Abstract
Ursolic acid (UA) has proved to have broad-spectrum anti-tumor effects, but its poor water solubility and incompetent targeting property largely limit its clinical application and efficiency. Here, we synthesized a nanoparticle-based drug carrier composed of chitosan, UA and folate (FA-CS-UA-NPs) and demonstrated that FA-CS-UA-NPs could effectively diminish off-target effects and increase local drug concentrations of UA. Using MCF-7 cells as in vitro model for anti-cancer mechanistic studies, we found that FA-CS-UA-NPs could be easily internalized by cancer cells through a folate receptor-mediated endocytic pathway. FA-CS-UA-NPs entered into lysosome, destructed the permeability of lysosomal membrane, and then got released from lysosomes. Subsequently, FA-CS-UA-NPs localized into mitochondria but not nuclei. The prolonged retention of FA-CS-UA-NPs in mitochondria induced overproduction of ROS and destruction of mitochondrial membrane potential, and resulted in the irreversible apoptosis in cancer cells. In vivo experiments showed that FA-CS-UA-NPs could significantly reduce breast cancer burden in MCF-7 xenograft mouse model. These results suggested that FA-CS-UA-NPs could further be explored as an anti-cancer drug candidate and that our approach might provide a platform to develop novel anti-cancer drug delivery system.
Highlights
Cancer remains one of the most devastating diseases threatening public health, causing high mortality worldwide every year
We demonstrated that FA-CS-Ursolic acid (UA)-NPs internalized into cancer cells via folate receptor-mediated pathway and induced apoptosis in MCF-7 cells through a mitochondria-dependent pathway
We develop a kind of novel FA-CS-UA-NPs to increase UA solubility, selectively target cancer cells and achieve better therapeutic efficacy against breast cancers in both in vitro and in vivo models
Summary
Anti-Breast Cancer Activities received: 26 March 2015 accepted: 08 July 2016 Published: 29 July 2016 in vitro and in vivo. In vivo experiments showed that FA-CS-UA-NPs could significantly reduce breast cancer burden in MCF-7 xenograft mouse model These results suggested that FA-CS-UANPs could further be explored as an anti-cancer drug candidate and that our approach might provide a platform to develop novel anti-cancer drug delivery system. Inorganic nanoparticles have been explored as drug carriers for new anti-cancer treatments, as nanoparticles can be synthesized to have regular shapes, size, surface chemical and physical properties for better targeting of cancer cells[3,4]. We formulated CS, folate(FA), and UA to develop biodegradable nanoparticles (FA-CS-UA-NPs), in which folate molecules were enriched on surface while UAs were encapsulated Such potentially useful FA-CS-UA-NPs could bind and target folate receptor expressed on cancer cells for delivering UA in the UA-loaded nanoparticles into cells. Our approach could provide a platform to design/develop anti-cancer nano-delivery system especially for drugs with poor water solubility
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