摘要
Tumor microenvironment has different morphologies of vessels in the core and rim regions, which influences the efficacy of tumor therapy. Our study purposed to improve the spatial uniformity of the anti-vascular effect and drug penetration within the tumor core and rim in combination therapies by regulating ultrasound-stimulated microbubble destruction (USMD). Focused ultrasound at 2 MHz and lipid-shell microbubbles (1.12±0.08 μm, mean±standard deviation) were used to perform USMD. The efficiency of the anti-vascular effect was evaluated by intravital imaging in order to determine the optimal USMD parameters. Tumor perfusion and histological alterations in the tumor core and rim were used to analyze the spatial uniformity of the anti-vascular effect and liposomal-doxorubicin (5 mg/kg) penetration in the combination therapy. Tumor vessels of specific sizes were disrupted by regulating USMD: vessels with sizes of 11±3, 14±5, 19±7, and 23±10 μm were disrupted by stimulation at acoustic pressures of 3, 5, 7, and 9 MPa, respectively (each p<0.05). The effective treatment time of USMD (at 2×10 <sup>7</sup> microbubbles/mouse, 7 MPa, and three cycles) was 60-120 min, which resulted in the disruption of 21-44% of vessels smaller than 50 μm. The reductions in perfusion and vascular density after combination therapy did not differ significantly between the tumor core and rim. This study found that regulating USMD can result in homogeneous anti-vascular effects and drug penetration within tumors and thereby improve the efficacy of combination therapies.