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Mitochondrial targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative for cancer treatment by inducing mitochondrial apoptosis pathways

Song, Jia ; Lin, Chuchu ; Yang, Xuan ; Xie, Yanqi ; Hu, Ping ; Li, Huatian ; Zhu, Wenbo ; Hu, Haiyan

Journal of controlled release, 2019-01, Vol.294, p.27-42 [Periódico revisado por pares]

Netherlands: Elsevier B.V

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Título:
Mitochondrial targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative for cancer treatment by inducing mitochondrial apoptosis pathways
Autor: Song, Jia ; Lin, Chuchu ; Yang, Xuan ; Xie, Yanqi ; Hu, Ping ; Li, Huatian ; Zhu, Wenbo ; Hu, Haiyan
Assuntos: A549 Cells ; Animals ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - chemistry ; Antitumor therapy ; Apoptosis - drug effects ; Apoptosis pathway ; Berberine - administration & dosage ; Berberine - analogs & derivatives ; Berberine - chemistry ; Berberine derivative ; Cytochromes c - metabolism ; Drug Delivery Systems ; Drug Liberation ; Female ; Humans ; Hyaluronic Acid - administration & dosage ; Hyaluronic Acid - chemistry ; Lung Neoplasms - drug therapy ; Lung Neoplasms - pathology ; Membrane Potential, Mitochondrial - drug effects ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria - drug effects ; Mitochondria - physiology ; Mitochondrial targeting ; Nanoparticles - administration & dosage ; Nanoparticles - chemistry ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Reactive Oxygen Species - metabolism ; Self-assembled nanodrugs
É parte de: Journal of controlled release, 2019-01, Vol.294, p.27-42
Descrição: 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. [Display omitted] •9-O-octadecyl berberine in nanodrugs was used as both drug and mitochondrial targeting ligand.•Nanodrugs characterized high drug loading (>70%) and mitochondira targeting via mitochondria apoptosis pathway.•Nanodrugs demonstrated significant anti-tumor efficacy in vivo and in vitro.
Editor: Netherlands: Elsevier B.V
Idioma: Inglês

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Mitochondrial targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative for cancer treatment by inducing mitochondrial apoptosis pathways

Song, Jia ; Lin, Chuchu ; Yang, Xuan ; Xie, Yanqi ; Hu, Ping ; Li, Huatian ; Zhu, Wenbo ; Hu, Haiyan

Netherlands: Elsevier B.V

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