Co-delivery of doxorubicin and CRISPR/Cas9 or RNAi-expressing plasmid by chitosan-based nanoparticle for cancer therapy.

Folic acid (FA) and 2-(Diisopropylamino) ethyl methacrylate (DPA) double grafted trimethyl chitosan (TMC) nanoparticles (FTD NPs) were synthesized for the co-delivery of doxorubicin (DOX) and Survivin CRISPR/Cas9-expressing plasmid (sgSurvivin pDNA) or Survivin shRNA-expressing plasmid (iSur pDNA). FA modification enhanced the uptake of DOX and pDNA loaded into FTD NPs in tumor cells. A rapid release of DOX was triggered under acidic conditions due to pH-sensitiveness of FTD NPs arising from DPA conjugation. Negligible differences between FTD/sgSurvivin pDNA NPs and FTD/iSur pDNA NPs demonstrated that RNA interference (RNAi) and CRISPR/Cas9 technologies possessed comparable antitumor efficiency. Notably, the in vitro and in vivo antitumor efficacies of FTD/DOX/sgSurvivin pDNA NPs were superior to those of single delivery of DOX or sgSurvivin pDNA, while were comparable to those of FTD/DOX/iSur pDNA NPs. These results suggested that the combination of chemotherapeutics and CRISPR/Cas9 systems would provide a potential modality for cancer therapy.

Li Q ，Lv X ，Tang C ，Yin C ... -  《-》

Enhanced antitumor efficacy of arginine modified amphiphilic nanoparticles co-delivering doxorubicin and iSur-pDNA via the multiple synergistic effect.

Arginine and α-tocopherol succinate (α-TOS) double grafted N-trimethyl chitosan chloride (TMC) nanoparticles (TAS NPs) were designed and developed for effective co-delivery of doxorubicin (DOX) and Survivin shRNA-expressing pDNA (iSur-pDNA). With DOX loading into the hydrophobic core and iSur-pDNA combining to the hydrophilic shell, TAS/DOX/pDNA NPs demonstrated favorable structural stability and sustained release properties in vitro. With the special non-clathrin-dependent endocytosis, TAS/DOX/pDNA NPs presented higher cellular uptake and mainly distributed in ER and Golgi rather than lysosomes following internalization. The in vitro nuclear localization, gene silencing efficiency, cell apoptosis, and growth inhibition of tumor cells were significantly promoted by arginine modification. In the tumor-bearing mice model, TAS/DOX/pDNA NPs possessed the maximum antitumor efficiency as compared with single delivery of DOX or iSur-pDNA. Particularly, blank TAS NPs were selectively be toxic to tumor cells as evidenced by their capabilities to inhibit proliferation and induce apoptosis of tumor cells. The promising tumor treatment of TAS/DOX/pDNA NPs via a multiple synergistic manner arising from DOX and pDNA as well as the vectors would provide a potential strategy for a dual-delivery system to improve their therapeutic efficacies.

Song Y ，Tang C ，Yin C 《-》

Enhanced antitumor efficacy of glutathione-responsive chitosan based nanoparticles through co-delivery of chemotherapeutics, genes, and immune agents.

To achieve the co-delivery of chemotherapeutic drugs, genes, and immune agents in a single nanoparticulate system, p-mercaptobenzoic acid-grafted N, N, N-trimethyl chitosan nanoparticles (MT NPs) were successfully synthesized. Paclitaxel (PTX) was encapsulated into the hydrophobic core of the MT NPs, and meanwhile, survivin shRNA-expressing plasmid (iSur-pDNA) and recombinant human interleukin-2 (rhIL-2) were loaded onto the hydrophilic shell of the MT NPs. Owing to the redox-sensitiveness of MT NPs, a rapid release of PTX was triggered by the high concentration of glutathione. The synergistic effects of PTX (1.5 mg/kg), iSur-pDNA (1.875 mg/kg), and rhIL-2 (6 × 105 IU/kg) at a low dose endowed the MT/PTX/pDNA/rhIL-2 NPs with enhanced antitumor efficacies and improved tumor-induced immunosuppression. These results demonstrated that the co-delivery of PTX, iSur-pDNA, and rhIL-2 by the amphiphilic chitosan based NPs with redox-sensitiveness could be a promising strategy in the treatment of tumors.

Zhang L ，Li Q ，Chen J ，Tang C ，Yin C ... -  《-》

Co-Delivery of Doxorubicin and Survivin shRNA-Expressing Plasmid Via Microenvironment-Responsive Dendritic Mesoporous Silica Nanoparticles for Synergistic Cancer Therapy.

Li Z ，Zhang L ，Tang C ，Yin C ... -  《-》

Enhanced antitumor efficacy of folate modified amphiphilic nanoparticles through co-delivery of chemotherapeutic drugs and genes.

Folate (FA) modified amphiphilic linoleic acid (LA) and poly (β-malic acid) (PMLA) double grafted chitosan (LMC) nanoparticles (NPs) with optimum grafting degrees of hydrophobic LA and hydrophilic PMLA were developed for the co-delivery of paclitaxel (PTX) and survivin shRNA-expressing plasmid (iSur-pDNA). The resultant NPs exhibited particle size of 161 nm and zeta potential of 43 mV. FA modification and the increasing grafting degrees of LA and PMLA were correlated with the suppressed protein adsorption, the inhibited release of PTX, and the accelerated dissociation of pDNA. PTX loading, cellular uptake, nuclear accumulation of pDNA, in vitro gene silencing efficiency, and cell growth inhibition were promoted by FA modification and higher grafting degree of LA, but impeded by increasing grafting degree of PMLA. In tumor-bearing mice, co-delivery of PTX and iSur-pDNA exhibited enhanced antitumor efficacy and prolonged survival period as compared with single delivery of PTX or iSur-pDNA. These results indicated that amphiphilic LMC NPs could serve as a promising platform for the co-delivery of antitumor drugs and genes, and highlighted the importance of adjusting the hydrophobic and hydrophilic grafting degrees.

Yu B ，Tang C ，Yin C 《-》