Hyaluronidase responsive second near-infrared fluorescent nanocomplex for combined HER2 blockade and chemotherapy of HER2+ breast cancer

Abstract

The human epidermal growth factor receptor-2-positive (HER2+) type is aggressive and has poor prognosis. Although anti-HER2 therapy alone or in combination with other treatment regimens showed significant improvement in survival outcomes, breast cancer patients are still suffering from tumor relapse and severe dose-limiting side effects. Thus, there is still an unmet challenge to develop effective therapeutic agents for HER2+ breast cancer treatment with minimized side effects. Herein, we produced a stimuli-responsive and tumor-targeted hyaluronic acid (HA) nanocomplex that combined HER2 blockade and chemotherapy for effective HER2+ breast cancer therapy. A hydrophobic NIR-II dye, IR1048, was covalently linked with HA to form a spherical HA-IR1048 nanoparticle (HINP), with Herceptin conjugated on the surface and paclitaxel (PTX) encapsulated inside. The fluorescent signals from the yielding Her-HINP/PTX are quenched originally, but a strong NIR-II signal is generated when HINP is degraded by the hyaluronidase that is overexpressed in breast tumors, thus allowing the tracking and visualization of Herceptin and PTX accumulation. Her-HINP/PTX peaked in HER2+ tumors at 24 h post injection as imaged by NIR-II fluorescent imaging. A significantly improved tumor growth inhibition effect was observed after five systemic treatments compared to single PTX (3.71 ± 0.41 times) or Herceptin (5.98 ± 0.51 times) treatment in a HER2-overexpressed breast cancer mouse model with prolonged survival. Collectively, the designed Her-HINP/PTX presents a new hyaluronidase-responsive and HER2 blockade nanoformulation that can visualize the accumulation of nanocomplexes and release drugs inside tumors for combined HER2+ breast cancer therapy with a great promise for translational study. Statement of significanceThe high expressions of a protein called human epidermal growth factor receptor 2 (HER2) in breast tumors make this subtype of cancer aggressive. Currently, chemotherapy combined with a HER2 antibody, Herceptin, is a preferred approach for HER2-positive breast cancer therapy. However, these breast cancer patients still suffer from tumor relapse and severe side effects because various therapeutic agents have inherent different biodistributions, resulting in insufficient treatment effects and unfavorable normal organ uptake of these therapeutic agents. Herein, we produced a nanocomplex carrying both Herceptin and chemotherapy drug to simultaneously deliver two drugs into tumors for efficient HER2+ tumor treatment with minimized side effects, providing new insights for designing a combined therapy strategy.