Captopril improves tumor nanomedicine delivery by increasing tumor blood perfusion and enlarging endothelial gaps in tumor blood vessels

摘要

Abstract Poor tumor perfusion and unfavorable vessel permeability compromise nanomedicine drug delivery to tumors. Captopril dilates blood vessels, reducing blood pressure clinically and bradykinin, as the downstream signaling moiety of captopril, is capable of dilating blood vessels and effectively increasing vessel permeability. The hypothesis behind this study was that captopril can dilate tumor blood vessels, improving tumor perfusion and simultaneously enlarge the endothelial gaps of tumor vessels, therefore enhancing nanomedicine drug delivery for tumor therapy. Using the U87 tumor xenograft with abundant blood vessels as the tumor model, tumor perfusion experiments were carried out using laser Doppler imaging and lectin-labeling experiments. A single treatment of captopril at a dose of 100?mg/kg significantly increased the percentage of functional vessels in tumor tissues and improved tumor blood perfusion. Scanning electron microscopy of tumor vessels also indicated that the endothelial gaps of tumor vessels were enlarged after captopril treatment. Immunofluorescence-staining of tumor slices demonstrated that captopril significantly increased bradykinin expression, possibly explaining tumor perfusion improvements and endothelial gap enlargement. Additionally, imaging in?vivo , imaging ex?vivo and nanoparticle distribution in tumor slices indicated that after a single treatment with captopril, the accumulation of 115-nm nanoparticles in tumors had increased 2.81-fold with a more homogeneous distribution pattern in comparison to non-captopril treated controls. Finally, pharmacodynamics experiments demonstrated that captopril combined with paclitaxel-loaded nanoparticles resulted in the greatest tumor shrinkage and the most extensive necrosis in tumor tissues among all treatment groups. Taken together, the data from the present study suggest a novel strategy for improving tumor perfusion and enlarging blood vessel permeability simultaneously in order to improve nanomedicine delivery for tumor therapy. As captopril has already been extensively used clinically, such a strategy has great therapeutic potential. Highlights ? Nanomedicine drug delivery system has become a main stream for tumor therapy. Low perfusion and unfavorable vessels permeability still posed great challenge in effective nanomedicine drug delivery for tumor treatment. Enhancement of tumor perfusion and enlargement of endothelial gap were well documented to achieve improved delivery of nanomedicine for tumor and better therapeutic benefits. ? This manuscript reports for the first time that we take advantage of captopril, a drug widely used in clinics capable of reducing blood pressure by dilating vessels, to improve tumor perfusion and enlarge endothelial gap simultaneously to enhance nanomedicine drug delivery for tumor. ? The present study thus provided a new strategy to improve nanoparticles drug delivery for tumor treatment with high potential of clinics translation.