In Nintedanib manufacturer vitro cellular uptake and RNAi experiments showed that the cross-linked dendritic systems with an appropriate level of GalNAc composition effectively interacted with HepG2 cells and inhibited the expression of a luciferase reporter gene [32].Recently, Tang et al. studied the siRNA delivery activities of MPEG-5000 modified G5/G6 PAMAM dendrimer in vitro and in vivo. The delivery of GFP-siRNA using PEG-modified dendrimers achieved knockdown of adenovirus-mediated GFP expression in both transiently adenovirus infected C57BL/6 mice and GFP transgenic mice [33]. Han et al. employed polysaccharide hyaluronic acid (HA) functionalized G5 PAMAM dendrimers as vectors for transporting doxorubicin (DOX) and major vault protein (MVP) targeted siRNA.

As a result of MVP expression knockdown, the codelivery system allowed efficient DOX access to the nucleus and exhibited much more cytotoxicity than siRNA absent case [34].2.3. PAMAM Dendrimers with New-Core IncorporationBesides the surface modification on traditional (e.g., EDA-core or NH3-core) PAMAM dendrimer, optimization of the molecular structure from the starting synthesis provides an alternative strategy to improve the performance of PAMAM dendrimers. In 2005, Wu et al. developed a series of PAMAM dendrimers with a triethanolamine (TEA) core (Figure 3(c)) [100]. These TEA-core PAMAM dendrimers were shown to interact with siRNA, forming stable nanoparticles to protect siRNA from degradation by RNase and to favor the cellular uptake process [35].

The potential of these flexible dendrimers as vectors for siRNA delivery were demonstrated, both in a luciferase model [36] and in a prostate cancer model [37]. The knockdown of heat-shock protein 27 (Hsp27) and the caspase-dependent apoptosis-induced anticancer activity were observed with higher generation dendrimers [37]. These dendrimers also efficiently delivered siRNA into human T cells and primary peripheral blood mononuclear cells (PBMC) cells and displayed an effective gene silencing effect [38]. By using sticky siRNA molecules bearing complementary An/Tn 3��-overhangs, G5 TEA-core PAMAM dendrimer was shown to effectively deliver siRNA to a prostate cancer model and achieve gene silencing of Hsp27 and anticancer activity in vitro and in vivo [39]. Recently, Peng’s group synthesized an amphiphilic dendrimer molecule bearing a hydrophobic alkyl chain and a hydrophilic PAMAM dendron with eight terminal primary amines.

This molecule combined the advantages of lipid and dendrimer vectors and was shown to deliver Hsp27 siRNA in a castration-resistant prostate cancer model and produce gene silencing and anticancer activity [40].In 2011 Deng et al. promoted a dendritic structure consisting of a ��-cyclodextrin core and PAMAM dendron arms. These dendrimers exhibited high siRNA transfection AV-951 efficiency and low cytotoxicity in fibroblast cells [41]. In the same year, Rodrigo et al.