Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma

Abstract

Purpose Ultrasound nanobubbles (NBs) can kill tumor cells, mediated by their effects of cavitation and acoustic perforation through ultrasound, while as novel drug carriers, biomaterial-modified NBs release drugs at a target region. In this work, the ultrasound NBs bridged by biotin-streptavidin were prepared simultaneously to be loaded with both programmed death ligand 1 monoclonal antibody (PD-L1 mAb) and doxorubicin (DOX), which are immune checkpoint inhibitors (ICIs) and chemotherapeutic agents, to synergize immunotherapy and chemotherapy combined with sonodynamic therapy (SDT). Methods The PD-L1 mAb/DOX NBs, using bridging affinity biotin (BRAB) technology as a bridge, were prepared by thin-film hydration and mechanical oscillation for the targeted delivery of biotinylated PD-L1 mAb and DOX. Characterization and pharmacokinetic studies of PD-L1 mAb/DOX NBs were performed in vitro and in vivo. The antitumor effect of ultrasound-mediated PD-L1 mAb/DOX-NBs was studied in the subcutaneously transplanted tumor of the H22 hepatoma model, and the mechanism of synergistic tumor repression was investigated. Results The data of in vitro targeting experiments, contrast-enhanced ultrasound imaging (CEUS), in vivo imaging of the small animals imaging system (IVIS), and frozen sections showed that PD-L1 mAb/DOX-NBs have well-targeted aggregation in the tumor. By observing tumor inhibition rate, tissue cell apoptosis, and apoptosis-related gene and protein expression, the PD-L1 mAb/DOX-NBs group showed the best immunotherapy effects, and its tumor volume and mass inhibition rates were about 69.64% and 75.97%, respectively ( P < 0.01). Therefore, blocking the PD-1/PD-L1 pathway could improve immune cells’ tumor-killing ability. Antitumor immune cytokines were further enhanced when combined with DOX-induced tumor cell apoptosis and immunogenic cell death (ICD). Conclusion In summary, ultrasound-mediated PD-L1 mAb/DOX-NBs showed significant synergistic antitumor effects, providing a potential combined immunotherapy strategy for HCC.

A Booster for Radiofrequency Ablation: Advanced Adjuvant Therapy via In Situ Nanovaccine Synergized with Anti-programmed Death Ligand 1 Immunotherapy for Systemically Constraining Hepatocellular Carcinoma

“…It is notable that intraperitoneal injection of αPD-L1 Ab generally requires a dose of 10 mg/kg combined with other therapeutic measures to control tumor progression in previous studies. , This finding provides a solution to the problem of high toxicity caused by high dosages of αPD-L1 Ab in clinical practice, as well as a combined treatment strategy for enhancing the efficacy of αPD-L1 Ab. Compared with several adjuvant nanomaterials, , sonodynamic and photothermal therapy-based nanoparticles, , LDHs-cGAMP could stimulate a persistent immune response and greatly enhance the killing function of CTLs, promoting αPD-L1 Ab to arrest liver cancer growth significantly.…”

Advances in experimental animal models of hepatocellular carcinoma

“…These models use homozygous immunocompetent hosts, and are mostly used to study the mechanisms of immune responses and immunotherapeutic efficacy 62 . Commonly used hepatoma cell lines including BNL‐MEA, Hepa1‐6, BNL, and H22 cells can be used to establish orthotopic or ectopic murine model in immune‐related studies 63–65 . In addition to common mouse HCC cell lines, seeding tumorigenic hepatocytes from Simian vacuolating virus 40 (SV40) T antigen (Tag) transgenic mice into immunocompetent mice is a novel orthotopic mouse model of HCC 61 …”

“…62 Commonly used hepatoma cell lines including BNL-MEA, Hepa1-6, BNL, and H22 cells can be used to establish orthotopic or ectopic murine model in immune-related studies. [63][64][65] In addition to common mouse HCC cell lines, seeding tumorigenic hepatocytes from Simian vacuolating virus 40 (SV40) T antigen (Tag) transgenic mice into immunocompetent mice is a novel orthotopic mouse model of HCC. 61 Animal mutations have been described in allograft models using immunocompetent mice and mouse derived HCC cell.…”

Intelligent Sonocatalytic Nanoagents for Energy Conversion‐Based Therapies

“…Widely recognized theories include mechanical, ROS production, and thermal effects (Figure 1). [61][62][63][64] 1) Mechanical effects primarily contribute to cavitation effects, such as inertial and non-inertial cavitations. In inertial cavitation, acoustic energy elevates the mechanical pressure, inducing the creation of cavitation microbubbles.…”