Hydrazone Linkers

A recent and important example for a N-containing linker system is the hydrazone linker developed by the group of Lazny [253]. This system is useful for the immobilization of aldehydes and ketones via hydrazone bonding. The linker was synthesized starting from commercially available 2-(AT-methylamino)ethanol (or corresponding aminoalcohols) which is nitrosated with t-butylnitrite and subsequently reduced with lithium aluminum hydride 

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Fig. 4 A second generation of the drug loading micelle with a pH-sensitive drug releasing property, a Formation of pH-sensitive polymeric micelles from PEG-(PAsp-Hyd-Dox) block copolymers. Antitumor drugs (Dox), conjugated through acid-labile hydrazone linkers, are released in lower pH conditions, b Time- and pH-dependent Dox release profile from the micelles. The micelles selectively release Dox under the pH condition of region B, which corresponds to the intracellular environment. The amount of loaded Dox in the micelles was calculated from the released Dox at pH 3.0 where all of the loaded drugs were assumed to be released from the micelle...

A recent trend is to design polymers with multiple functions including cationic units to bind nucleic acids as well as pH-sensitive carboxylic acids for endosomal dismption. Using a block copolymer architecture, comb-like polymers with cationic grafts were extended from aspartic acid units via a hydrazone linkers.The second block was composed of... 

Zhou et al. described the synthesis of pH-sensitive biodegradable PUs. They used a novel pH-sensitive macrodiol containing acid-cleavable hydrazone linkers, poly(E-caprolactone)-hydrazone-poly(ethylene glycol)-hydiazone- ly(E-caprolactone) diol (PCL-Hyd-PEG-Hyd-PCL). The macrodiol was used with L-lysine ethyl ester diisocyanate (LDI) and L-lysine-derived tripeptide as chain extender [47]. These PUs could self-assemble into micelles in aqneons solutions. Later, the same research group synthesized pH-sensitive polymers nsing 1,4-bntanediol as chain extenders and suggested its use as antitumor drug carriers [41]. 

Figure 3.21 Epirubicin linked via a pH cleavable hydrazone linker and its pH dependent release from the macromolecular carrier. Reproduced with permission from I. Teasdale, S. Wilfert, I. Nischang and O. Briiggemann, Polymer Chemistry, 2011, 2, 4, 828. 2011, Royal Society of Chemistry [137]...

Scheme 1.8. Multifunctional cleavage from Kamogawa s hydrazone linker.

Walker et al. [133] reported the use of pH-sensitive hydrazone linkers for Unking PEG to a polycationic carrier. Polyplexes containing such a biore-versible PEG-polycation conjugate upon exposure to endosomal pH undergo deshieldingbyPEGremovalwithinlessthan 1 hat37 °C(seealsobelow,Sect. 5). 

She et al. prepared self-assembled nanoparticles of heparin-doxorubicin using pH-sensitive pol5mier, dendrimer [53]. They showed about 20% of the drug was released at pH 7.4 after 56 h incubation while a much higher and faster release of doxorubicin was observed from the nanoparticles at low pH because of the cleavage of hydrazone linkers at low pH. Thus, the system remains stable in circulation for a long period of time. 

DOX was observed from the nanoparticles at low pH because ofthe cleavage of hydrazone linkers at low pH. Thus, the system remains stable in circulation system. 

Scheme 51 Multifunctional cleavage from the hydrazone linker...

SYNTHESIS OF NORBORNENE DERIVED DOXORUBICIN HYDRAZONE LINKER (MONO 2)... 

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