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 《-》

Biodegradable nanoparticles based on linoleic acid and poly(beta-malic acid) double grafted chitosan derivatives as carriers of anticancer drugs.

Zhao Z ，He M ，Yin L ，Bao J ，Shi L ，Wang B ，Tang C ，Yin C ... -  《-》

Effects of poly(ethylene glycol) grafting density on the tumor targeting efficacy of nanoparticles with ligand modification.

Zhang S ，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 《-》

Effects of hydrophobic and hydrophilic modifications on gene delivery of amphiphilic chitosan based nanocarriers.

The structure-activity relationships between hydrophobic and hydrophilic modification on chitosan and resultant physicochemical properties along with performances in dealing with critical gene delivery barriers were investigated through amphiphilic linoleic acid(LA) and poly (β-malic acid) (PMLA) double grafted chitosan (LMC)/plasmid DNA (pDNA) nanocomplexes. LMC polymers with various LA and PMLA substitution degrees were synthesized and their hydrophilicity/hydrophobicity was characterized. Compared to chitosan, LMC nanoparticles retained the pDNA binding ability at pH 5.5 when they formed nanocomplexes with pDNA encoding enhanced green fluorescence protein (pEGFP) and the resultant complexes showed diameters below 300 nm. Hydrophobic LA and hydrophilic PMLA substitution contributed to suppressed non-specific adsorption, reduced interactions inside LMC/pDNA nanocomplexes, and enhanced pDNA dissociation. However, enzymatic degradation resistance, cell adsorption, and cellular uptake through clathrin-mediated pathway were promoted by hydrophobic LA grafting while being inhibited by hydrophilic PMLA substitution. In vitro transfection assay suggested the optimal LMC/pEGFP nanocomplexes mediated an 8.0-fold improved transfection compared to chitosan/pEGFP nanocomplexes. The 4.2-fold and 2.2-fold higher intramuscular gene expression in mice compared to chitosan/pEGFP and polyethyleneimine (PEI)/pEGFP nanocomplexes further demonstrated the superiority of LMC/pDNA nanocomplexes. Therefore, amphiphilic chitosan derivates with appropriate combination of hydrophobic and hydrophilic modification would be promising gene delivery nanocarriers.

Wang B ，He C ，Tang C ，Yin C ... -  《-》