Enhanced antitumor efficacies of multifunctional nanocomplexes through knocking down the barriers for siRNA delivery.

Multifunctional nanocomplexes (NCs) consisting of urocanic acid-modified galactosylated trimethyl chitosan (UA-GT) conjugates as polymeric vectors, poly(allylamine hydrochloride)-citraconic anhydride (PAH-Cit) as charge-reversible crosslinkers, and vascular endothelial growth factor (VEGF) siRNA as therapeutic genes, were rationally designed to simultaneously overcome the extracellular, cellular, and intracellular barriers for siRNA delivery. The strong physical stability of UA-GT/PAH-Cit/siRNA NCs (UA-GT NCs) at pH 7.4 and 6.5 endowed protection from massive dilution, competitive ions, and ubiquitous nucleases in the blood and tumorous microenvironment. Their internalization into hepato-carcinoma cells was facilitated through the recognition of galactose receptors, followed by effective escape from endosomes/lysosomes owing to the strong buffering capacity of imidazole residues. At the meantime, the endosomal/lysosomal acidity triggered the charge reversal of PAH-Cit in UA-GT NCs, thus evoking their structural disassembly and subsequently accelerated release of siRNA in the cytosol. As a result, robust in vivo performance in terms of both gene silencing and tumor inhibition was achieved by UA-GT NCs at a low siRNA dose. Moreover, neither histological nor hematological toxicity was detected following repeated intravenous administration. Therefore, UA-GT NCs potentially served as an efficient and safe candidate in the treatment of hepatocellular carcinoma through knocking down the overall barriers for siRNA delivery.

Substituted poly(methyl vinyl ether-alt-maleic anhydride) for the release control and targeting of methotrexate.

Poly(methyl vinyl ether-alt-maleic anhydride) substituted with cholamine (CA), aminoethylcholamine (AECA), or aminooctylcholamine (AOCA) at different substitution degrees, were used for methotrexate (MTX) complexation. The solid complexes, isolated by precipitation from the preparative mixture, showed lower fractional releases at pH 7.4 than at 5.5. This was ascribed to the establishment of ionic interactions between the ionized carboxyls of both the polymer and the drug and the quaternary ammonium groups of the substituents (CA, AECA, AOCA) inducing polymer self-aggregation and thus complex stabilization. The fractional release in pH 7.4 decreases with the increase in the substitution degree until a minimum characteristic for each substituent analyzed is reached and then rises with the increase in substitution degree. The minimum release at pH 7.4 was observed in the presence of AECA at the degree of substitution corresponding to 0.35 mole of substituent per mole of dimer (methyl vinyl ethermaleic anhydride). None of the substituted polymers studied had any haemolytic effect, indicating good biocompatibility.