Transferrin-Conjugated Polymeric Nanoparticles via Polymerization-Induced Self-Assembly for Enhanced BBB Transport and Glioblastoma Therapy

Transferrin-coated nanoparticles show promise in delivering chemotherapeutic drugs across biological barriers for treating glioblastoma multiforme (GBM). Employing a synthetic approach integrating advanced chemistries and bespoke in vitro biological assays, we developed versatile transferrin-conjugated polymeric nanoparticles designed for both blood–brain barrier (BBB) penetration and GBM targeting. First, tunable azido-functional polymeric nanoparticles were synthesized through reversible addition–fragmentation chain-transfer (RAFT)-mediated polymerization-induced self-assembly (PISA). Subsequently, holo-transferrin, modified with a diarylcyclooctyne (DBCO)-modified polyethylene glycol (PEG) linker, was conjugated onto the polymeric nanoparticles through copper-free click chemistry. The transferrin-functionalized polymeric nanoparticles were conjugated with doxorubicin via a pH-sensitive imine bond and displayed a pH-responsive drug release. Evaluation of cellular targetability, cytocompatibility, cytotoxicity, and the anticancer effect on GBM after crossing the BBB was conducted through a series of in vitro platforms of increasing physiological complexity: 2D cell culture, a static Transwell model, and a dynamic microfluidic BBB-GBM-on-a-chip model, utilizing immortalized human brain microvascular endothelial cells (hCMEC/D3) and malignant glioma cells (U87-MG). Our results demonstrate the potential of the transferrin-conjugated polymeric nanoparticles in facilitating doxorubicin delivery across the BBB and enhancing cytotoxicity on GBM while concurrently mitigating the adverse side effects on the BBB associated with free doxorubicin.