Enhanced Tumor Penetration of HER2-Targeting Nanodrugs by Vascular Disrupting Agent

The effect of actively targeting nanomaterials on deep tumor penetration is poor, limiting their efficacy. Increasing drug penetration by improving tumor vascular permeability is a promising solution. Herein, we developed nanoparticles consisting of HER2 monoclonal antibody conjugated to poly( l -glutamic acid)-7-ethyl-10-hydroxycamptothecin (HER2-PLG-SN38) and combined them with the vascular disrupting agent combretastatin A4 phosphate (CA4P) to target HER2-expressing gastric cancer cells of the National Cancer Institute-N87 (NCI-N87) cell line. The nanoparticles were synthesized by using click chemistry. In vitro assays showed that HER2-PLG-SN38 significantly increased tumor cell death compared to IgG-PLG-SN38. The amount of HER2-PLG-SN38 infiltrating from the tumor vasculature into the tumor tissue was increased after CA4P treatment. HER2-PLG-SN38 combined with CA4P achieved a tumor suppression rate of 90.8% in vivo compared to that (70.0%) achieved with HER2-PLG-SN38 alone. Our findings suggest that combining HER2-PLG-SN38 with CA4P enhances tumor targeting and penetration, offering a potential strategy for improving the efficacy of nanomaterial-based cancer therapies. This research inspires further exploration of synergistic approaches to overcome the penetration limitations of nanomedicine in cancer treatment.