Clotted
plasma proteins are present on the walls of
tumor vessels and in
tumor stroma.
Tumor-homing
peptide Cys-Arg-Glu-Lys-Ala (CREKA) could recognize the clotted
plasma proteins in
tumor vessels. Thermosensitive
liposomes could immediately release the encapsulated
drug in the vasculature of the heated
tumor. In this study, we designed a novel form of targeted thermosensitive
liposomes, CREKA-modified lysolipid-containing thermosensitive
liposomes (LTSLs), containing
doxorubicin (DOX) (DOX-LTSL-CREKA), to investigate the hypothesis that DOX-LTSL-CREKA might target the clotted
plasma proteins in
tumor vessels as well as
tumor stroma and then exhibit burst release of the encapsulated DOX at the heated
tumor site. We also hypothesized that the high local
drug concentration produced by these thermosensitive
liposomes after
local hyperthermia treatment will be useful for treatment of multidrug resistance. The multidrug-resistant human breast
adenocarcinoma (MCF-7/ADR) cell line was chosen as a
tumor cell model, and the targeting and immediate release characteristics of DOX-LTSL-CREKA were investigated in vitro and in vivo. Furthermore, the antitumor activity of DOX-LTSL-CREKA was evaluated in MCF-7/ADR
tumor-bearing nude mice in vivo. The targeting effect of the CREKA-modified thermosensitive
liposomes on the clotted
plasma proteins was confirmed in our in vivo imaging and immunohistochemistry experiments. The burst release of this delivery system was observed in our in vitro temperature-triggered DOX release and flow cytometry analysis and also by confocal microscopy experiments. The antitumor activity of the DOX-LTSL-CREKA was confirmed in
tumor-bearing nude mice in vivo. Our findings suggest that the combination of targeting the clotted
plasma proteins in the
tumor vessel wall as well as
tumor stroma by using
CREKA peptide and temperature-triggered drug release from
liposomes by using thermosensitive
liposomes offers an attractive strategy for chemotherapeutic
drug delivery to
tumors.