The network of
collagen I in
tumors could prevent the penetration of drugs loaded in nanoparticles, and this would lead to impaired antitumor efficacy. In this study, free
losartan (an
angiotensin inhibitor) was injected before treatment to reduce the level of
collagen I, which could facilitate the penetration of nanoparticles. Then the pH-sensitive cleavable
liposomes (Cl-Lip) were injected subsequently to exert the antitumor effect. The Cl-Lip was constituted by PEG(5K)-Hydrazone-PE and DSPE-PEG(2K)-R8. When the Cl-Lip reached to the
tumor site by the enhanced permeability and retention (EPR) effect, PEG(5K)-Hydrazone-PE was hydrolyzed from the Cl-Lip under the low extra-cellular pH conditions of
tumors, then the
R8 peptide was exposed, and finally
liposomes could be internalized into
tumor cells by the mediation of
R8 peptide. In vitro experiments showed both the cellular uptake of Cl-Lip by 4T1 cells and cytotoxicity of
paclitaxel loaded Cl-Lip (PTX-Cl-Lip) were pH sensitive. In vivo experiments showed the Cl-Lip had a good
tumor targeting ability. After depletion of
collagen I, Cl-Lip could penetrate into the deep place of
tumors, the
tumor accumulation of Cl-Lip was further increased by 22.0%, and the
oxygen distributed in
tumor tissues was also enhanced. The antitumor study indicated free
losartan in combination with PTX-Cl-Lip (59.8%) was more effective than injection with PTX-Cl-Lip only (37.8%) in 4T1
tumor bearing mice. All results suggested that depletion of
collagen I by
losartan dramatically increased the penetration of PTX-Cl-Lip and combination of free
losartan and PTX-CL-Lip could lead to better antitumor efficacy of chemical drugs. Thus, the combination strategy might be a promising tactic for better treatment of solid
tumors with a high level of
collagen I.