Cationic Carbosilane Dendritic Systems as Promising Anti‐Amyloid Agents in Type 2 Diabetes

Abstract

The most common denominator of many of the neurodegenerative diseases is badly folded protein accumulation, which results in the formation of insoluble protein deposits located in different parts of the organism, causing cell death and tissue degeneration. Dendritic systems have turned out to be a promising new therapeutic approach for the treatment of these diseases due to their ability to modulate the folding of these proteins. With this perspective, and focused on type 2 diabetes (T2D), characterized by the presence of deposits containing the amyloidogenic islet amyloid polypeptide (IAPP), we demonstrate how different topologies of cationic carbosilane dendrimers inhibit the formation of insoluble protein deposits in pancreatic islets isolated from transgenic Tg‐hIAPP mice. Also, the results obtained by the modification of dendritic carbosilane wedges with the chemical chaperone 4‐phenylbutyric acid (4‐PBA) at the focal point confirmed their potential as anti‐amyloid agents with a concentration efficiency in their therapeutic action five orders of magnitude lower than that observed for free 4‐PBA. Computational studies, which determined the main interaction between IAPP and dendrimers at the atomic level, support the experimental work.

Interaction of Cationic Carbosilane Dendrimers and Their siRNA Complexes with MCF-7 Cells

“…The new second generation carbosilane dendrimers, CBD-1 and CBD-2, were synthesized in the Department of Organic and Inorganic Chemistry, University of Alcalá, Madrid, Spain [42]. Carbosilane dendrimer CBD-1 contains 8 surface tertiary ammonium groups (RNHMe2Cl), Mw = 1997.01 g/mol; C80H182Cl8N8O2S8Si6.…”

Eradication of Candida albicans Biofilm Viability: In Vitro Combination Therapy of Cationic Carbosilane Dendrons Derived from 4-Phenylbutyric Acid with AgNO3 and EDTA

“…Cationic carbosilane dendrons derived from 4-phenylbutyric acid (Sigma-Aldrich, Saint Louis, MO, USA) (Figure 1) soluble in water, were synthesized according to protocol described in literature [33]. Three generation of dendrons ArCO 2 G n (SNMe 3 I) m (n = 1; m = 2 (1), n = 2; m = 4 (2) and n = 3; m = 8 (3)) were tested to study their in vitro ability to prevent biofilm formation and eliminate C. albicans established biofilms.…”

Cationic Carbosilane Dendrimers Prevent Abnormal α-Synuclein Accumulation in Parkinson’s Disease Patient-Specific Dopamine Neurons

“…Among them, dendrimers are especially interesting as they are highly branched polymers with well-defined geometry and unique properties that can be functionalized according to the specific application for which they are designed. A variety of dendritic systems of different natures and topologies have been tested in the context of neurodegenerative diseases, including PAMAM, polypropyleneimine dendrimers, glycodendrimers, and phosphorous or carbosilane dendrimers, and shown to have an effect on α-syn aggregation. ,,, Moreover, dendrimers have also been reported to inhibit the aggregation of insoluble forms of amyloid and prion peptides and to facilitate their degradation. , …”

“…For the present studies, we focused on carbosilane dendrimers as they have been proven to be effective in a variety of biomedical applications in a topology-dependent manner ,− and non-toxic at concentrations below 5 μM when used as transfecting or anti-cancer agents. , One of the main properties of carbosilane dendrimers is their inherent hydrophobicity, provided by their characteristic skeleton, which allows interaction with biological membranes in an efficient manner and the presence of a permanent number of charges. For this reason, low generations of carbosilane dendrimers are effective for most applications, unlike the case of other dendritic skeletons.…”

“…For this reason, low generations of carbosilane dendrimers are effective for most applications, unlike the case of other dendritic skeletons. Specifically, in the context of protein misfolding diseases, cationic carbosilane systems have shown their ability to inhibit rotenone-induced α-syn fibrillation in mouse hippocampal cells and amyloidogenic islet amyloid polypeptide (IAPP) aggregation in a mouse model of type II diabetes . In this work, we investigated how the topology of cationic carbosilane dendrimers (spherical, dendritic wedge, or bow-tie) could influence the interaction with α-syn to avoid aggregation.…”