Tissue Distribution of Macromolecular Conjugate, Adriamycin Linked to Oxidized Dextran, in Rat and Mouse Bearing Tumor Cells.

Munechika, Koji; Sogame, Yoshihisa; Kishi, Norihide; Kawabata, Yoshinari; Ueda, Yasuo; Yamanouchi, Kouichi; Yokoyama, Kazumasa

doi:10.1248/bpb.17.1193

Cited by 14 publications

(7 citation statements)

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“…We employed Schiff base formation method for DA5018 conjugation because it has been shown to be effective for the conjugation of drugs having primary amine group to the aldehyde group of oxidized dextran (Muenchika et al 1994). Prior to conjugation to DA5018, therefore, oxidized CMD (OCMD) was prepared.…”

Section: Effect Of Chemical Modification On the Pharmacokinetics And mentioning

confidence: 99%

“…[ 14 C]CMD, [ 14 ]OCMD, and [ 14 C]OCMD-drug conjugates were synthesized by previously reported methods (Muenchika et al 1994;Ueda et al 1989) with slight modi cations. Brie y, for the preparation of [ 14 C]CMD, 100 mg of dextran T-70 and 200 mg of monochloroacetic acid, containing 37 MBq of [ 14 C]monochloroacetic acid, were dissolved in 0.33 ml of distilled water, and 0.5 ml of 10 M NaOH solution was added.…”

Section: Preparation Of [ 14 C]cmd [ 14 C]ocmd and [ 14 C]ocmd-drugmentioning

confidence: 99%

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

2002

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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.

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Section: Effect Of Chemical Modification On the Pharmacokinetics And mentioning

confidence: 99%

Section: Preparation Of [ 14 C]cmd [ 14 C]ocmd and [ 14 C]ocmd-drugmentioning

confidence: 99%

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

2002

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“…Furthermore, the dextran–doxorubicin conjugate also showed a different biodistribution profile from that of free doxorubicin. In mice and rats, plasma and tumor levels of the conjugate were higher than those of the free drug 44–45. Tissue distribution studies also showed that dextran–doxorubicin conjugate accumulated more in tumor tissues almost twice as much as free doxorubicin but very less in heart and skeletal muscles.…”

Section: Dextran–doxorubicin Conjugatementioning

confidence: 95%

“…In mice and rats, plasma and tumor levels of the conjugate were higher than those of the free drug. [44][45] Tissue distribution studies also showed that dextran-doxorubicin conjugate accumulated more in tumor tissues almost twice as much as free doxorubicin but very less in heart and skeletal muscles. Therefore, a different pattern of in vivo antitumor activity with respect to biodistribution of the conjugate as compared to free doxorubicin was suggested.…”

Section: Protection Of Conjugated Drugs From Biodegradationmentioning

confidence: 98%

Dextran–doxorubicin/chitosan nanoparticles for solid tumor therapy

Bisht

Maitra

2009

WIREs Nanomed Nanobiotechnol

104

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Chemotherapy is a major therapeutic approach for the treatment of localized and metastasized cancers. Whereas potent chemotherapeutic agents seem promising in the test tube, clinical trials often fail due to unfavorable pharmacokinetics, poor delivery, low local concentrations, and limited accumulation in the target cell. The pathophysiology of the tumor vasculature and stromal compartment presents a major obstacle to effective delivery of agents to solid tumors. Poor perfusion of the tumor, arterio-venous shunting, necrotic and hypoxic areas, as well as a high interstitial fluid pressure work against favorable drug uptake. Thus, targeted drug delivery using long-circulating particulate drug carriers such as hydrogels of controlled size (<100 nm diameter) holds immense potential to improve the treatment of cancer by selectively providing therapeutically effective drug concentrations at the tumor site [through enhanced permeability and retention (EPR) effect] while reducing undesirable side effects. This review focuses on the progress of targeted delivery of nanoparticulated anticancer drug such as doxorubicin chemically conjugated with dextran and encapsulated in chitosan nanoparticles to solid tumor with reduced side effect of drug. Regulated particle size and long circulation of these hydrogel nanoparticles in blood help them accumulate in tumor tissue through EPR effect as evident from the significant regression of the tumor volume. The cardiotoxicity of doxorubicin can be minimized by coupling the drug with dextran and encapsulating it in chitosan nanoparticles.

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“…On the contrary, Dex-DOXO accumulated in heart and muscles is remarkably less than free DOXO. A comparative study performed with radiolabeled drug conjugate (Dex-14 C-DOXO) of radiolabeled polymer conjugate ( 14 C-Dex-DOXO) suggested that after accumulation in the tumor DOXO was released and then the polymer chains with low drug content were cleared by kidney ultrafiltration [111].…”

Section: Doxorubicinmentioning

confidence: 99%

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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Tissue Distribution of Macromolecular Conjugate, Adriamycin Linked to Oxidized Dextran, in Rat and Mouse Bearing Tumor Cells.

Cited by 14 publications

References 0 publications

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

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

Dextran–doxorubicin/chitosan nanoparticles for solid tumor therapy

Polysaccharide-Based Anticancer Prodrugs

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