Construction of Multifunctionalizable, Core-Cross-Linked Polymeric Nanoparticles via Dynamic Covalent Bond

Well-defined hydrazide-containing copolymers poly(poly(ethylene glycol) methacrylate-co-methacryoyl hydrazide) (P(PEG-co-MAH)) via reversible addition fragmentation chain transfer radical polymerization were used as a reactive scaffold for bioconjugations to prepare polymers for protein recognition. The nucleophilic reaction of hydrazide and glucose generated glycoconjuagted copolymer that can recognize Con A. Biotinylated copolymer was prepared by the conjugation of aldehyde-functionalized biotin to the copolymer via hydrazone bond. Subsequently, dynamic covalent cross-linked nanoparticles were constructed via reversible acylhydrazone linkages by the reaction of copolymer and terephthaldicarboxaldehyde. The crosslinked nanoparticles demonstrated reversible pH-dependent formation/disintegration and adaptive characters. The cross-linked nanoparticles were further adorned through successive reactions of their remaining hydrazide units with aldehyde-functionalized biotin and fluorescein isothiocyanate to generate multifunctional nanoparticles. An in vitro study confirmed that the cross-linked nanoparticles were nontoxic to HeLa cells. These nanoparticles can encapsulate a cargo of small hydrophobic molecules, Nile red. The dye-loaded nanoparticles exhibited pH-triggered release behavior around the acidic tumoral environment, implying that these nanoparticles via hydrazone linkages have promise as therapeutic nanocarriers in a drug delivery system. Therefore, these dynamic covalent nanoparticles generated from hydrazide-containing copolymers can be utilized not only as building blocks for the construction of multifunctional materials with pH-responsive and adaptive characters but also as smart nanocarriers in biomedicine.