A novel method for coupling doxorubicin to lactosaminated human albumin by an acid sensitive hydrazone bond: synthesis, characterization and preliminary biological properties of the conjugate

Synthesis of a Covalent Epirubicin-(C3-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

“…Increasing the number of available reduced sulfhydryl groups can be achieved by the application of 1,4-dithiothreitol which reduces intramolecular cystine-cystine bonds 28,31,32 and similar disulfide structures 113 (DTT: R-CH 2 -S-S-CH 2 -R / 2 R-CH 2 -SH). The actual synthetic introduction of ''new'' or additional reduced sulfhydryl groups at the e-amine of lysine amino acid residues is possible with reactions that utilize 2-iminothiolane (2-IT), 2,6,26,30,114 mercaptosuccinimide, 115 or N-succinimidyl-S-acetylthioacetate (SATA). 7,114,116 Alternatively, carboxyl groups on molecules like heparin and hyaluronic acid can be thiolated with 3,3¢dithiobis(propanoic)-hydrazide 113,117 or divinylsulfone, 92,118 for hydroxyl groups of molecules with a cholesterol-like core.…”

“…97 Perhaps one of the most important features of the synthesis methodology is a lack of a requirement for cystinecystine disulfide bond reduction or pre-thiolation which by design allows the application of synthetic chemistry reactions that are highly efficient under relatively milder conditions and promote a lower risk of protein fragmentation or secondary polymerization through premature intermolecular or intramolecular disulfide bond formation. 2 Realized benefits therefore include greater retained biological activity (e.g., antigen binding-avidity) and total final yield. Lastly, lack of a requirement for either converting existing cystine-cystine disulfide bonds to their reduced form or the introduction of reduced sulfhydryl groups into immunoglobulin fractions reduces restrictions and limitations on the magnitude of the molar-incorporation-index that can be attained.…”

Design, Synthesis, and Characterization of pH-Sensitive PEG−PE Conjugates for Stimuli-Sensitive Pharmaceutical Nanocarriers: The Effect of Substitutes at the Hydrazone Linkage on the pH Stability of PEG−PE Conjugates

“…Different approaches have been employed to develop pH-responsive carriers, one being incorporation of acidsensitive linkages between drug-ligand or into the molecules of the carrier-forming components. These include cis-aconityls (18,19), electron-rich trityls (20), polyketals (21), acetals (22,23), vinyl ethers (24,25), hydrazones (26)(27)(28), poly(ortho-esters) (29), and thiopropionates (30). Such constructs may turn out to be useful for the site-specific delivery of drugs at the tumor sites (12), infarcts (31), inflammation zones (32) or cell cytoplasm or endosomes (33), since at these "acidic" sites, pH drops from the normal physiologic value of pH 7.4 to pH 6.0 and below.…”

Hydrazone, Amide, Carbamate, Macromolecular and Other Prodrugs of Doxorubicin

“…6) were activated by humanglucuronidase. DOX-GA3 was found to be stable upon incubation with human serum [26] and was shown to be even more effective than DOX [23]. DOX-GA3 was 12-fold less toxic than DOX in cells, in the human ovarian cancer cell line [27].…”

“…L-HAS coupled DOX has been increased DOX concentration in the tumors [21]. According to literature, L-HSA-DOX conjugate was synthesized using a (6-maleimidocaproyl)hydrazone derivative of DOX (DOXO-EMCH) [22,23].…”