Effect of Chemical Modification on the Pharmacokinetics and Biodistribution of Carboxymethyl Dextran as a Drug Carrier

Abstract

The in vivo fate of drugs conjugated to macromolecules inevitably depends on that of macromolecules. However, the in vivo fate of macromolecules also may be altered by conjugation to drugs. For the efficient design of carboxymethyldextran (CMD) conjugates of a new analgesic drug, DA5018, we investigated whether the chemical modifications alter the pharmacokinetics and tissue distribution of CMD itself. [(14)C]CMD, oxidized [(14)C]CMD ([(14)C]OCMD), [(14)C]OCMD conjugates of DA5018 ([(14)C]OCMD-DA5018) and [(14)C]OCMD conjugates of ethanolamine ([(14)C]OCMD-EA) were prepared and their molecular sizes were compared by size exclusion HPLC. The pharmacokinetics, biliary excretion, and tissue distribution of total radioactivity were compared after intravenous administration of each CMD derivative, 2.0 MBq/kg, to rats. The effective molecular sizes of CMD derivatives decreased in the order of [(14)C]CMD, [(14)C]OCMD-DA5018, [(14)C]OCMD, and [(14)C]OCMD-EA. After administration of each derivative, the mean AUC values of total radioactivity decreased with the decrease in the effective molecular size. The values of CL, Vss, and the amount of total radioactivity excreted in 24-hr urine increased considerably with the decrease in the effective molecular size. The tissue-to-plasma ratios of total radioactivity remaining in heart, liver, lung, kidney, and spleen at 24 hr also increased in the opposite order of the effective molecular size. Taken together, all these results demonstrate that the chemical modifications and physicochemical properties of attached chemicals can alter the pharmacokinetics and tissue distribution of CMD. One possible reason might be the difference in the effective molecular size of various CMD derivatives. Our study demonstrates that it may be necessary to consider the effect of chemical modification on the in vivo fate of macromolecules in designing macromolecular drug conjugates.

Enhancement of anti-tumor activity of hybrid peptide in conjugation with carboxymethyl dextran via disulfide linkers

“…It was previously reported that the tissue distribution of the CMD polymer and its derivatives bearing high molecular weights is higher in the kidneys, lungs and spleen [23,37]. The fluorescence intensities of the kidneys and spleen of mice injected with the CMD-s-s-peptide conjugates in this study were greater than those of mice treated with peptide alone, and may correspond to the tissue distribution of the CMD polymer; however, further investigations are needed to elucidate these suggestions.…”

“…We could remove the peptide-s-s-peptide by centrifugation method, but it is hard to remove completely the CMD-s-s-CMD from CMD-s-s-peptide conjugate. However, it is known that the CMD polymer itself is non-toxic [23], and thus it is suggested that the CMD-s-s-CMD in conjugate has no influence on both cytotoxic and anti-tumor activities.…”

“…Glucose polymers in the form of dextrans have been used for more than 50 years as plasma volume expanders because of their relatively low immunogenicity [21]. Carboxymethyl dextran (CMD) is a dextran derivative and is frequently used as a macromolecular carrier for the delivery of drugs because of its low glomerular filtration rate and lower hepatic uptake [22][23][24][25]. Furthermore, it has been previously reported that thiolated CMD is a potential candidate for GSH-responsive drug release and could enhance the therapeutic efficacies of drugs [26,27].…”

Edible Nanoencapsulation Vehicles for Oral Delivery of Phytochemicals: A Perspective Paper

“…More precise control could be gained by introducing magnetic nanoparticles, surface chemical modification, and biorelevant ligands (oligosaccharides, antibodies, polypeptides, viral proteins, etc.) to ENVs. − …”

A pH‐responsive carboxymethyl dextran‐based conjugate as a carrier of docetaxel for cancer therapy

“…Owing to its biocompatibility and biodegradability, dextran and its derivatives have been widely investigated for biomedical applications such as drug delivery and tissue engineering . Carboxymethyl dextran (CMD) is one of the emerging derivatives for drug delivery applications because it has multiple functional groups including carboxyl, hydroxyl, and aldehyde groups, allowing for facile chemical modification . In this study, we developed a polymeric conjugate with a pH‐sensitive ester linkage between CMD and DTX as a drug carrier for cancer therapy.…”