Study on co-delivery of pemetrexed disodium and Bcl-2 siRNA by poly-γ-glutamic acid-modified cationic liposomes for the inhibition of NSCLC.

Due to the complexity of the pathophysiology of non-small cell lung cancer (NSCLC) and the susceptibility of single chemotherapy to drug resistance, the combination of drugs and small interfering RNA (siRNA) may produce a desired therapeutic effect on NSCLC through the action of multiple pathways. We designed to develop poly-γ-glutamic acid-modified cationic liposomes (γ-PGA-CL) to co-deliver pemetrexed disodium (PMX) and siRNA to treat NSCLC. Firstly, γ-PGA was modified on the surface of PMX and siRNA co-loaded cationic liposomes by electrostatic interaction (γ-PGA modified PMX/siRNA-CL). In order to evaluate whether the prepared γ-PGA modified PMX/siRNA-CL could be taken up by tumor cells and exert significant anti-tumor effects, in vitro and in vivo studies were performed, with A549 cells and LLC-bearing BABL/c mice as experimental models, respectively. The particle size and zeta potential of γ-PGA modified PMX/siRNA-CL was (222.07 ± 1.23) nm and (-11.38 ± 1.44) mV. A preliminary stability experiment showed the complex could protect siRNA from degradation. In vitro cell uptake experiment indicated the complex group exerted stronger fluorescence intensity and expressed higher flow detection value. Cytotoxicity study showed the cell survival rate of γ-PGA-CL was (74.68 ± 0.94)%. Polymerase chain reaction (PCR) analysis and western blot technology displayed that the complex could inhibit the expression of Bcl-2 mRNA and protein to promote cell apoptosis. In vivo anti-tumor experiments represented the complex group showed a significant inhibitory effect on tumor growth, while the vector showed no obvious toxicity. Therefore, the current studies proved the feasibility of combining PMX and siRNA by γ-PGA-CL as a potential strategy for the treatment of NSCLC.

Intra-articular Injection of Lornoxicam and MicroRNA-140 Co-loaded Cationic Liposomes Enhanced the Therapeutic Treatment of Experimental Osteoarthritis.

Osteoarthritis is a chronic joint disease characterized by chronic inflammation, progressive destruction of articular cartilage, and subchondral bone sclerosis. When compared to individual treatment, the combined administration of genes and small-molecule drugs for osteoarthritis may not only provide superior inflammation control and pain relief, but may also repair cartilage damage. Here, cationic liposomes (CL) were used to deliver small hydrophobic drugs and microRNA into chondrocytes to treat osteoarthritis. Lornoxicam cationic liposomes (Lnxc-CL) were prepared by film dispersion, and loaded with microRNA-140 (miR-140) by electrostatic interaction to obtain cationic liposomes co-loaded with lornoxicam and miR-140 (Lnxc-CL/miR-140). The prepared Lnxc-CL/miR-140 had a particle size of 286.6 ± 7.3 nm, polydispersity index (PDI) of 0.261 ± 0.029 and zeta potential of 26.5 ± 0.5 mV and protected miR-140 from RNase degradation for 24 h. Lnxc-CL/miR-140 was evaluated for its ability to regulate gene expression in chondrocytes in vitro and to provide in vivo therapeutic effects for knee osteoarthritis in rats. The results of in vitro uptake experiments and polymerase chain reaction (PCR) analysis showed that Lnxc-CL/miR-140 efficiently delivered miR-140 into chondrocytes and up-regulated the expression of miR-140 and COL2A1 mRNA. Pharmacodynamics studies demonstrated that Lnxc-CL/miR-140 effectively treated osteoarthritis by eliminating joint inflammation and repairing damaged cartilage cells, with superior therapeutic effects compared to Lnxc or miR-140 alone. Overall, the findings of this study support the co-delivery of Lnxc and miR-140 with cationic liposomes as a potential new therapeutic strategy for the treatment of osteoarthritis.

Preparation and Evaluation of Stearylamine-Bearing Pemetrexed Disodium-Loaded Cationic Liposomes In Vitro and In Vivo.

Pemetrexed disodium (PMX) stands out in the treatment of non-small cell lung cancer (NSCLC), but with short half-life and toxic side effects. This study was to design cationic liposomes for targeting delivery PMX to the lungs. The PMX cationic liposome was prepared by thin-film hydration using stearylamine (SA) as the positive component of charge-regulating charge. Then, the PMX cationic liposome (SA-PMX-Lips) was characterized by particle size, morphology, entrapment efficiency (EE), and drug loading (DL). Finally, the drug release behavior in vitro, the pharmacokinetic study, and tissue distribution of SA-PMX-Lips were evaluated separately, with PMX solution (PMX-Sol) and PMX liposome (PMX-Lips) as the control. According to results, SA-PMX-Lips were spherical and the particle size was 219.7 ± 4.97 nm with a narrow polydispersity index (PDI) (0.231 ± 0.024) and a positive zeta potential 22.2 ± 0.52 mV. Its EE was 92.39 ± 1.94% and DL was 9.15 ± 0.07%. The results of in vitro and in vivo experiments showed that SA-PMX-Lips released slowly, prolonged retention time and increased the value of AUC. More notably, SA-PMX-Lips could improve the accumulation of drugs in the lungs and the relative uptake rate (Re) was 2.35 in the lungs, which indicated its lung targeting. In summary, SA-PMX-Lips showed the potential for the effective delivery of PMX and the treatment of NSCLC.