Codelivery of salinomycin and docetaxel using poly(D,L-lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles to target both gastric cancer cells and cancer stem cells

Abstract

Cancer stem cells (CSCs) in gastric cancer (GC) have been established recently as key therapeutic targets for the successful treatment of GC. Emerging evidence suggests that both CSCs and cancer cells should be eradicated to achieve optimal therapeutic efficacy. In the present study, salinomycin, which has been reported to kill CSCs, was used in combination with docetaxel, a chemotherapeutic drug that is used as first-line therapy in GC, to eradicate both GC stem cells (SCs) and cancer cells. Salinomycin and docetaxel were loaded separately into poly(D,L-lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles of ∼140 nm with a narrow size distribution, high drug loading, and sustained drug release. GC SCs were isolated by magnetic-activated cell sorting on the basis of CD44 expression as the CSC phenotype. CD44 GC SCs showed the characteristics of CSCs, including increased SC gene expression, tumorsphere formation capacity, and tumorigenicity in nude mice. We found that both salinomycin and salinomycin-loaded nanoparticles (salinomycin-NPs) could selectively eradicate GC SCs, as reflected by reduced tumorsphere formation capacity and the frequency of CD44 GC cells, whereas docetaxel and docetaxel-loaded nanoparticles (docetaxel-NPs) could significantly eradicate GC cells. In nude mice bearing GC xenografts, salinomycin-NPs and salinomycin significantly decreased the intratumor population of GC SCs. Notably, salinomycin-NPs combined with docetaxel-NPs suppressed tumor growth more effectively than did salinomycin combined with docetaxel, single salinomycin-NPs, or docetaxel-NPs. Therefore, salinomycin-NPs combined with docetaxel-NPs represent a promising strategy for the treatment of GC by eradicating both GC SCs and cancer cells.

Recent advances in drug delivery systems for targeting cancer stem cells

“…Therefore, several suitable delivery carriers and systems have been developed. Table 4 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 summarizes recent DDSs for targeting CSC genes and epigenetics.…”

Emerging agents that target signaling pathways in cancer stem cells

“…Notably, salinomycin can increase the production of lipid peroxidation by blocking iron transport and depleting ferritin, by which it can specifically kill CSCs [143]. Other studies indicate that a combination of salinomycin and docetaxel can effectively kill gastric CSCs [144]. Salinomycin can effectively destroy non-CSCs and CSCs, as well as cancer cells with a multi-drug resistance (MDR) phenotype; therefore, it shows strong antitumor activity against a variety of cancers [145].…”

Nanotechnology for Cancer Therapy Based on Chemotherapy

“…Salinomycin (SAL), a carboxylic acid polyether antibiotic, can eliminate cancer stem cells by activating p38 mitogen-activated protein kinase (p38 MAPK), aggregating reactive oxygen species and inhibiting the Wnt signaling pathway and the activity of P-glycoprotein [ 68 , 69 , 70 , 71 ]. Combined use of poly( d , l -lactic-coglycolic acid)-poly(ethylene glycol) nanoparticles of ~140 nm which were separately loaded SAL and chemotherapeutic drug docetaxel (DTX) eradicated both gastric cancer cells and cancer stem cells, suppressing the tumor growth more potently compared with single drug-loaded nanoparticles [ 72 ]. Similarly, staurosporine (STS) is a protein kinase inhibitor which eliminates CSCs effectively by inhibiting multiple related signal pathways [ 73 ].…”