (MNPs) (chi-MNPs) after encapsulation inside polyethylglycol (PEG)ylated liposomes that produced lipid-encapsulated chitosan-coated MNPs (lip-MNPs), and also to evaluate how these particles would distribute in vivo [...] Read more.
The aim of the present study was to evaluate the transfection potential of chitosan-coated, green-fluorescent magnetic nanoparticles (MNPs) (chi-MNPs) after encapsulation inside polyethylglycol (PEG)ylated liposomes that produced lipid-encapsulated chitosan-coated MNPs (lip-MNPs), and also to evaluate how these particles would distribute in vivo after systemic injection. The transfection potential of both chi-MNPs and lip-MNPs was evaluated in vitro in rat brain endothelial 4 (RBE4) cells with and without applying a magnetic field. Subsequently, the MNPs were evaluated in vivo in young rats. The in vitro investigations revealed that the application of a magnetic field resulted in an increased cellular uptake of the particles. The lip-MNPs were able to transfect the RBE4 cells with an incidence of approximately 20% of a commercial transfection agent. The in vivo distribution studies revealed that lip-MNPs had superior pharmacokinetic properties due to evasion of the RES, including hepatic Kuppfer cells and macrophages in the spleen. In conclusion, we were able to design a novel lipid-encapsulated MNP with the ability to carry genetic material, with favorable pharmacokinetic properties, and under the influence of a magnetic field with the capability to mediate transfection in vitro. Full article
(This article belongs to the Special Issue Drug Delivery Using Nanotechnology)
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Open AccessArticle Preclinical Absorption, Distribution, Metabolism, and Excretion of an Oral Amide Prodrug of Gemcitabine Designed to Deliver Prolonged Systemic Exposure
Pharmaceutics 2013, 5(2), 261-276; doi:10.3390/pharmaceutics5020261
Received: 19 February 2013 / Revised: 26 April 2013 / Accepted: 2 May 2013 / Published: 8 May 2013
Cited by 8 | PDF Full-text (353 KB) | HTML Full-text | XML Full-text
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, [...] 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)
Open AccessArticle Encapsulation of Hydrocortisone and Mesalazine in Zein Microparticles
Pharmaceutics 2013, 5(2), 277-293; doi:10.3390/pharmaceutics5020277
Received: 4 February 2013 / Revised: 29 April 2013 / Accepted: 3 May 2013 / Published: 10 May 2013
Cited by 8 | PDF Full-text (682 KB) | HTML Full-text | XML Full-text
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, [...] 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)
Open AccessCommunication Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs
Pharmaceutics 2013, 5(2), 318-328; doi:10.3390/pharmaceutics5020318
Received: 21 March 2013 / Revised: 7 May 2013 / Accepted: 10 May 2013 / Published: 22 May 2013
PDF Full-text (210 KB) | HTML Full-text | XML Full-text
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 [...] 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)

Review

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Open AccessReview Glutathione Transferase (GST)-Activated Prodrugs
Pharmaceutics 2013, 5(2), 220-231; doi:10.3390/pharmaceutics5020220
Received: 28 February 2013 / Revised: 21 March 2013 / Accepted: 22 March 2013 / Published: 2 April 2013
Cited by 6 | PDF Full-text (417 KB) | HTML Full-text | XML Full-text
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. [...] 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)
Open AccessReview Delivery of Cancer Therapeutics Using Nanotechnology
Pharmaceutics 2013, 5(2), 294-317; doi:10.3390/pharmaceutics5020294
Received: 24 December 2012 / Revised: 15 April 2013 / Accepted: 3 May 2013 / Published: 15 May 2013
Cited by 15 | PDF Full-text (1014 KB) | HTML Full-text | XML Full-text
Abstract
Nanoparticles have been investigated as drug carriers, because they provide a great opportunity due to their advantageous features: (i) various formulations using organic/inorganic materials, (ii) easy modification of targeting molecules, drugs or other molecules on them, (iii) effective delivery to target sites, [...] Read more.
Nanoparticles have been investigated as drug carriers, because they provide a great opportunity due to their advantageous features: (i) various formulations using organic/inorganic materials, (ii) easy modification of targeting molecules, drugs or other molecules on them, (iii) effective delivery to target sites, resulting in high therapeutic efficacy and (iv) controlling drug release by external/internal stimuli. Because of these features, therapeutic efficacy can be improved and unwanted side effects can be reduced. Theranostic nanoparticles have been developed by incorporating imaging agents in drug carriers as all-in-one system, which makes it possible to diagnose and treat cancer by monitoring drug delivery behavior simultaneously. Recently, stimuli-responsive, activatable nanomaterials are being applied that are capable of producing chemical or physical changes by external stimuli. By using these nanoparticles, multiple tasks can be carried out simultaneously, e.g., early and accurate diagnosis, efficient cataloguing of patient groups of personalized therapy and real-time monitoring of disease progress. In this paper, we describe various types of nanoparticles for drug delivery systems, as well as theranostic systems. Full article
(This article belongs to the Special Issue Drug Delivery Using Nanotechnology)
Open AccessReview Polysaccharide-Based Micelles for Drug Delivery
Pharmaceutics 2013, 5(2), 329-352; doi:10.3390/pharmaceutics5020329
Received: 22 January 2013 / Revised: 9 May 2013 / Accepted: 16 May 2013 / Published: 27 May 2013
Cited by 33 | PDF Full-text (345 KB) | HTML Full-text | XML Full-text
Abstract
Delivery of hydrophobic molecules and proteins has been an issue due to poor bioavailability following administration. Thus, micelle carrier systems are being investigated to improve drug solubility and stability. Due to problems with toxicity and immunogenicity, natural polysaccharides are being explored as [...] Read more.
Delivery of hydrophobic molecules and proteins has been an issue due to poor bioavailability following administration. Thus, micelle carrier systems are being investigated to improve drug solubility and stability. Due to problems with toxicity and immunogenicity, natural polysaccharides are being explored as substitutes for synthetic polymers in the development of new micelle systems. By grafting hydrophobic moieties to the polysaccharide backbone, self-assembled micelles can be readily formed in aqueous solution. Many polysaccharides also possess inherent bioactivity that can facilitate mucoadhesion, enhanced targeting of specific tissues, and a reduction in the inflammatory response. Furthermore, the hydrophilic nature of some polysaccharides can be exploited to enhance circulatory stability. This review will highlight the advantages of polysaccharide use in the development of drug delivery systems and will provide an overview of the polysaccharide-based micelles that have been developed to date. Full article
(This article belongs to the Special Issue Micellar Drug Delivery)
Open AccessReview The Potential Role of Nanotechnology in Therapeutic Approaches for Triple Negative Breast Cancer
Pharmaceutics 2013, 5(2), 353-370; doi:10.3390/pharmaceutics5020353
Received: 22 February 2013 / Revised: 16 May 2013 / Accepted: 24 May 2013 / Published: 18 June 2013
Cited by 4 | PDF Full-text (381 KB) | HTML Full-text | XML Full-text
Abstract
Triple Negative Breast Cancer, TNBC, a highly aggressive and metastatic type of breast cancer, is characterized by loss of expression of the estrogen receptor (ER), progesterone receptor (PR), and a lack of overexpression of the human epidermal growth [...] Read more.
Triple Negative Breast Cancer, TNBC, a highly aggressive and metastatic type of breast cancer, is characterized by loss of expression of the estrogen receptor (ER), progesterone receptor (PR), and a lack of overexpression of the human epidermal growth factor receptor 2 (HER2). It is a heterogeneous group of tumors with diverse histology, molecular uniqueness and response to treatment. Unfortunately, TNBC patients do not benefit from current anti-HER2 or hormone positive targeted breast cancer treatments; consequently, these patients rely primarily on chemotherapy. However, the 5-year survival rate for woman with metastatic TNBC is less than 30%. As a result of ineffective treatments, TNBC tumors often progress to metastatic lesions in the brain and lung. Brain metastases of invasive breast cancer are associated with 1 and 2 year survival rate of 20% and <2% respectively. Because the only current systemic treatment for TNBC is chemotherapy, alternative targeted therapies are urgently needed to improve the prognosis for TNBC patients. This review is focused on opportunities for developing new approaches for filling the current void in an effective treatment for TNBC patients. Full article
(This article belongs to the Special Issue Drug Delivery Using Nanotechnology)

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