Mitochondrial targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative for cancer treatment by inducing mitochondrial apoptosis pathways.
Mitochondria are ideal anti-tumor target due to mitochondria's central regulation role in cell apoptosis and tumor resistance to apoptosis. There are several challenges for mitochondrial targeting drug delivery, including complex multistep preparations, low drug- loading and systemic toxicity from the carriers. To address these issues, we firstly constructed mitochondria-targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative (BD) using simple nano-precipitation approach. BD-based nanodrugs were modified by DSPE-PEG2000 (distearylphosphatidylethanolamine- methoxypolyethylene glycol 2000) to increase stability. Negatively charged hyaluronic acid (HA) was further coated to conceal positive charges and achieve tumor targeting. PEG and HA dually modified BD NDs (HA/PEG/BD NDs) were prepared with surface charge of -25.8 mV and high drug loading >70%. The degradation of HA by hyaluronidase (HAase) at tumor tissue allowed the exposure of the positively charged PEG/BD NDs to the cells, which is beneficial for cell uptake and further lysosome escape and mitochondrial targeting. Then, HA/PEG/BD NDs were investigated to induce apoptosis through dissipating mitochondria membrane potential, releasing cytochrome C, increasing the activities of caspase 9/3, activating the pro-apoptotic Bax, suppressing the anti-apoptotic Bcl-2 and upregulating ROS levels. In the A549 xenografted tumor model, HA/PEG/BD NDs exhibited obvious tumor cell mitochondrial targeting and significant anti-tumor efficacy. Overall, comparing to conventional nanoparticles, mitochondrial targeting HA/PEG/BD NDs provide a new strategy for cancer treatment with enhanced drug-loading, relatively simplified preparation processes and reduced carrier toxicities.
['Song|Jia|J|', 'Lin|Chuchu|C|', 'Yang|Xuan|X|', 'Xie|Yanqi|Y|', 'Hu|Ping|P|', 'Li|Huatian|H|', 'Zhu|Wenbo|W|', 'Hu|Haiyan|H|']
D000072283:A549 Cells D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D001599:Berberine D045304:Cytochromes c D016503:Drug Delivery Systems D065546:Drug Liberation D005260:Female D006801:Humans D006820:Hyaluronic Acid D008175:Lung Neoplasms D053078:Membrane Potential, Mitochondrial D008807:Mice, Inbred BALB C D008819:Mice, Nude D008928:Mitochondria D053758:Nanoparticles D019253:Proto-Oncogene Proteins c-bcl-2 D017382:Reactive Oxygen Species
Mitochondrial targeting Berberine derivative Apoptosis pathway Antitumor therapy Self-assembled nanodrugs