2 research outputs found
Losartan loaded liposomes improve the antitumor efficacy of liposomal paclitaxel modified with pH sensitive peptides by inhibition of collagen in breast cancer
<p>The dense collagen network in tumors restricts the penetration of drugs into tumors. Free losartan could inhibit collagen, but it would cause hypotension at the dosage of 10 mg/kg/d. In this study, losartan was encapsulated in liposomes (LST-Lip) and the collagen inhibition ability of LST-Lip was investigated. Our results showed the blood pressure was not affected by LST-Lip at the dosage of 2.5 mg/kg every other day. The amount of Evans Blue in tumor in LST-Lip group was 1.98 times of that in control group. Confocal laser scanning microscopy images showed that prior injection of LST-Lip could inhibit collagen and further improve the tumorous accumulation of liposomes modified with TH peptides (AGYLLGHINLHHLAHL(Aib)HHIL-NH<sub>2</sub>) (TH-Lip) in 4T1 tumors. Compared with control group, the tumor inhibition rate of combined strategy of LST-Lip and paclitaxel loaded TH-Lip (PTX-TH-Lip) was 41.73%, while that of group only treated with PTX-TH-Lip was 14.94%. Masson’s trichrome staining confirmed that collagen was inhibited in LST-Lip group. Thus, the administration of LST-Lip in advance could inhibit the collagen in tumors effectively and did not affect the blood pressure, then PTX-TH-Lip injected subsequently could exert enhanced antitumor efficacy. In conclusion, this combined strategy might be promising for breast cancer therapy.</p
High Tumor Penetration of Paclitaxel Loaded pH Sensitive Cleavable Liposomes by Depletion of Tumor Collagen I in Breast Cancer
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<sub>5K</sub>-Hydrazone-PE
and DSPE-PEG<sub>2K</sub>-R8. When the Cl-Lip reached to the tumor
site by the enhanced permeability and retention (EPR) effect, PEG<sub>5K</sub>-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. <i>In vitro</i> 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. <i>In
vivo</i> 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