MiR-375 and Doxorubicin Co-delivered by Liposomes for Combination Therapy of Hepatocellular Carcinoma

Abstract

Doxorubicin (DOX) is one of the most frequently used anti-cancer drugs and the front line option for hepatocellular carcinoma (HCC) treatment. However, the clinical applications of DOX are restricted largely due to its toxicity and chemoresistance. Here, we report that miR-375 and DOX were co-delivered by liposomes (named L-miR-375/DOX-NPs) for combination therapy of HCC and drug resistance reversion of DOX. In vitro, L-miR-375/DOX-NPs could deliver DOX and miR-375 efficiently and simultaneously into HCC cells and ensure the successful release of mature miR-375 and DOX. Then, the released miR-375 suppressed the malignant hallmarks of HCC by significantly decreasing the expression of AEG-1, YAP1, and ATG7, while the released DOX evidently accelerated cell apoptosis and blocked cycle at a G2/M stage by activating the P53/Bax/Bcl-2, caspase-3, and P-JNK, P-P38 pathway. Furthermore, miR-375 dramatically inhibited drug resistance of DOX by reducing the expression of multidrug resistance gene 1 (MDR1). In vivo, L-miR-375/DOX-NPs exhibited enhanced anti-tumor efficiency in xenograft HCC mouse models with mild adverse effects compared with doxorubicin or miR-375 alone. In conclusion, our research demonstrated that L-miR-375/DOX-NPs had significant synergetic anti-tumor effects and added values in overcoming drug resistance, which may represent a promising approach for the therapy of HCC.

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

“…Doxorubicin, an antibiotic anthracycline, is commonly considered to exert its anti-tumor activity at two fundamental levels, altering DNA and producing free radicals to trigger apoptosis of cancer cells through DNA damage. Doxorubicin-induced G2/M checkpoint arrest is attributed to elevated cyclin G2 (CycG2) expression and phospho-modification of proteins in the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) signaling pathways 42, 43, 44. In addition, compared with the controls of no treatment and siNC 50 nM, cells treated with siRRM2 (50 and 25 nM) displayed a remarkable and dose-dependent increase in S-phase populations; and the G2/M-phase population decreased significantly (Figures 4E and 4F).…”

Overcoming multidrug resistance through inhalable siRNA nanoparticles-decorated porous microparticles based on supercritical fluid technology

“…The results demonstrate that the codelivery of DOX and siRNA could obviously improve their therapeutic efficacy compared with that of DOX alone in the MDR cells due to the gene silencing effect of MRP1 siRNA in the cells and then increase their sensitivity to DOX. 64 PLLA and CS are generally considered as biocompatible substrates, which are predominantly utilized for the fabrication of drug delivery systems. However, the parameters or processing effects may sometimes result in the compatibility issues.…”

Biocompatible supramolecular pseudorotaxane hydrogels for controllable release of doxorubicin in ovarian cancer SKOV-3 cells

“…24,25 To reduce the toxic side effects and improve the curative effects of the chemotherapy drug doxorubicin and prevent drug resistance, researchers have made great efforts to change the dosage form of doxorubicin and increase its ability to target tumor tissues. 26,27 The introduction of doxorubicin into hydrogels has great potential in the eld of drug delivery.…”