In Situ Micro-Nano Conversion Augmented Tumor-Localized Immunochemotherapy.

Abstract

The immune checkpoint blockade (ICB) therapy based on monoclonal antibodies still suffers from a lower immune response rate and severe immune-related side effects, which greatly compromise its therapeutic benefits. Herein, ultrasound (US) microbubbles (MBs) that locally delivered the camptothecin-floxuridine (CF) drug combination and anti-PD-L1 blocking antibody (αPD-L1) to tumors were developed to improve ICB therapy. The resulting αPCF MBs exhibited good stability, allowing their use as US imaging contrast agents to trace the drug delivery in vivo. Furthermore, the combination of αPCF MBs treatment and disrupted US irradiation triggered tumor in situ conversion of αPCF MBs to αPCF NPs while promoting higher tumor cell uptake and deeper tumor penetration as confirmed by the US/fluorescence bimodal imaging. Camptothecin (CPT) and floxuridine (FUDR) were further released at a fixed 1:1 molar ratio within the tumor microenvironment (TME) to synergistically elicit an immunogenic tumor phenotype and sensitize tumors to αPD-L1-mediated ICB therapy, while the local simultaneous delivery of immunotherapeutic αPD-L1 further reversed the immunosuppressive tumor microenvironment and promoted the infiltration of cytotoxic T lymphocytes (CTLs), thus achieving a synergistic therapeutic effect of chemotherapy and immunotherapy in the CT26 tumor-bearing mice. Thus, αPCF MBs + US mediated local co-delivering of the drug combination and αPD-L1 well augmented the ICB therapy while effectively minimizing the off-target side effects, providing a safe and universal therapeutic strategy for tumor immunotherapy.