Abstract:
Vascular disrupting agents (VDAs) have aroused increasing interest due to their great potential in cancer therapy. As compared to combretastatin A4 phosphate (CA4P), a polymeric VDA prodrug which has been in Phase III clinical trials, poly(
L-glutamic acid)-
g-methoxy poly(ethylene glycol)/combretastatin A4 (C-NPs), can significantly improve the tumor blood vessels targeting and enhance therapeutic effect due to the low permeability of nanodrug in solid tumors. However, C-NPs was found to induce the polarization of TAMs toward an M2-like phenotype (M2-TAMs) and further tumor recurrence, thereby limiting its antitumor application. BLZ945 was a highly selective CSF-1R inhibitor which can decrease the number of M2-TAMs through inhibiting CSF-1/CSF-1R signal pathway. However, CSF-1R is widely expressed in most cells of mononuclear phagocytic system, resulting in the lack of tumor selectivity and therapeutic side effect of BLZ945. Firstly, the reduction of M2-TAMs after BLZ945 treatment was verified by flow cytometry analysis; and
in vivo antitumor efficacy showed that the combination of C-NPs and BLZ945 remarkably enhanced anticancer efficacy with a tumor suppression rate of 74.1%. Then, the co-bonded nanodrug poly(
L-glutamic acid)-
g-methoxy poly(ethylene glycol)-combretastatin A4/BLZ945 (CB-NPs) was developed for further enhance the synergistic anticancer efficacy. The chemical structure of CB-NPs was confirmed by nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FT-IR). The obtained CB-NPs had a hydrodynamic radius of (56 ± 19) nm in aqueous solution determined by dynamic light scattering (DLS). The drug loading content of CA4 and BLZ945 in CB-NPs measured by HPLC was 10.7% and 8.4%, respectively. An
in vivo study with the C26 murine colon carcinoma model showed that CB-NPs exhibited the most prominent suppression of tumor growth, significantly higher than the combination therapy with C-NPs plus BLZ945. The tumor suppression rate to C26 tumor with an initial volume of 410 mm
3 was 79%. Therefore, CB-NPs enhanced tumor targeting ability of BLZ945 and improved its synergistic antitumor ability. This work provides a valuable cooperative strategy therapeutic choice of VDAs for solid tumor therapy.