Cytotoxic agent combretastatin A4

This study aimed to investigate the synergistic potential of TROP-2-targeted CAR-T cells combined with the vascular disrupting agent PLG-g-mPEG/CA4/BLZ945 (CBP). We hypothesized that CBP would disrupt the tumor neovascular, thereby enhancing infiltration of the CAR-T cells.

Analyzed TROP-2 expression in breast cancer using bioinformatics, qRT-PCR, and sequencing. Constructed and evaluated TROP-2 CAR-T cells in vitro. Finally, we prepared an animal model of breast cancer, and verified the anti-tumor therapeutic effect, safety evaluation and biologic mechanisms of TROP-2 CAR-T combined with CBP in vivo.

Bioinformatics analysis and in vitro experiments showed that TROP-2 was widely expressed in breast cancer cells. The successfully constructed TROP-2 CAR-T cells exhibited high cytotoxicity in vitro. The experimental results in mice showed that the combination therapy of CBP and TROP-2 CAR-T significantly enhanced the anti-tumor effect, and no significant decrease in survival rate or major organ damage was observed. Mechanism studies have shown that the anti-tumor effect of the combination therapy group may be related to immune cell infiltration, CAR-T cell infiltration, and upregulation of immune related factors.

Our findings demonstrated the potential of TROP-2 as a viable target for CAR-T therapy in breast cancer. The combination of TROP-2 CAR-T cells with CBP not only enhances the therapeutic efficacy but also maintains a favorable safety profile, offering a promising new strategy for the treatment of breast cancer.

Microtubules represent a clinically validated target for anticancer therapy. However, the clinical utility of existing tubulin inhibitors is frequently compromised by the emergence of drug resistance and systemic toxicities. Herein, we designed and synthesized a series of indazole-based Combretastatin A-4 (CA-4) analogues as potent tubulin polymerization inhibitors. Among them, SMU-G4 potently inhibited the proliferation of B16-F10 melanoma cells (IC₅₀ = 4 nM). Moreover, SMU-G4 significantly induced G2/M phase cell cycle arrest and triggered apoptosis, while effectively suppressing tumor cell migration in vitro. Most importantly, SMU-G4 demonstrated potent in vivo antitumor efficacy in a B16-F10 xenograft mouse model (TGI = 74.4%, 15 mg/kg) without inducing significant systemic toxicity or observable adverse effects. These findings suggest that SMU-G4, characterized by its novel scaffold and potent inhibitory profile, serves as a promising lead compound for the development of next-generation microtubule-targeting agents.