Macrophages play an essential role in the long effects of low-dose photodynamic therapy on vessel permeability

Abstract

Low-dose photodynamic therapy (L-PDT) has been used to transiently increase the permeability of tumor vessels to improve the delivery of chemotherapeutic drugs to lung tumors. However, the effects of L-PDT in a long-term on delivery of chemotherapeutic drugs are unknown. In this study, we studied this question as well as the underlying mechanisms. We found that the effects of L-PDT on tumor vessel permeability appeared to be prolonged. Moreover, L-PDT significantly increased the number of tumor associated macrophages, and appeared to induce macrophage polarization to a M1 phenotype. Further analyses showed that L-PDT upregulated stromal cell-derived factor 1 (SDF-1) in tumor to recruit macrophages through a SDF-1/Chemokine (C-X-C Motif) Receptor 4 (CXCR4) axis, which accounted for the prolonged effects of L-PDT on vessel permeability. Application of a specific CXCR4 inhibitor significantly suppressed the L-PDT-induced macrophage recruitment, resulting in abolishment of the prolonged effects of L-PDT on vessel permeability. Furthermore, the inhibitory effects of Liporubicin™ on the growth of the implanted tumor in L-PDT-treated mice were significantly attenuated by CXCR4 inhibition. Thus, our data demonstrate a previously unappreciated long-lasting effect of L-PDT on vessel permeability, and suggest that this long-lasting effects of L-PDT treatment on vessel permeability may result from modulation of macrophage recruitment and polarization. Hence, L-PDT may be a promising method to assist chemotherapeutic approaches.