Targeted hybrid nanogels for sialic acid-overexpressing lung cancers: DNA-mediated chelation of doxorubicin and adsorption of zinc ions.

This study introduces a novel strategy for targeted and pH-responsive cancer therapy using nanocarriers constructed from naturally derived polymers, alginic acid (AA) and hyaluronic acid (HA). These nanogels (NGs), prepared via a water-in-oil emulsification method, are chemically modified with 3-aminophenylboronic acid (APBA). This conjugation of phenylboronic acid onto natural polymers represents a pioneering approach for targeted nanocarrier design. This modification allows the NGs to specifically target the sialic acid marker overexpressed on cancer cells. Designed to deliver a pre-mixed DNA-Doxorubicin (DOX) or DNA-Zinc ion (Zn2+) payload, the APBA-crosslinked NGs leverage the acidic tumor microenvironment to ensure precise and controlled therapeutic release. The APBA-modified oxidized alginic acid NGs (APBA-OAA NGs) demonstrated superior performance, significantly boosting drug uptake and triggering apoptosis, as evidenced by a much lower IC50 compared to APBA-OHA NGs and confirmed by elevated reactive oxygen species (ROS) generation, JC-1 and cleaved PARP assays. Crucially, in vivo evaluations using H1299 xenograft models further validated these findings, demonstrating that the APBA-OAA nanogel formulations significantly suppressed tumor growth and were well-tolerated throughout the localized treatment period. The research holds significant promise for revolutionizing cancer treatment by utilizing nanocarriers to specifically deliver the therapeutic agent Zn2+, which has a remarkably low toxicity profile for normal cells, offering a safer and more effective alternative to conventional chemotherapy with minimal side effects for patients.