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FXIIIa substrate peptide decorated BLZ945 nanoparticles for specifically remodeling tumor immunity

Combretastatin A4 nanoparticles (CA4-NPs), which notably inhibit tumor growth, were found to cause tumor regrowth due to the intratumoral enrichment of M2-type macrophages after treatment. Since BLZ945, an inhibitor of CSF-1 receptor (CSF-1R), depletes and inhibits the proliferation of M2-type macrophages, it has the potential to relieve the immunosuppressive microenvironment and improve anti-tumor therapy of CA4-NPs. However, CSF-1R exists widely, not only in macrophages, and BLZ945 could cause potential hepatotoxicity. It is necessary to establish a tumor-targeting drug delivery system to reduce the off-target and side effects of BLZ945. In this study, FXIIIa substrate peptide A15 decorated BLZ945 nanoparticles (A15-BLZ-NPs) were developed, in which, BLZ945-poly(d,l-lactide) (BLZ945-PLA), produced by ring-opening polymerization, was encapsulated in poly(ethylene glycol)-poly(d,l-lactide) (PEG5k-PLA5k), and A15 was decorated on the surface PEG segment. A15-BLZ-NPs could crosslink with fibrin through elevated FXIIIa and specifically target intratumoral coagulation spots induced by CA4-NPs. In vivo studies showed that CA4-NPs induced enhanced distribution of BLZ945 in tumors, as the BLZ945 content was 3.75-fold in the CA4-NP + A15-BLZ-NP group compared to that of A15-BLZ-NP single treatment. Meanwhile, compared to the CA4-NP group, the combination treatment significantly reduced the proportion of M2-type macrophages (from 64.4% to 24.5%) and enriched cytotoxic T lymphocytes (from 1.5% to 18.9%) in tumors, suggesting that A15-BLZ-NPs remodeled and activated tumor immunity after CA4-NP treatment. Furthermore, the combined treatment effectively improved the tumor inhibition rate to 73.4%, which was significantly higher than that of CA4-NP (15.5%) or A15-BLZ-NP (23.9%) single treatment. This work established a novel combination strategy for anti-tumor therapy.

Related Products

Cat.No. Product Name Information
S7204 Fosbretabulin (Combretastatin A4 Phosphate) Disodium Fosbretabulin (Combretastatin A4 Phosphate) Disodium is the water-soluble prodrug of Combretastatin A4 (CA4), which is a microtubule-targeting agent that binds β-tubulin with Kd of 0.4 μM in a cell-free assay. Fosbretabulin Disodium inhibits the polymerization of tubulin with IC50 of 2.4 μM, and also disrupts tumor vasculature. Fosbretabulin disodium induces mitotic arrest and apoptosis in endothelial cells. Phase 3.

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Microtubule Associated Apoptosis related