The aim of the present study was to develop zeta potential-changing polyphosphate nanoparticles (pp-NPs) in order to overcome the diffusion barrier of the mucus gel layer and to provide an enhanced cellular uptake. pp-NPs were obtained by in situ gelation between cationic polyethylene imine and anionic polyphosphate. The resulting pp-NPs were characterized with regard to size and zeta potential. Phosphate release studies were carried out by incubation of pp-NPs with isolated as well as cell-associated intestinal alkaline phosphatase (IAP) and quantified by malachite green assay. Correspondingly, change in the zeta potential was measured, and pp-NPs were analyzed by scanning electron microscopy studies. Mucus permeation studies were performed with porcine intestinal mucus via the transwell insert method and rotating tube method. Furthermore, cell viability and cellular uptake were investigated on Caco-2 cells. The resulting pp-NPs displayed a mean size of 269.16 ± 1.12 nm and a zeta potential between −9 and −10 mV in the characterization studies. Within 4 h, a remarkable amount of phosphate was released from pp-NPs incubated with isolated IAP as well as cell-associated IAP and zeta potential raised up from −9.14 ± 0.45 to −1.75 ± 0.46 mV. Compared with dephosphorylated polyphosphate nanoparticles (de-pp-NPs), a significantly enhanced mucus permeation of pp-NPs was observed. Moreover, pp-NPs did not exhibit cytotoxicity. Cellular uptake increased 2.6-fold by conversion of pp-NPs to de-pp-NPs following enzymatic cleavage. Taking the comparatively simple preparation method and the high mucus-permeating properties of pp-NPs and high cellular uptake properties of de-pp-NPs into account, these nanocarriers might be promising novel tools for mucosal drug delivery.

Drug delivery to the brain is an engaged research topic in the field of nanomedicine. The passage of therapeutics into the brain parenchyma is more complicated than other body tissues due to it is limited by restrict barrier structure called blood-brain barrier (BBB). Nanotechnology holds great promise to overcome the BBB and thereby enable treatment of neurodegenerative diseases. Nanocarriers have been investigated several times as effective brain drug delivery systems in the past few decades. Physicochemical properties and surface modifications of these carriers play a significant role in terms of brain up-taking of nanocarriers. Chemical structures of possible nano sized drug delivery systems have an importance in terms of interactions between cell membranes of brain endothelial cell lines and these interactions can be modified with surface coating strategies using suitable agents. Particle size, surface charge and total molecular mass are also crucial issues which require special attention in order to better understand appropriate properties of nanocarriers to overcome the BBB structure. Different strategies have been demonstrated to facilitate the passage of nanoparticles into the brain parenchyma including attachment of targeting ligands on the nanoparticles' surfaces; this attempt provides site specific action in the brain tissues. This study aims to provide a review of nanocarriers for effective brain drug delivery, in the light of current literature.

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