Rational Design of Multifunctional Polymeric Micelles with Stimuli-Responsive for Imaging-Guided Combination Cancer Therapy

摘要

Multidrug resistance (MDR) of tumor cells is one of the major obstacles for the failure chemotherapy. Currently, there is still unmet demand for innovative strategies to overcome MDR as well as effective imaging-guided therapy. Here, we developed a novel multifunctional doxorubicin (Dox)/Elacridar (Ela) co-loaded FA/Cy7-PEG-PCL nanomicelles [ denoted as FA/Cy7-MCs(Dox/Ela)] to overcome MDR and imaging in breast cancer. The nanomicelles exhibited an average size of around 43 nm in diameter with well dispersed and a pH responsive drug release. The FA/Cy7-MCs(Dox/Ela) nanomicelles had also an evident effect on the inhibition of Ela-induced P-gp ATPase activity and exhibited good photostability. In vitro cell culture experiments, FA/Cy7-MCs(Dox/Ela), showed higher cellular uptake and more significant cytotoxicity effect against MCF-7/MDR cells than the free Dox due to FA-receptor mediated cell endocytosis and Ela mediated P-gp inhibition. The in vivo imaging study revealed FA/Cy7-MCs(Dox/Ela) nanomicelles exhibit longer retention time and higher fluorescence intensity in the tumor sites when compared to Cy7 alone. In vivo antitumor efficacy assay displayed in FA/Cy7-MCs(Dox/Ela) have significantly higher antitumor activity compared with free Dox at the same dosage in MCF-7/ADR tumor bearing nude mice. In vitro and in vivo toxicity results indicated that the nanomicelles were of low cytotoxicity and also harmless to normal organs in mice. These findings suggest that these FA/Cy7-MCs(Dox/Ela) nanomicelles have great potential for effective therapy of resistant cancers by combining with chemotherapeutic agent and P-gp ATPase activity inhibitor. It may also serve as a targeted cancer theranostic for real-time monitored in vivo dynamic distribution with high spatial resolution.