Guanidinoamidized Linear Polyethyleneimine for Gene Delivery

Guanidine was introduced to low molecular weight linear polyethyleneimine （LPEI） via amide groups, to explore the effect of both guanidine degree and pendant chain length on its transfection behavior. The resulting guanidinoamidized LPEIs （GLPEIs） could dramatically reduce LPEI＇s toxicity, enhance its DNA-packaging capability, cellular uptake and therefore transfection efficiency. These polyplexes were taken up very efficiently via caveolae-mediated endocytosis and their transfection efficiencies in ovarian cancer cells were significantly improved compared to native LPEIlok polyplexes. Among these GLPEIs, LPEI-C3-G100 showed higher DNA affinity even than LPEI25k and the highest transfection efficiency, probably due to the optimization of polymer chain flexibility. Of notice, LPEI-C3-G100 polyplexes could more effectively accumulate into cytoplasm than LPEI25k, although the transfection efficiency of LPEI-C3-G100 polyplexes was not superior to that of LPEI25k polyplexes, which would be probably attributed to the more efficient release of LPEI25k polyplexes than LPEI-C3-G100 polyplexes in the cytoplasm.

Parthenolide inhibits proliferation of vascular smooth muscle cells through induction of G_0/G_1 phase cell cycle arrest

Objective： This study is to determine the effect of the natural product parthenolide, a sesquiterpene lactone isolated from extracts of the herb Tanacetum parthenium, on the proliferation of vascular smooth muscle cells （VSMCs）. Methods： Rat aortic VSMCs were isolated and cultured in vitro, and treated with different concentrations ofparthenolide （l 0, 20 and 30 μmol/L）. [^3H]thymidine incorporation was used as an index of cell proliferation. Cell cycle progression and distribution were determined by flow cytometric analysis. Furthermore, the expression of several regulatory proteins relevant to VSMC proliferation including IκBα, cyclooxygenase-2 （Cox-2）, p21, and p27 was examined to investigate the potential molecular mechanism. Results： Treatment with parthenolide significantly decreased the [^3H]thymidine incorporation into DNA by 30%-56% relative to control values in a dose-dependent manner （P〈0.05）. Addition of parthenolide also increased cell population at G0/G1 phase by 19.2%-65.7% （P〈0.05） and decreased cell population at S phase by 50.7%-84.8% （P〈0.05）, which is consistent with its stimulatory effects on p21 and p27. In addition, parthenolide also increased IκBα expression and reduced Cox-2 expression in a time-dependent manner. Conclusion： Our results show that parthenolide significantly inhibits the VSMC proliferation by inducing G0/G1 cell cycle arrest. IκBα and Cox-2 are likely involved in such inhibitory effect ofparthenolide on VSMC proliferation. These findings warrant further investigation on potential therapeutic implications ofparthenolide on VSMC proliferation in vivo.