Functionalized polymeric nanogels with pH-sensitive benzoic-imine cross-linkages designed as vehicles for indocyanine green delivery

To expand clinical applications of indocyanine green (ICG) by overcoming its several drawbacks such as self-aggregation under physiological conditions, poor aqueous photostability, lack of target specificity and rapid renal elimination from the body, the functionalized polymeric nanogels with pH-responsive benzoic-imine cross-linkages employed as carriers for ICG delivery were developed by one-step cross-linking of the branched poly(ethylenimine)-g-methoxy poly(ethylene glycol) (PEI-g-mPEG) copolymer with hydrophobic terephthalaldehyde (TPA) molecules in aqueous solution of pH 7.4. Based on the findings of fluorescence, dynamic and static light scattering, and transmission electron microscopy measurements, the resulting polymeric nanogels exhibited a spherical structure comprising multiple hydrophobic benzoic-imine-rich microdomains covered by positively-charged PEI networks capable of holding large amounts of water, and hydrophilic mPEG segments. Moreover, the cross-linking of more TPA molecules with PEI-g-mPEG segments led to the formation of more microdomains inside the polymeric nanogels, thus making the colloidal structure more hydrophobic and compact. More importantly, through the electrostatic attraction of amphiphilic ICG molecules with protonated PEI segments as well as their hydrophobic association with microdomains upon π-π stacking, the ICG species can be efficiently encapsulated into the nanogels. Notably, the robust ICG-loaded nanogels showed several outstanding properties, including (1) significantly enhanced the photo-stability of ICG in phosphate buffer, (2) considerably retarded ICG leakage from nanogels at pH 7.8, (3) acid-triggered ICG release by the cleavage of benzoic-imine bonds in response to pH reduction from 7.8 to 6.4. This work demonstrates that the pH-responsive polymeric nanogels have promising potential for tumor-targeted ICG delivery.