Covalent linkage of carboxypeptidase G2 to soluble dextrans—II

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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“…Dex conjugation increased its permanence in the bloodstream and its localization in the liver [142].…”

Section: Proteinsmentioning

confidence: 99%

Polysaccharide-Based Anticancer Prodrugs

Caliceti

Salmaso

Bersani

2009

Macromolecular Anticancer Therapeutics

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“…Other examples include dextran conjugates of asparaginase, carboxypeptidase G 2 , and hemoglobin, respectively, as well as CMD‐insulin conjugates …”

Section: Carbohydrate Polymersmentioning

confidence: 99%

“…The improved PK profile and the increased resistance toward H 2 O 2 inactivation further translated into improved pharmacological properties of the SOD-dextran conjugate, as visualized by ac arrageenan-induced paw edema test. [32b] Other examples include dextran conjugates of asparaginase, [45] carboxypeptidase G 2 , [34,46] andh emoglobin, [47] respectively,asw ell as CMD-insulin conjugates. [48]…”

Section: Dextran Conjugationmentioning

confidence: 99%

Half‐Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation

2016

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Peptides and proteins constitute a vast pool of excellent drug candidates. Evolution has equipped these molecules with superior drug-like properties such as high specificity and potency. However, native peptides and proteins suffer from an inadequate pharmacokinetic profile, and their outstanding pharmacological potential can only be realized if this issue is addressed during drug development. To overcome this challenge, a variety of half-life extension techniques relying on covalent chemical modification have been developed. These methods include PEGylation, fusion to unstructured polypeptide-based PEG mimetics, conjugation of large polysaccharides, native-like glycosylation, lipidation, fusion to albumin or the Fc domain of IgG, and derivatization with bio-orthogonal moieties that direct self-assembly. This review provides an overview of available conjugation chemistries, biophysical properties, and safety data associated with these concepts. Moreover, the effects of these modifications on peptide and protein pharmacokinetics are demonstrated through key examples.

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“…Later studies demonstrated that simultaneous administration of carboxypeptidase G1 and nonclassical folate antagonists (which the enzyme did not cleave) enhanced the antitumor effects of the drugs 66,67. In 1987, carboxypeptidase G2 was covalently linked to soluble dextran and injected into mice,68 and this dextran-carboxypeptidase G2 conjugate had a prolonged lifetime in the circulation. The authors proposed using such systems to target therapeutic enzymes specifically to the liver.…”

Section: Other Potential Clinical Applications For Carboxypeptidase G2mentioning

confidence: 99%

Glucarpidase to combat toxic levels of methotrexate in patients

Green¹

2012

TCRM

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In January 2012, glucarpidase (Voraxaze®) received approval from the US Food and Drug Administration for intravenous treatment of toxic plasma methotrexate concentrations due to impaired renal clearance. Methotrexate, an antifolate agent, has been used for over 60 years in the treatment of various cancers. High-dose methotrexate has been particularly useful in the treatment of leukemias and lymphomas. However, even with aggressive hydration and urine alkalinization, such regimens can lead to acute renal dysfunction, as indicated by decreases in urine production and concomitant increases in blood urea nitrogen and serum creatinine levels. Because methotrexate is largely excreted by the kidneys, this can greatly potentiate tissue damage. Toxic levels of blood methotrexate can be rapidly and effectively decreased by intravenous administration of glucarpidase. Glucarpidase is a recombinant form of carboxypeptidase G2, a bacterial enzyme that rapidly cleaves methotrexate to form the amino acid glutamate and 2,4-diamino-N10-methylpteroic acid. Catabolites of methotrexate are much less toxic than the parent compound, and are primarily excreted by hepatic mechanisms. Glucarpidase has been available on a compassionate basis since the 1990s, and a variety of case reports and larger clinical trials have demonstrated the safety and efficacy of this drug in patients ranging in age from infants to the elderly and in a variety of races and ethnic groups. Glucarpidase should not be administered within 2 hours of leucovorin, because this agent is a reduced folate which competes with methotrexate for the enzyme and glucarpidase inactivates leucovorin. Side effects of glucarpidase are rare and relatively mild, and include paraesthesia, flushing, nausea, vomiting, pruritus, and headache. Glucarpidase has seen limited use in intrathecal treatment of methotrexate toxicity for which it is also effective. Future applications of this enzyme in chemotherapy continue to be an active area of research.

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Covalent linkage of carboxypeptidase G2 to soluble dextrans—II

Cited by 33 publications

References 18 publications

Polysaccharide-Based Anticancer Prodrugs

Polysaccharide-Based Anticancer Prodrugs

Half‐Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation

Glucarpidase to combat toxic levels of methotrexate in patients

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