Facial Solid-Phase Synthesis of Well-Defined Zwitterionic Amphiphiles for Enhanced Anticancer Drug Delivery

Serum protein adsorption on the nanoparticle surface determines the biological identity of polymeric nanocarriers and critically impacts the in vivo stability following intravenous injection. Ultrahydrophilic surfaces are desired in delivery systems to reduce the serum protein corona formation, prolong drug pharmacokinetics, and improve the in vivo performance of nanotherapeutics. Zwitterionic polymers have been explored as alternative stealth materials for biomedical applications. In this study, we employed facial solid-phase peptide chemistry (SPPC) to synthesize multifunctional zwitterionic amphiphiles for application as a drug delivery vehicle. SPPC facilitates synthesis and purification of the well-defined dendritic amphiphiles, yielding high-purity and precise architecture. Zwitterionic glycerylphosphorylcholine (GPC) was selected as a surface moiety for the construction of a ultrahydrophilic dendron, which was coupled on solid phase to a hydrophobic dendron using multiple rhein (Rh) molecules as drug-binding moieties (DBMs) for doxorubicin (DOX) loading via pi–pi stacking and hydrogen bonding. The resulting zwitterionic amphiphilic Janus dendrimer (denoted as GPC8–Rh4) showed improved stabilities and sustained drug release compared to the analogue with poly­(ethylene glycol) (PEG) surface (PEG5k–Rh4). In vivo studies in xenograft mouse tumor models demonstrated that the DOX–GPC8–Rh4 nanoformulation significantly improved anticancer effects compared to DOX–PEG5k–Rh4, owing to the improved in vivo pharmacokinetics and increased tumor accumulation.