In Vitro Characteristics and in Vivo Plasma Disposition of Cisplatin Conjugated with Oxidized and Dicarboxymethylated Dextrans.

Nakashima, Makoto; Ichinose, Kunihiro; Kanematsu, Takashi; Masunaga, Tatsunori; Ohya, Yusuke; Ouchi, Tatsuro; Tomiyama, Naoki; Sasaki, Hirokazu; Ichikawa, Masataka

doi:10.1248/bpb.22.756

Cited by 22 publications

(14 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The macromolecular, water-soluble conjugates obtained by treatment of these carriers with DACH-Pt (NO 2 ) 2 (trans-1,2-diaminocyclohexanediaquaplatinum(II) dinitrate) have been screened in vitro for cytotoxicity against the HeLa human cervical adenocarcinoma and three additional human cancer cell lines. The highly promising, although still preparatory test results, expressed in terms of IC 50 values, reveal cytotoxic activities equal to, or exceeding (by a factor of 100 in tests against the HeLa line) those of the cisplatin standard. Most remarkably, activities determined for the five conjugates as a group against the HeLa line on average are more than 1,000-fold higher than observed for a group of three platinum conjugates, included for comparison, in which the metal, rather than dicarboxylato-chelated, is polymer-conjugated simply by coordination involving carrier-attached amine or diamine ligands.…”

Section: Discussionmentioning

confidence: 91%

“…In follow-on studies, ethylene oxide polymers modified with malonic acid terminals served as the carrier structures, to be platinated with cisplatin. While showing slightly decreased cytotoxic activity relative to cisplatin, the conjugates retained that activity over an extended life-time in serumcontaining medium [50,51]. Separately, the Kansai group synthesized dicarboxymethyldextrans and malonic acid-terminated ethylene oxide polymers, each one modified with branched galactose units and, lastly, platinated with cisplatin.…”

Section: Scheme 4 Formation Of Dach-pt(no 3 ) 2 From Trans-12-diaminmentioning

confidence: 99%

See 1 more Smart Citation

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

Komane

Mukaya

Neuse

et al. 2007

J Inorg Organomet Polym

View full text Add to dashboard Cite

Cancerous diseases, together with cardiac afflictions, account for the predominant causes of death among the adult population of the Western world. The classical platinum drugs, with cisplatin as their parent, have established themselves for years as leading components in the oncologist's arsenal of antitumor agents. As with most other antineoplastic drugs, however, incisive pharmacological deficiencies, notably excessive systemic toxicity and induction of drug resistance, have severely curtailed their overall efficaciousness. With the objective of overcoming these counterproductive deficiencies, the technique of polymer-drug conjugation, representing an advanced modality of drug delivery, has been developed in recent years to high standards worldwide. In a drug conjugate, water-soluble macromolecular carrier constructs designed in compliance with stringent pharmacological specifications are covalently, yet bioreversibly, interconnected with the bioactive agent. As a macromolecule following a pharmacokinetic pathway different from that of non-polymeric compounds, the conjugate acts as a pro-drug favorably transporting the agent through the various body compartments to, and into, the target cell, where the agent is enzymatically or hydrolytically separated from the carrier for its biological action. In the authors' laboratories the conjugation strategy has been adopted as the primary tool for drug efficacy enhancement. The present paper describes a special type of platinum complex carrier-bound via dicarboxymetal chelation, synthesized from carboxyl-functionalized polyamide-type carriers by platination with trans-1,2-diaminocyclohexanediaquaplatinum(II) dinitrate. In a series of in vitro tests antiproliferative activities have been determined against several human cancer cell lines. Whereas no improvements are observed in tests against a colorectal cancer, outstanding findings of the screening program include a 10-to 100-fold increase in cell-killing performance of the conjugates relative to the (non-polymeric) cisplatin standard against the HeLa adenocarcinoma, and distinctly reduced resistance factors (again, relative to cisplatin) in tests against the A2780 and A2780-cis pair of ovarian cell lines. These findings augur well for future developments of this class of platinum drugs. This article is dedicated to Professor Astruc.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Scheme 4 Formation Of Dach-pt(no 3 ) 2 From Trans-12-diaminmentioning

confidence: 99%

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

Komane

Mukaya

Neuse

et al. 2007

J Inorg Organomet Polym

View full text Add to dashboard Cite

show abstract

“…The in vivo behavior of drugs conjugated to dextran derivatives is highly affected by the physicochemical properties of dextran, including the degree of polydispersity, surface charge, and molecular weight of dextrans (Yamaoka et al 1995;Nakashima et al 1999). Among dextran derivatives, carboxymethyl dextran (CMD) with high molecular weight and weak anionic charge tends to be retained for a relatively long period of time in the circulation system because of its low glomerular ltration and less hepatic uptake (McIntosh et al 1997;Nakashima et al 1999).…”

Section: Effect Of Chemical Modification On the Pharmacokinetics And mentioning

confidence: 99%

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

2002

View full text Add to dashboard Cite

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.

show abstract

“…11,12) For this reason, sustained release formulations of CDDP or CDDP derivatives have been developed. [13][14][15][16] However, it has not been clear whether continuous exposure with low-dose CDDP can induce apoptosis as effectively as a single high-dose exposure CDDP.We therefore compared the ability of CDDP to induce apoptosis when delivered as a single high-dose exposure or as multiple low-dose exposures. In these studies, the induction of apoptosis was assessed by measuring caspase-3 activity, DNA fragmentation, and the percent of cells in the sub-G1 phase.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Continuous Exposure to Low-Dose Cisplatin and Apoptosis

Kishimoto

Kawazoe

Ikeno

et al. 2005

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Cisplatin (CDDP) is widely used for the treatment of a variety of human malignancies.1) CDDP is a well-known DNAdamaging agent, and it is currently thought that DNA platination is an essential first step in its cytotoxic activity. [2][3][4][5] Recent evidence has shown that apoptosis is a marker of tumor cells that have been exposed to CDDP. [6][7][8] In addition, CDDP has been reported to induce apoptosis at higher concentrations than the clinical dose.The CDDP is a type of drug whose effects depends on the area under the concentration-time curve (AUC ), 9,10) which means that continuous exposure low concentrations of the drug have the same effect as a single short-term exposure at a high concentration. Continuous infusion or multiple administrations of low-dose CDDP is an excellent regimen for cancer patients. 11,12) For this reason, sustained release formulations of CDDP or CDDP derivatives have been developed. [13][14][15][16] However, it has not been clear whether continuous exposure with low-dose CDDP can induce apoptosis as effectively as a single high-dose exposure CDDP.We therefore compared the ability of CDDP to induce apoptosis when delivered as a single high-dose exposure or as multiple low-dose exposures. In these studies, the induction of apoptosis was assessed by measuring caspase-3 activity, DNA fragmentation, and the percent of cells in the sub-G1 phase. MATERIALS AND METHODSCell Culture Rat ascites hepatoma AH-109A cells were serially transplanted by intraperitoneal injection in Donryu rats. The cells taken from ascites were grown in RPMI-1640 medium containing 20% fetal bovine serum.Drug Exposure Cells were seeded into 25 cm 2 flasks at 4ϫ10 5 cells/ml. Single exposures to CDDP (1.0 mg/ml, Kyowa Hakko Kogyo, Tokyo, Japan) were carried out at the starting point (0 h). When CDDP was delivered as 8 low-concentration exposures, the cells were dosed every 2 h between 0 to 9 h and between 24 to 33 h, and when 16 low-concentration doses, it was delivered every 1.5 h between 0 and 10.5 h and between 24 to 34.5 h.Growth Inhibition Assay Cells were seeded into 96-well plates at 4ϫ10 5 cells/0.1 ml/well following single or multiple exposures to CDDP. To determine the growth inhibitory effect, 20 ml of a solution containing 2 mM WST-1 (Dojindo, Kumamoto, Japan) and 0.2 mM 1-methoxy methylphenazinium methylsulfate was added to each well followed by incubation for 6 h. The absorbance of each well was measured at 450 nm with a reference wavelength of 650 nm using a Model 550 microplate reader (BIO-RAD, Tokyo, Japan).DNA Fragmentation Assay DNA laddering in apoptotic cells was detected using an ApopLadder Ex kit (Takara Bio, Shiga, Japan). Briefly, cells were suspended in lysis buffer and centrifuged. The supernatants were mixed with 10% Sodium dodecylsulfate (SDS) and Enzyme A and then incubated at 56°C for 1 h. Enzyme B was then added, and the mixture was incubated for an additional 1 h at 37°C. To precipitate DNA fragments, the preparation was mixed with precipitant and ethanol and then stored for 15 min a...

show abstract

In Vitro Characteristics and in Vivo Plasma Disposition of Cisplatin Conjugated with Oxidized and Dicarboxymethylated Dextrans.

Cited by 22 publications

References 0 publications

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

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

Continuous Exposure to Low-Dose Cisplatin and Apoptosis

Contact Info

Product

Resources

About