Low Molecular-Weight Chitosan as a pH-Sensitive Stealth Coating for Tumor-Specific Drug Delivery

When a nanoparticle is developed for systemic application, its surface is typically protected by poly­(ethylene glycol) (PEG) to help prolonged circulation and evasion of immune clearance. On the other hand, PEG can interfere with interactions between nanocarriers and target cells and negatively influence the therapeutic outcomes. To overcome this challenge, we propose low molecular-weight chitosan (LMWC) as an alternative surface coating, which can protect the nanomedicine in neutral pH but allow cellular interactions in the weakly acidic pH of tumors. LMWCs with a molecular weight of 2–4 kDa, 4–6.5 kDa, and 11–22 kDa were produced by hydrogen peroxide digestion and covalently conjugated with poly­(lactic-<i>co</i>-glycolic acid) (PLGA). Nanoparticles created with PLGA-LMWC conjugates showed pH-sensitive cell interactions, which enabled specific drug delivery to cells in a weakly acidic environment. The hydrophilic LMWC layer reduced opsonization and phagocytic uptake. These properties qualify LMWCs as a promising biomaterial for pH-sensitive stealth coating