Dextran-methylprednisolone succinate as a prodrug of methylprednisolone: in vitro immunosuppressive effects on rat blood and spleen lymphocytes

Rensberger, Katherine L; Hoganson, Dean A; Mehvar, Reza

doi:10.1016/s0378-5173(00)00544-5

Cited by 13 publications

(9 citation statements)

References 10 publications

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“…The tissue/plasma AUC ratio of the active drug is a more appropriate measure of the targetability of a drug to specific tissues than the absolute tissue concentrations or AUCs. Recent studies29 in our laboratory demonstrated that DMP by itself lacks a significant immunosuppressive activity and should release MP to be effective. Therefore, a comparison of the tissue/plasma AUC ratios of the unconjugated MP after the administration of MP and DMP should determine the usefulness of dextran conjugation for targeted delivery of the steroid.…”

Section: Discussionmentioning

confidence: 98%

“…In a series of studies,6,25–33 Jusko and colleagues prepared a liposomal formulation of MP and investigated the pharmacokinetics and pharmacodynamics of the formulation. The liposomal formulation selectively delivered the drug to the reticuloendothelial system with a 77‐fold increase in the spleen/plasma AUC ratio when compared with the parent drug 31.…”

Section: Discussionmentioning

confidence: 99%

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Dextran–methylprednisolone succinate as a prodrug of methylprednisolone: Plasma and tissue disposition**A preliminary account of this study was presented at the Twelfth Annual Meeting of the American Association of Pharmaceutical Sciences, Boston, MA, November 2–6, 1997 (Mehvar R. 1997. Targeted delivery of methylprednisolone using a dextran prodrug. Pharm Res 14:S336).

Zhang

Mehvar

2001

Journal of Pharmaceutical Sciences

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Dextran–methylprednisolone succinate as a prodrug of methylprednisolone: Plasma and tissue disposition**A preliminary account of this study was presented at the Twelfth Annual Meeting of the American Association of Pharmaceutical Sciences, Boston, MA, November 2–6, 1997 (Mehvar R. 1997. Targeted delivery of methylprednisolone using a dextran prodrug. Pharm Res 14:S336).

Zhang

Mehvar

2001

Journal of Pharmaceutical Sciences

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“…Our previous study31 clearly showed that MP attached to dextran macromolecule via a succinate linker is not effective by itself and has to release MP in order to be effective. In our current studies with new conjugates containing peptide linkers, hydrolysis of the conjugates in different media resulted in the generation of both free MP and its peptidyl derivatives (Figs.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and in Vitro Characterization of Novel Dextran–Methylprednisolone Conjugates with Peptide Linkers: Effects of Linker Length on Hydrolytic and Enzymatic Release of Methylprednisolone and its Peptidyl Intermediates

Penugonda

Kumar

Agarwal

et al. 2008

Journal of Pharmaceutical Sciences

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To control the rate of release of methylprednisolone (MP) in lysosomes, new dextran-MP conjugates with peptide linkers were synthesized and characterized. Methylprednisolone succinate (MPS) was attached to dextran 25 kDa using linkers with 1-5 Gly residues. The release characteristics of the conjugates in pH 4.0 and 7.4 buffers, blood, liver lysosomes, and various lysosomal proteinases were determined using a size-exclusion and/or a newly-developed reversed-phase HPLC method capable of simultaneous quantitation of MP, MPS, and all five possible MPS-peptidyl intermediates. We synthesized conjugates with ≥ 90% purity and 6.9-9.5% (w/w) degree of MP substitution. The conjugates were stable at pH 4.0, but released MP and intact MPS-peptidyl intermediates in the pH 7.4 buffer and rat blood, with faster degradation rates for longer linkers. Rat lysosomal fractions degraded the conjugates to MP and all the possible intermediates also at a rate directly proportional to the length of the peptide. Whereas the degradation of the conjugates by cysteine peptidases (papain or cathepsin B) was relatively substantial, no degradation was observed in the presence of aspartic (cathepsin D) or serine (trypsin) proteinases, which do not cleave peptide bonds with Gly. These newly-developed dextran conjugates of MP show promise for controlled delivery of MP in lysosomes.

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“…In the case of spleen lymphocytes, 50% cell proliferation inhibition was obtained with about 35 and 100 nM free MP and Dex-MP, respectively, while in the case of blood lymphocytes the 50% inhibition concentrations were about 15 and 30 nM, respectively. The lower immunomodulating effect of Dex-MP with respect to the free drug may be due to a direct effect of the conjugate and poor MP release under the experimental conditions [133].…”

Section: Methylprednisolone and Tacrolimusmentioning

confidence: 97%

Polysaccharide-Based Anticancer Prodrugs

Caliceti

Salmaso

Bersani

2009

Macromolecular Anticancer Therapeutics

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So far, polysaccharides have been widely used in pharmaceutical technology as first choice excipients for production of traditional formulations. Nevertheless, in the recent years these natural and semisynthetic macromolecules have been addressed for new challenging applications as functional materials for innovative formulations. Their peculiar physicochemical and biological properties have been exploited to develop macromolecular prodrugs which can exhibit favorable biopharmaceutical properties and enforce the therapeutic performance of the parent drugs. These polymers display, in fact, high biocompatibility and biodegradability, multiple insertion points, and biological properties that can be advantageously exploited in drug delivery. In particular, the multifunctional structures of these polymers are anchoring points for conjugation of several anticancer drugs, which usually suffer from poor physicochemical, biopharmaceutical, and therapeutic properties that limit their therapeutic performance and proper use in anticancer treatment. Polysaccharide-based anticancer prodrugs can be designed to endow derivatives with new bioresponse, targeting, or environmental triggering properties or to combine molecules with synergistic therapeutic effect. Over the years, a variety of synthetic protocols have been set up to conjugate anticancer drugs to the polysaccharide backbone via specific linkages or through spacers which convey to the conjugates selective drug-delivery properties. Furthermore, the intrinsic antitumor activity and cell-targeting properties of few polysaccharides represent an additional value to the final therapeutic systems. Anticancer drugs with different pharmacodynamic, pharmacokinetic, and physicochemical properties have been successfully conjugated to various natural and semisynthetic polysaccharides highlighting the interesting perspectives for exploitation of new promising anticancer polymer therapeutics.

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Dextran-methylprednisolone succinate as a prodrug of methylprednisolone: in vitro immunosuppressive effects on rat blood and spleen lymphocytes

Cited by 13 publications

References 10 publications

Synthesis and in Vitro Characterization of Novel Dextran–Methylprednisolone Conjugates with Peptide Linkers: Effects of Linker Length on Hydrolytic and Enzymatic Release of Methylprednisolone and its Peptidyl Intermediates

Polysaccharide-Based Anticancer Prodrugs

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