Cis-aconityl spacer between daunomycin and macromolecular carriers: A model of pH-sensitive linkage releasing drug from a lysosomotropic conjugate

Shen, Wei‐Chiang; Ryser, Hugues J.‐P.

doi:10.1016/0006-291x(81)91644-2

Cited by 265 publications

(149 citation statements)

References 4 publications

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“…17) These authors coupled daunorubicin to aminoethyl polyacrylamide polymer beads or poly-D-lysine using the aconityl spacer. Thereafter, a number of daunorubicin conjugates with monoclonal antibodies and synthetic polymers have been developed with this method.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that most of the free g-carboxylic group of the aconityl spacer molecule is coupled to macromolecular moiety. 17) In this case the free g-carboxylic group may also participate to the coupling to PVA via ethylenediamine spacer, resulting the macromolecular conjugates of PVA-cis-ADOX and PVA-trans-ADOX, respectively. The conjugates were generated from the combination of PVA and DOX for the first time.…”

Section: Discussionmentioning

confidence: 99%

“…17) The amino group of the sugar ring of doxorubicin (DOX) was reacted with cis-aconitic anhydride to form a-unsaturated amide bond. Two isomers of trans-ADOX (trans-configuration) and cis-ADOX (cis-configuration) were generated (Fig.…”

Section: Synthesis Of Aconityl-doxorubicinmentioning

confidence: 99%

“…Synthesis of Aconityl-doxorubicin Aconityl-doxorubicin (ADOX) was synthesized by the modified method of Shen and Ryser. 17) Briefly, doxorubicin hydrochloride (10 mg) was dissolved in distilled water (10 ml) and cooled on ice. cis-Aconitic anhydride (10 mg) was dissolved in pdioxane (6 ml) and added slowly to the solution with stirring, and the pH was immediately adjusted to 9.0 by careful addition of 0.5 M NaOH.…”

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confidence: 99%

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Synthesis of Poly(vinyl alcohol)-Doxorubicin Conjugates Containing cis-Aconityl Acid-Cleavable Bond and Its Isomer Dependent Doxorubicin Release

Kakinoki

Kaneo

Ikeda

et al. 2008

Biological & Pharmaceutical Bulletin

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Aconityl-doxorubicin (ADOX) was synthesized by the modified method of Shen and Ryser. Two isomers of cis-ADOX (cis-configuration) and trans-ADOX (trans-configuration) were generated in the reaction of DOX and cis-aconitic anhydride. These products were separated completely by using HPLC and analyzed by TOF-MS spectroscopy and 1 H-and 13 C-NMR experiments. The yields of cis-ADOX and trans-ADOX were 36.3 and 44.8%, respectively. The free g g-carboxylic group of ADOX molecule was coupled to poly(vinyl alcohol) (PVA) via ethylenediamine spacer, resulting the macromolecular conjugates of PVA-cis-ADOX and PVA-trans-ADOX, respectively. The DOX content of the conjugates estimated by the hydrolysis method detected the aglycone of DOX which can be estimated as the PVA-bound DOX selectively was 4.4 w/w% which was similar to 4.6 w/w% by the ordinary UV method. Both PVA-cis-ADOX and PVA-trans-ADOX were very stable at neutral pH, but the release of DOX was increased markedly under acidic conditions. Half-life of the release of DOX from PVA-cis-ADOX at pH 5.0 was 3 h which was 4.7-fold shorter than that from PVA-trans-ADOX (14 h). The cytotoxicities of PVA-cis-ADOX and PVA-trans-ADOX were evaluated by using J774.1 cells employing a [ 3 H]uridine incorporation assay as a measure of RNA synthesis. A significant difference in antitumor activity between PVA-cis-ADOX and PVA-trans-ADOX was observed where the former was much active than the later. It was suggested that the conjugate enters the cells and reaches the lysosomal/endosomal compartment, and that the aconityl spacer releases DOX from the conjugate in the acidic compartment of lysosomes/endosomes due to the participation of a free carboxylic group.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Synthesis Of Aconityl-doxorubicinmentioning

confidence: 99%

mentioning

confidence: 99%

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Synthesis of Poly(vinyl alcohol)-Doxorubicin Conjugates Containing cis-Aconityl Acid-Cleavable Bond and Its Isomer Dependent Doxorubicin Release

Kakinoki

Kaneo

Ikeda

et al. 2008

Biological & Pharmaceutical Bulletin

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“…The release of free drug from carrier-drug conjugates by chemical hydrolysis at acid pH, which occurs for instance in endosomes and lysosomes of cells, can be accomplished by using the acid-labile cis-aconityl linkers introduced by Shen and Ryser [34]. We have prepared improved linkers allowing unequivocal binding of drug and carrier [ 11,12,20].…”

Section: Discussionmentioning

confidence: 99%

Synthesis and biological evaluation of immunoconjugates of adriamycin and a human IgM linked by poly[N5-2-hydroxyethyl)-l-glutamine]

Hoes

Ankone

Grootoonk

et al. 1996

Journal of Controlled Release

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The synthesis and purification of radiolabelled immunoconjugates, composed of a human IgM monoclonal antibody (IgM 16.88) directed against an intracellular tumour-associated antigen, the drug carrier poly [NS-(2-hydroxyethyl)-L-glutamine] (PHEG) and the cytostatic drug adriamycin (ADR) are described. The immunoconjugates were constructed to allow selective release of ADR in the putatively acidic environment of the tumour through a novel acid-labile maleamic acid linker. The conjugate of PHEG and the acid-labile ADR derivative effectively released ADR in cytotoxic amounts at a pH of 6.0 as judged from incubation in buffer and from inhibition of the growth of HT-29 colon tumour cells in vitro. Immunoconjugates were prepared by coupling of PHEG-ADR having a hydrolytically stable amide bond with J3q-labelled antibody through tbioether bond formation involving a single thiol group at the C-terminus of the polymer chain and maleimido groups introduced onto the * Corresponding author. Abbreviations: AcOSu,N-succinimidyl acetate; ADR, adriamycin; AEC, anion-exchange chromatography; ASI, active specific immunotherapy; BOC, tert-butox ycarbonyl ; (BOC) 20, di-tert-butyldicarbonate; BOC-AB, N-tert-butox ycarbonyl-1,4-diaminobutane; BOC-OEA, N-tert-buto xycarbonyl-2,2'-oxybis(ethylamine); CDI, N,N'-carbonyldiimidazole; CHC13, chloroform; CH2CIz, dichloromethane; CTA-I, colon tumourassociated antigen; Cys, cysteine; d. doublet; dd, double doublet; dt, double triplet; DAB, 3,3'-aminobenzidine; DMF. N,N'-dimethylformamide; DMSO, dimethylsulfoxide; DPn, number-average degree of polymerization; DPw, weight-average degree of polymerization; DSS, 4,4-dimethyl-4-silapentane sodium sulphonate; DTNB, 5,5'-dithiobis ( 2-nitrobenzoic acid) ; DTP, 4,4'-dithiodipyridine; DTT, dithiothreitol; e, molar absorbance coefficient; EEDQ, N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline; EIA, enzyme-linked immunoassay; Et20, diethyl ether; FABMS, fast atom bombardment mass spectrometry; FCS, fetal calf serum; GABA, y-aminobutyric acid; GMB, y-maleimidobutyryl; GMBS, N-(ymaleimidobutyryloxy)succinimide; HOAc, acetic acid; HONSu, N-hydroxysuccinimide; HPMA, N-(2-hydroxypropyl)methacrylamide; HP-SEC, high-performance size exclusion chromatography; HRP, horseradish peroxidase; LALLS, low-angle laser light scattering; m, multiplet; M,. number-average molecular weight; Mw, weight-average molecular weight; MRW, mean residue weight; MoAb, monoclonal antibody: MSA, methanesulphonic acid; MTT, 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; NAN,, sodium azide; NCA, N-carboxyanhydride; PBLG, poly( T-benzyl-L-glutamate); PBS, phosphate-buffered saline; PDT, 2-pyridyldithio; PGA, poly Hoes et al. / Journal of Controlled Release 38 (1996) antibody. The immunoreactivity of IgM-PHEG-ADR conjugate was almost fully preserved. Tumour uptake and biodistribution of ~251-1abelled PHEG-ADR and of ~3q-labelled IgM-PHEG-ADR, which was co-administered with ~H-labelled IgM 16.88, in nude mice carrying MRI-W207 human ovarian tumour xenografts were s...

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Synthesis of soluble polymers for medicine that degrade by intramolecular acid catalysis

Clochard

Rankin

Brocchini³

2000

Macromol. Rapid Commun.

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Cis-aconityl spacer between daunomycin and macromolecular carriers: A model of pH-sensitive linkage releasing drug from a lysosomotropic conjugate

Cited by 265 publications

References 4 publications

Synthesis of Poly(vinyl alcohol)-Doxorubicin Conjugates Containing cis-Aconityl Acid-Cleavable Bond and Its Isomer Dependent Doxorubicin Release

Synthesis of Poly(vinyl alcohol)-Doxorubicin Conjugates Containing cis-Aconityl Acid-Cleavable Bond and Its Isomer Dependent Doxorubicin Release

Synthesis and biological evaluation of immunoconjugates of adriamycin and a human IgM linked by poly[N5-2-hydroxyethyl)-l-glutamine]

Synthesis of soluble polymers for medicine that degrade by intramolecular acid catalysis

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