Sialic acid-modified mesoporous polydopamine induces tumor vessel normalization to enhance photodynamic therapy by inhibiting VE-cadherin internalization

Abstract Tumor hypoxia do harm to the therapeutic efficiency of photodynamic therapy (PDT) since sufficient local O2 concentration is necessary for the generation of toxic singlet O2 (1O2). Herein, a sialic acid-PEG-modified mesoporous polydopamine nanoparticle dual loaded with indocyanine green and 3PO-loaded (SPMI/3) was fabricated. Owing to the specific combination between sialic acid and E-selectin overexpressed on the inflammatory endothelial cells around tumors, SPMI/3 demonstrated a 1.39-fold higher accumulation than that of the PMI/3-treated group. After laser irradiation, SPMI/3 revealed a potent anti-tumor efficacy due to the combination therapy of PDT and photothermal therapy in the early stage of treatment. Later, thanks to the overexpression of vascular endothelial growth factor induced by PDT, the slowly released 3PO from SPMI/3 reduced by 65.20% endocytosis of VE-cadherin compared to the PBS group. Accordingly, SPMI/3 normalized tumor vessels by increasing laminin and pericyte coverage, contributing to the decreased vascular permeability and improved tissue hypoxia. All these improvements contributed to the normalized tumor vasculature and inhibition of metastasis. In conclusion, this finding provides a novel strategy to enhance PDT therapy via tumor vessel normalization.