Systematic design of polybasic nanogels: influence of hydrophobic monomers on tunable physicochemical and biological properties

Endosomal entrapment limits the intracellular delivery of many chemotherapeutics, creating a need for nanoparticle systems that promote endosomal escape and improve therapeutic efficacy. This study presents the design and characterization of a novel family of pH responsive polybasic nanogels prepared by UV initiated polymerization. Their pH dependent swelling behavior, which is critical for targeted delivery, was systematically tuned by incorporating different hydrophobic groups into the P(DEAEMA) grafted PEGMA system using n-alkyl methacrylate monomers that vary in steric bulk and chain length. These parameters altered the nanogel pKa, the critical swelling pH, and the onset of swelling, enabling strong endosomolytic activity at the pH values of early and late endosomes. The resulting nanogels have an appropriate size to exploit the enhanced permeability and retention effect, exhibit high drug loading, remain stable in biological media, and show no intrinsic toxicity. Together these features create an efficient platform for intracellularly targeted drug delivery.