Antitumor effect of BPR-DC-2, a novel synthetic cyclic cyanoguanidine derivative, involving the inhibition of MDR-1 expression and down-regulation of p-AKT and PARP-1 in lung cancer.

In our previous study, a series of novel cyclic cyanoguanidine compounds, eg. 5-substituted 2-cyanoimino-4-imidazodinone and 2-cyanoimino-4- pyrimidinone derivatives have been successfully synthesized and showed remarkable cytotoxicity in several cancer cell lines. In this present study, it is our aim to screen more potential candidates among the cyclic pyridyl cyanoguanidine compounds (BPR-DC-1, 2, 3) by in vitro and in vivo studies for the therapy of lung cancer, alternatively. Our results showed that BPR-DC-2 significantly inhibited proliferation of tumor cells with an IC50 of 3.60 ± 1.27 and 14.81 ± 4.23 µM in human lung carcinoma cells, H69 and A549, respectively by the MTT assay at 48 hr; BPR-DC-2 also obviously suppressed the tumor proliferation and MDR-1 gene expression, even induced cell apoptosis in the ex vivo histocultured lung tumor. We further demonstrated that, in the nude mouse model of metastatic lung cancer, BPR-DC-2 could diminish the tumor mass, retard the progression of metastasis, and prolong the survival time. In addition, it was found that BPR-DC-2 exerted its anti-tumor effects through the inhibition of MDR-1 gene expression and down-regulation of tumor anti-apoptosis signals (activated p-AKT and over-expression of PARP-1) by western blotting analysis. In conclusion, in this present study we have demonstrated that BPR-DC-2, derived from a series of novel synthetic cyclic cyanoguanidine compounds, has proved its potential as an anti-tumor drug candidate in treating lung cancer.

Oral delivery of peptide drugs using nanoparticles self-assembled by poly(gamma-glutamic acid) and a chitosan derivative functionalized by trimethylation.

In the study, chitosan (CS) was conjugated with trimethyl groups for the synthesis of N-trimethyl chitosan (TMC) polymers with different degrees of quaternization. Nanoparticles (NPs) self-assembled by the synthesized TMC and poly(gamma-glutamic acid) (gamma-PGA, TMC/gamma-PGA NPs) were prepared for oral delivery of insulin. The loading efficiency and loading content of insulin in TMC/gamma-PGA NPs were 73.8 +/- 2.9% and 23.5 +/- 2.1%, respectively. TMC/gamma-PGA NPs had superior stability in a broader pH range to CS/gamma-PGA NPs; the in vitro release profiles of insulin from both test NPs were significantly affected by their stability at distinct pH environments. At pH 7.0, CS/gamma-PGA NPs became disintegrated, resulting in a rapid release of insulin, which failed to provide an adequate retention of loaded insulin, while the cumulative amount of insulin released from TMC/gamma-PGA NPs was significantly reduced. At pH 7.4, TMC/gamma-PGA NPs were significantly swelled and a sustained release profile of insulin was observed. Confocal microscopy confirmed that TMC40/gamma-PGA NPs opened the tight junctions of Caco-2 cells to allow the transport of insulin along the paracellular pathway. Transepithelial-electrical-resistance measurements and transport studies implied that CS/gamma-PGA NPs can be effective as an insulin carrier only in a limited area of the intestinal lumen where the pH values are close to the p K a of CS. In contrast, TMC40/gamma-PGA NPs may be a suitable carrier for transmucosal delivery of insulin within the entire intestinal tract.

Synthesis of a novel glycoconjugated chitosan and preparation of its derived nanoparticles for targeting HepG2 cells.

In the study, a novel chitosan (CS) derivative conjugated with multiple galactose residues in an antennary fashion (Gal-m-CS) was synthesized. A galactosylated CS (Gal-CS) was also prepared by directly coupling lactobionic acid on CS. Using an iontropic gelation method, CS and the synthesized Gal-CS and Gal-m-CS were used to prepare nanoparticles (CS, Gal-CS, and Gal-m-CS NPs) for targeting hepatoma cells. TEM examinations showed that the morphology of all three types of NPs was spherical in shape. No aggregation or precipitation of NPs in an aqueous environment was observed during storage for all studied groups, as a result of the electrostatic repulsion between the positively charged NPs. Little fluorescence was observed in HepG2 cells after incubation with the FITC-labeled CS NPs. The intensity of fluorescence observed in HepG2 cells incubated with the Gal-m-CS NPs was stronger than that incubated with the Gal-CS NPs. These results indicated that the prepared Gal-m-CS NPs had the highest specific interaction with HepG2 cells among all studied groups, via the ligand-receptor-mediated recognition.