Abstract
One of the major obstacles to successful chemotherapy is multi-drug resistance (MDR). A multi-drug resistant cancerous cell abnormally overexpresses membrane transporters that pump anticancer drugs out of the cell, resulting in low anticancer drug delivery efficiency. To overcome the limitation, many attempts have been performed to inhibit the abilities of efflux receptors chemically or genetically or to increase the delivery efficiency of anticancer drugs. However, the results have not yet been satisfactory. In this study, we developed nanoparticle-microbubble complexes (DOX-NPs/Ce6-MBs) by conjugating doxorubicin loaded human serum albumin nanoparticles (DOX-NPs) onto the surface of Chlorin e6 encapsulated microbubbles (Ce6-MBs) in order to maximize anticancer efficiency by overcoming MDR. Under the ultrasound irradiation, DOX-NPs and Ce6 encapsulating self-assembled liposomes or micelles were effectively delivered into the cells due to the sonoporation effect caused by the microbubble cavitation. At the same time, reactive oxygen (ROS) generated from intracellularly delivered Ce6 by laser irradiation arrested the activity of ABCG2 efflux receptor overexpressed in doxorubicin-resistant breast cancer cells (MCF-7/ADR), resulting in increased the chemotherapy efficacy. In addition, the total number of side population cells that exhibit the properties of cancer stem-like cells were also reduced by the combination of photodynamic therapy and chemotherapy. In conclusion, DOX-NPs/Ce6-MBs will provide a platform for simultaneously overcoming MDR and increasing drug delivery and therefore, treatment efficiency, under ultrasound irradiation.
Highlights
Multi-drug resistance (MDR), which is the phenomenon of showing resistance to anticancer drugs, is one of the major barriers in chemotherapy [1]
Our results showed that the doxorubicin loaded human serum albumin nanoparticles (DOX-NPs)/Chlorin e6 encapsulated microbubbles (Ce6-MBs) complex system using Photodynamic therapy (PDT) and US has a high potential as a novel carrier for MDR cells by overcoming limited drug delivery efficiency due to overexpressed efflux pump receptors
3.1 Characteristics of DOX‐NPs/Ce6‐MBs complexes The DOX-NPs/Ce6-MBs complex was developed by conjugating doxorubicin-encapsulating human serum albumin nanoparticles (DOX-NPs) onto the surface of Chlorin e6-encapsulating microbubbles (Ce6-MBs)
Summary
Multi-drug resistance (MDR), which is the phenomenon of showing resistance to anticancer drugs, is one of the major barriers in chemotherapy [1]. Many studies have been reported to overcome these multi-drug resistances. The inhibitors were toxic, and they inhibited the intracellular influx of co-delivered anticancer drugs [7, 8]. Another reported study to overcome multi-drug resistance was to deliver large amounts of chemotherapeutic agents with nanomedicines intracellularly beyond the efflux capacity of cancer cells [9]. The delivery efficiency of nanoparticles is still lower than expected, because the endocytosis of nanoparticles leads to endosomal entrapment or lysosomal degradation, and because the MDR efflux receptor pumps intracellularly delivered drugs out of the cells [11]. A new strategy to overcome the limitations of chemotherapy due to the overexpression of efflux receptors is required
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