Reversing hypoxia-mediated multidrug resistance (MDR) presents a unique challenge in clinical chemotherapy. Here, a sequential dual delivery system composited with Cyclooxygenase-2 siRNA (siCOX-2) in poly-d-arginine (9R)/2-deoxyglucose (DG)-loaded gold nanostar (GNS) (siCOX-2@RDG) and paclitaxel (PTX)-loaded thermosensitive liposome (PTSL) was proposed to conquer the hypoxia-mediated MDR in tumors. As a result, the prepared siCOX-2@RDG exhibited a starlike morphology with a uniform particle size of 194.36 ± 1.44 nm and a ζ-potential of −11.83 ± 2.01 mV. In vitro, PTSL displayed expected thermal-responsive release properties. As expected, siCOX-2@RDG displayed exceptional DG-mediated hypoxia-targeting capability both in vitro and in vivo and downregulated the expression of COX-2 successfully. Meanwhile, GNS-triggered hyperthermia elevated the cellular uptake of PTSL in PTX-resistant HepG2(HepG2/PTX) cells in vitro and enhanced the permeability of tumor tissues, thus elevating the valid retention of PTX into solid tumors. Finally, we demonstrated that the sequential dual systems composed of siCOX-2@RDG and PTSL could reverse hypoxia-mediated MDR and exhibit excellent synergistic antitumor effects both in vitro and in vivo, prolonging the survival of tumor-bearing mice. The devised sequential dual systems, composed of two independent nanosystems, have a promising potential to overcome hypoxia-mediated MDR in clinical practice.
In this study, we prepared gold nanostar (GNS) composite nanoparticles containing siRNA of cyclooxygenase-2(siCOX-2) that were modified by tumor targeting ligand 2-deoxyglucose (DG) and transmembrane peptide 9-poly-D-arginine (9R) to form siCOX-2(9R/DG-GNS). Paclitaxel loaded temperature sensitive liposomes (PTX-TSL) were surface-modified to produce PTX-TSL-siCOX-2(9R/DG-GNS) displaying homogeneous star-shaped structures of suitable size (293.93 nm ± 3.21) and zeta potentials (2.47 mV ± 0.22). PTX-TSL-siCOX-2(9R/DG-GNS) had a high thermal conversion efficiency under 808 nm laser radiation and a superior transfection efficiency, which may be related to the targeting effects of DG and increased heat induced membrane permeability. COX-2 expression in HepG2/PTX cells was significantly suppressed by PTX-TSL-siCOX-2(9R/DG-GNS) in high temperatures. The co-delivery system inhibited drug-resistant cell growth rates by ≥77% and increased the cell apoptosis rate about 47% at elevated temperatures. PTX-TSL and siCOX-2 loaded gold nanostar particles, therefore, show promise for overcoming tumor resistance.Keywords:gold nanostars;temperature sensitive liposome;siCOX-2;paclitaxel-resistance;hepatic carcinoma
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