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Bile acid sequestrants (BAS) represent a therapeutic approach for the management of hypercholesterolemia that relies on the cationic polymeric nature of BAS to selectively bind negatively charged bile acids. We hypothesized that the cross-linking of β-cyclodextrin (β-CD) and saccharides such as starch or dextrin with divinyl sulfone (DVS) yields homo- and hetero-polymeric materials with the ability to trap sterols. Our hypothesis was put to test by synthesizing a library of 22 polymers that were screened to evaluate their capability to sequester both cholesterol (CHOL) and cholic and deoxycholic acids (CA and DCA). Three polymers synthesized in high yield were identified as promising. Two were neutral hetero-polymers of β-CD and starch or dextrin and the third was a weakly cationic homo-polymer of starch, highlighting the importance of the cavity effect. They were tested in hypercholesterolemic male Wistar rats and their ability to regulate hypercholesterolemia was similar to that for the reference BAS cholestyramine, but with two additional advantages: (i) they normalized the TG level and (ii) they did not increase the creatinine level. Neither hepatotoxicity nor kidney injury was detected, further supporting them as therapeutical candidates to manage hypercholesterolemia.

The receptor for advanced glycation end products (RAGE) is involved in diabetes or angiogenesis in tumors. Under pathological conditions, RAGE is overexpressed and upon ligand binding and internalization stimulates signaling pathways that promote cell proliferation. In this work, amino dendritic polymers PEI 25 kDa and alkylated derivatives of PAMAM-G2 were engineered by the nonenzymatic Maillard glycation reaction to generate novel AGE-containing gene delivery vectors targeting the RAGE. The glycated dendritic polymers were easily prepared and retained the capability to bind and protect DNA from endonucleases. Furthermore, while glycation decreased the transfection efficiency of the dendriplexes in CHO-k1 cells which do not express RAGE, glycated dendriplexes acted as efficient transfection reagents in CHO-k1 cells which stably express recombinant RAGE. In addition, preincubation with BSA-AGEs, a natural ligand of the RAGE, or dansyl cadaverine, an inhibitor of the RAGE internalization, blocked transfection, confirming their specificity toward RAGE. The results were confirmed in NRK and RAW264.7 cell lines, which naturally express the receptor. The glycated compounds retain their transfection efficiency in the presence of serum and promote in vivo transfection in a mouse model. Accordingly, RAGE is a suitable molecular target for the development of site-directed engineered glycated nonviral gene vectors.