The reduction of tumor interstitial fluid pressure by liposomal imatinib and its effect on combination therapy with liposomal doxorubicin

Abstract

Interstitial fluid pressure (IFP) in tumor is much higher than that in normal tissue and it constitutes a great obstacle for the delivery of chemodrugs, which makes it a potential target for cancer therapy. In this study, imatinib, a molecular targeting drug, was loaded in sterically stabilized liposomes (SSL-IMA) to reduce the tumor IFP, in an attempt to deliver more liposomal doxorubicin (SSL-DOX) into tumor tissue. In a mouse B16 melanoma model, intravenous injection of 20 mg/kg SSL-IMA achieved the most reduction of tumor IFP and the effect lasted for at least 50 h with the least hematotoxicity. However, intragastric administration of 100 mg/kg free IMA did not decrease the tumor IFP significantly. Mechanisms of the reduction of tumor IFP by SSL-IMA were proved to be the inhibition of PDGF receptor beta, the inhibition of tumor fibroblasts as well as the anti-angiogenesis effect of SSL-IMA. Then it was demonstrated by in vivo imaging that the decrease of tumor IFP by SSL-IMA led to a more and longer intratumoral distribution of the lipid vehicles. The improved delivery was proved again in the anti-tumor study. The combination of SSL-IMA and SSL-DOX inhibited tumor growth and induced apoptosis of tumor cells the most, at a low dose in which neither SSL-DOX nor SSL-IMA showed obvious anti-tumor efficacy. Since no synergy against B16 cells was found between SSL-IMA and SSL-DOX, it was clear that the improved combinational therapy was basically due to the decrease of tumor IFP by SSL-IMA. In conclusion, reducing tumor IFP by SSL-IMA seems to be a promising strategy to potentiate chemotherapies.