A general orthogonal functionalization strategy for tailoring zwitterionic polymers with adjustable isoelectric points

Zwitterionic polymers, bearing a pair of oppositely charged groups in their repeat units, have demonstrated significant promise in both biomedical and engineering fields. Tunability of isoelectric points (IEPs) is of great value for bio-applications as it relates to key properties such as the surface charge reversal behavior, biocompatibility and the affinity to biomacromolecules. However, zwitterionic polymers with adjustable IEPs are difficult to obtain due to the fixed combination of ion pairs such as carboxybetaine-, sulfobetaine- and phosphorylcholine-based structures. To address this issue, we present a general approach to tailor zwitterionic polymers with adjustable IEPs. By developing an orthogonal functionalization strategy with sequence-controlled alternating polyesters, a series of zwitterionic polymers featuring customizable ion pairs were synthesized. This strategy, which involves aza-Michael addition and thiol-ene reaction, enables precise control over the alternating sequence of cations and anions, thereby allowing the generation of customizable ion pairs in each repeat unit. By forming block copolyesters with a hydrophobic polycaprolactone block, these polymers self-assemble into nanoparticles with tunable IEPs (e.g., 6.03, 6.37, and 6.54) and surface-charge-reversal properties, responding to physiological (pH 7.4) and tumor microenvironment (pH 6.5 ∼ 6.9) conditions. Notably, PCL54-b-P(MA-alt-AGE-g-Pip/NAC)9 (PPS3) nanoparticles, with the optimal IEP values, exhibited remarkable efficacy in inhibiting murine melanoma tumors in vivo when loaded with curcumin. This innovative approach holds promise for developing biocompatible and biodegradable drug delivery systems with tailored properties for potential clinical applications.