Synthesis of multifunctional nanogels using a protected macromonomer approach

Nanoparticles possessing multiple functionalities provide synthetic handles for varied surface chemistries, making them useful for a range of applications such as biotargeting and drug delivery. However, the combination of interfering functionalities on the same particle is often challenging. We have employed a synthetic scheme involving chemical protection/deprotection to combine interfering functional groups on the same hydrogel nanoparticle. The synthesis of amine-containing poly(N-isopropylacrylamide) nanogels was carried out via free radical precipitation polymerization by incorporating a Fmoc-protected amine poly(ethylene glycol) (PEG) macromonomer. The Fmoc group was then removed to obtain free amines, which were shown to be available for conjugation. We further explored pNIPAm-co-acrylic acid nanogels with a protected amine-PEG, yielding zwitterionic particles. With careful attention to the order of the chemoligation and deprotection steps, these interfering functional groups can be forced to behave in a pseudo-orthogonal fashion, allowing for multiple chemoligation steps that employ both the amine and carboxylic acid groups.