Quantitative acid hydrolysis of DE-310, a macromolecular carrier system for the camptothecin analog DX-8951f

Shiose, Yoshinobu; Kuga, Hiroshi; Yamashita, Fumiyoshi; Hashida, Mitsuru

doi:10.1016/j.jpba.2006.10.034

Cited by 4 publications

(2 citation statements)

References 19 publications

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“…The supernatant was analyzed to determine the amount of total G-DX-8951 by HPLC, conjugated-DX-8951 calculated by deduction of G-DX-8951 from total amount of G-DX-8951. 16) HPLC Analysis The concentrations of DX-8951 and G-DX-8951 in the medium and cell extracts were determined by reversed-phase HPLC (CCPM-II pump, Tosoh, Tokyo, Japan) at 40°C implementing Symmetry Shield RP18 (4.6ϫ100 mm; Waters, Milford, MA, U.S.A.). The mobile phase was a mixture of 36.5% of acetonitrile/methanol (2/1, v/v) and 64.5% of 0.1% trifluoroacetic acid at Symmetry Shield RP18 column, flowed at 1.0 ml/min.…”

Section: Cathepsins Activities In Tumor Cellsmentioning

confidence: 99%

Relationship between Drug Release of DE-310, Macromolecular Prodrug of DX-8951f, and Cathepsins Activity in Several Tumors

Shiose

Ochi

Kuga

et al. 2007

Biological & Pharmaceutical Bulletin

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Utilization of drug delivery systems is an attractive approach to improving efficacy and safety of anticancer drugs. Long-circulating macromolecular or particulate carriers are known to preferentially accumulate in solid tumors, due to the "enhanced permeability and retention (EPR)" effect, 1) i.e., leakiness of tumor angiogenic blood vessels and lack of effective lymphatic drainage. SMANCS (neocartinostatin polymer conjugate), Doxil (doxorubicin liposome), and Daunozome (daunorubicin liposome) 2,3) that exploit the EPR effect have already been launched in the market. Besides, PK1 (doxorubicin-HPMA polymer), 4) XYOTAX (paclitaxelpolyglutamate), 5) and NK911 (doxorubicin micelle) 6) are under clinical investigation.DE-310 is a novel macromolecular prodrug of the topoisomerase-I inhibitor (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]-pyrano) [3Ј,4Ј:6,7]indolizino[1,2-b]quinoline-10,13-dione (DX-8951).7) DX-8951 is covalently linked with carboxymethyl dextran polyalcohol (CM-Dex-PA) via the Gly-Leu-Phe-Gly (GGFG) tetrapeptide spacer (Fig. 1). 7) It has been demonstrated that a single dose of 11.4 mg/kg DE-310 exhibited stronger anti-tumor activity in mice than repeated doses (10 mg/kg daily for 5 d) of DX-8951f (exatecan; DX-8951 monomethansulfonate salt).8) Taking into account that DX-8951f belongs to time-dependent anti-cancer drugs, 9) slow release of DX-8951 from DE-310 in addition to long-term retention in tumor tissues would have been beneficial in exhibiting such an effective anti-tumor activity.The peptide spacer of DE-310 was designed to be cleaved by cysteine protease, cathepsins. Expression of cathepsins B, H, and L in tumor tissues and their involvement in tumor progression have been indicated. 10) Cathepsin B is expressed more highly in malignant tumors 11) and is responsible for destruction of basal membranes, processing of matrix proteases, and inactivation of protein inhibitors.12) On the other hand, cathepsin H is highly expressed in colon cancer cells, 13) and cathepsin L is secreted in metastatic bone marrow tumor.14) It is likely that the level of cathepsin species in tumor tissues would be one of the factors determining antitumor activity of DE-310.In this study, we examined the drug release from DE-310 by cathepsins B, H, and L obtained from human liver to identify the products of hydrolysis and determine the rate of hydrolysis for each cathepsin species. Then, we examined in vitro drug release from DE-310 in different murine or human tumor cell types, in addition to the activity or expression of cathepsins B, H and L in the cells. Correlation between the drug release and cathepsin levels was analyzed to quantitatively delineate the mechanism of drug release from DE-310. In addition, tumor tissue distribution of DE-310 was investi-

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Section: Cathepsins Activities In Tumor Cellsmentioning

confidence: 99%

Relationship between Drug Release of DE-310, Macromolecular Prodrug of DX-8951f, and Cathepsins Activity in Several Tumors

Shiose

Ochi

Kuga

et al. 2007

Biological & Pharmaceutical Bulletin

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“…Drug delivery systems (DDSs) can significantly improve the performance of antitumor drugs by delivering therapeutic molecules to specific areas, thereby increasing drug efficacy and increasing the therapeutic index [1][2][3][4]. To date, many synthetic biomaterials have been used as building blocks to fabricate drug carriers for targeted delivery [5][6][7][8]. Synthetic biomaterials are usually less biocompatible and always induce immunoreaction, however, which limits their application in clinical medicine.…”

Section: Introductionmentioning

confidence: 99%

Fabrication of a nanocarrier system through self-assembly of plasma protein and its tumor targeting

et al. 2011

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Human serum albumin (HSA) nanoparticles hold great promise as a nanocarrier system for targeted drug delivery. The objective of this study was to explore the possibility of preparing size controllable albumin nanoparticles using the disulfide bond breaking reagent β-mercaptoethanol (β-ME). The results showed that the protein concentration and temperature had positive effects on the sizes of the albumin nanoparticles, while pH had a negative effect on the rate of nanoparticle formation. The addition of β-ME induced changes in HSA secondary structure and exposed the hydrophobic core of HSA, leading to the formation of nanoparticles. Human serum albumin nanoparticles could be internalized by MCF-7 cells and mainly accumulated in cytoplasm. After injection in tumor bearing mice, the HSA nanoparticles accumulated in tumor tissues, demonstrating the targeting ability of the nanoparticles. Therefore, human serum albumin can be fabricated into nanoparticles by breaking the disulfide bonds and these nanoparticles exhibit high tumor targeting ability. Human serum albumin nanoparticles could be ideal for the targeted delivery of pharmacologically active substances.

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Application of Nanotechnology in Cancer Therapy and Imaging

Wang

Yang

Chen

et al. 2008

CA: A Cancer Journal for Clinicians

597

393

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Recent developments in nanotechnology have provided researchers with new tools for cancer imaging and treatment. This technology has enabled the development of nanoscale devices that can be conjugated with several functional molecules simultaneously, including tumor-specific ligands, antibodies, anticancer drugs, and imaging probes. Since these nanodevices are 100 to 1,000-fold smaller than cancer cells, they can be easily transferred through leaky blood vessels and interact with targeted tumor-specific proteins both on the surface of and inside cancer cells. Therefore, their application as cancer cell-specific delivery vehicles will be a significant addition to the currently available armory for cancer therapeutics and imaging. (CA Cancer J Clin 2008;58:97-110.)

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Quantitative acid hydrolysis of DE-310, a macromolecular carrier system for the camptothecin analog DX-8951f

Cited by 4 publications

References 19 publications

Relationship between Drug Release of DE-310, Macromolecular Prodrug of DX-8951f, and Cathepsins Activity in Several Tumors

Relationship between Drug Release of DE-310, Macromolecular Prodrug of DX-8951f, and Cathepsins Activity in Several Tumors

Fabrication of a nanocarrier system through self-assembly of plasma protein and its tumor targeting

Application of Nanotechnology in Cancer Therapy and Imaging

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