Ultrasound-targeted photodynamic and gene dual therapy for effectively inhibiting triple negative breast cancer by cationic porphyrin lipid microbubbles loaded with HIF1α-siRNA.

Abstract

Triple-negative breast cancer (TNBC), which is a kind of aggressive breast cancer, has a much higher recurrence rate and a shorter overall survival rate than other breast cancer subtypes owing to its lack of expression of the progesterone receptor (PR), estrogen receptor (ER) and HER2. For improving the therapeutic efficacy of TNBC, we developed a new kind of multifunctional cationic porphyrin-grafted lipid (CPGL) microbubble loaded with HIF 1α siRNA (siHIF@CpMB). Owing to the amphiphilic structure of CPGL, it can be self-assembled into microbubbles (MBs) with conventional lipids and the porphyrin group could be used as a photosensitizer for photodynamic therapy (PDT), while the amino group could adsorb HIF 1α siRNA (siHIF) through electrostatic adsorption. Such MBs possess a remarkably high drug loading content and less premature drug release. Distribution of MBs could be easily monitored by real-time US imaging (3-12 MHz). Furthermore, with the assistance of ultrasound targeted microbubble destruction (UTMD), siHIF@CpMBs could be efficiently converted into nanoparticles in situ, facilitating the accumulation of porphyrin and siRNA at the tumor site through the cavitation effect. HIF 1α siRNA down-regulated the HIF 1α level, which was induced by the common hypoxic tumor environment or the ROS (generated by PDT), enhanced the PDT efficacy and partly inhibited the tumor progression. Therefore, UTMD assisted combination of PDT and gene therapy was believed to be an effective therapeutic strategy for TNBC.