Multifunctionalized polyethyleneimine-based nanocarriers for gene and chemotherapeutic drug combination therapy through one-step assembly strategy

Abstract

Gene therapy combined with chemotherapy to achieve synergistic therapeutic effects has been a hot topic in recent years. In this project, the human tumor necrosis factor-related apoptosis-inducing ligand-encoding plasmid gene ( TRAIL ) and doxorubicin (Dox)-coloaded multi-functional nanocarrier was constructed based on the theory of circulation, accumulation, internalization, and release. Briefly, polyethyleneimine (PEI) was selected as skeleton material to synthesize PEI–polyethylene glycol (PEG)–TAT (PPT). Dox was conjugated to PEI using C6-succinimidyl 6-hydrazinonicotinate acetone hydrazone (C6-SANH), and a pH-sensitive Dox-PEI (DP) conjugate was obtained. Then, intracellular cationic pH-sensitive cellular assistant PPT and DP were mixed to condense TRAIL , and TRAIL –Dox coloaded PPT/DP/ TRAIL (PDT) nanocarriers were obtained by one-step assembly. TRAIL was completely condensed by DP or PPT when mass ratios (DP/PPT to TRAIL ) were up to 100:64, which indicated that DP and PPT could be mixed at any ratio for TRAIL condensation. The intracellular uptake rate of PDT was enhanced ( P <0.05) when the contents of PPT in PPT+DP increased from 0 to 30%. Free Dox and TRAIL -loaded nanocarriers (PPT/C6-SANH-PEI/ TRAIL [PCT]) were selected as controls to verify the synergistic antitumor effects of PDT. Compared with free TRAIL , TRAIL-protein expression was upregulated by PDT and PCT on Western blotting assays. The in vitro cytotoxicity of PDT was significantly enhanced compared to free Dox and PCT ( P <0.01). Furthermore, murine PDT nanocarriers showed higher in vivo antitumor ability than both the Dox group ( P <0.05) and the murine PCT group ( P <0.05). These results indicated that the TRAIL + Dox synergistic antitumor effect could be achieved by PDT, which paves the way to gene–drug combination therapy for cancer.

Why the Orientational Mobility in Arginine and Lysine Spacers of Peptide Dendrimers Designed for Gene Delivery Is Different?

“…Gene delivery can be performed using viral [ 14 ] or non-viral [ 15 ] carriers. The first non-viral carriers were linear cationic homopolymers, block-copolymers [ 16 ] and liposomes [ 17 ] based on cationic lipids. Cationic polysaccharides [ 18 ] and cationic peptides [ 19 , 20 ] were also used for this purpose.…”

Quercetin and doxorubicin co-delivery using mesoporous silica nanoparticles enhance the efficacy of gastric carcinoma chemotherapy

“…36,37 As a result, DOX is often used together with other agents to further improve its anticancer performance as well as reduce the side effects. 38,39 Co-delivering systems have been widely explored by precious works, in which polymer-based DDS, such as HA, 40 polyethylene glycol, 4 chondroitin sulfate, 36 etc have shown great promise in overcoming the abovementioned dilemma. However, compared with previous works' focus on co-delivering QC and DOX, 41,42 persistent work is still required on the fabrication of a reliable and reproducible hybrid platform with decent drug-loading capability as well as tumor targetability to enhance the co-delivering efficacy in GC chemotherapy.…”

Polymer‐mediated gene therapy: Recent advances and merging of delivery techniques

“…The TAT‐targeted version of the PEI‐PEG complexes (PPT) and pH‐sensitive material (DP), when complexed with DOX—TRAIL (PDT), demonstrated synergistic antitumor effects in both HEPG2 and SKOV3 cells, as evaluated by an MTT cell viability assay with varying concentrations of Dox and TRAIL‐loaded PPT, PDT, and intermediate products for DP synthesis. This combination treatment also inhibited the growth of subcutaneous H22 hepatoma tumor xenografts in BALB/c mice following intravenous injection and without any significant effect on body weight as compared to controls (D. Jiang et al, ). Moreover, Feng and coworkers reported codelivery of DOX and the therapeutic gene encoding human tumor necrosis factor‐related apoptosis‐inducing ligand (pORF‐hTRAIL) via the redox‐sensitive disulfide‐bridged poly(ethylene glycol‐co‐ethyleneimine‐co‐caprolactone)‐SS‐poly(caprolactone‐co‐ethyleneimine‐co‐ethylene glycol) (PEG‐PEI‐PCL‐SS‐PCL‐PEG) polymer (Figure c; L. Feng et al, ).…”