For the first time, an overview of dendrimers in combination with natural products and analogues as anti-cancer agents is presented. This reflects the development of drug delivery systems, such as dendrimers, to tackle cancers. The most significant advantages of using dendrimers in nanomedicine are their high biocompatibility, good water solubility, and their entry - with or without encapsulated, complexed or conjugated drugs - through an endocytosis process. This strategy has accelerated over the years in order to develop nanosystems as nanocarriers, to decrease the intrinsic toxicity of anti-cancer agents, to decrease the drug side effects, to increase the efficacy of the treatment, and consequently to improve patient compliance.
Mycobacterium tuberculosis mannose-capped lipoarabinomannan inhibits the release of proinflammatory cytokines by LPS-stimulated human dendritic cells (DCs) via targeting the C-type lectin receptor DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN). With the aim of mimicking the bioactive supramolecular structure of mannose-capped lipoarabinomannan, we designed and synthesized a set of poly(phosphorhydrazone) dendrimers grafted with mannose units, called mannodendrimers, that differed by size and the number and length of their (α1→2)-oligommanoside caps. A third-generation dendrimer bearing 48 trimannoside caps (3T) and a fourth-generation dendrimer bearing 96 dimannosides (4D) displayed the highest binding avidity for DC-SIGN. Moreover, these dendrimers inhibited proinflammatory cytokines, including TNF-α, production by LPS-stimulated DCs in a DC-SIGN-dependent fashion. Finally, in a model of acute lung inflammation in which mice were exposed to aerosolized LPS, per os administration of 3T mannodendrimer was found to significantly reduce neutrophil influx via targeting the DC-SIGN murine homolog SIGN-related 1. The 3T mannodendrimer therefore represents an innovative fully synthetic compound for the treatment of lung inflammatory diseases. T o secure their colonization and survival, some bacterial intracellular pathogens have evolved tactics to undermine host innate immune responses, including inflammation. Mycobacterium tuberculosis, the causative agent of human tuberculosis, uses multiple mechanisms to survive within its host cellular niches of alveolar macrophages and dendritic cells (DCs). In particular, M. tuberculosis exposes surface lipoglycans at its cell envelope, namely mannose-capped lipoarabinomannans (ManLAMs), which inhibit the production of proinflammatory cytokines IL-12 and TNF-α by LPS-stimulated human DCs (1-3) via binding to the C-type lectin DC-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) (4, 5). DC-SIGN reportedly modulates immune responses to several other pathogens, supporting its important role as an immunomodulatory receptor (6). ManLAMs are complex amphipathic macromolecules with an average molecular weight of 17 kDa that are composed of three domains: (i) a mannosyl-phosphatidyl-myo-inositol (MPI) anchor; (ii) a heteropolysaccharidic core composed of D-mannan and D-arabinan; and (iii) mannose caps consisting of mono, (α1→2)-di-, and (α1→2)-trimannosides (7). MPI anchor fatty acyl appendages induce a supramolecular organization of ManLAMs in aqueous solution, resulting in the formation of a 30-nm spherical structure of ∼450 molecules with the mannose caps exposed at the surface (8). This multivalent supramolecular structure allows multipoint attachment of ManLAMs, via mannose caps, to multimeric DC-SIGN receptors (9, 10) expressed at the surface of DCs, thereby ensuring high-affinity binding to the receptor (8-10) and induction of antiinflammatory activity (1, 2, 7).The strategy used by M. tuberculosis to down-regulate the...
Alzheimer's disease (AD) is characterized by pathological aggregation of β-amyloid peptides and MAP-Tau protein. β-Amyloid (Aβ) is a peptide responsible for extracellular Alzheimer's plaque formation. Intracellular MAP-Tau aggregates appear as a result of hyperphosphorylation of this cytoskeletal protein. Small, oligomeric forms of Aβ are intermediate products that appear before the amyloid plaques are formed. These forms are believed to be most neurotoxic. Dendrimers are highly branched polymers, which may find an application in regulation of amyloid fibril formation. Several biophysical and biochemical methods, like circular dichroism (CD), fluorescence intensity of thioflavin T and thioflavin S, transmission electron microscopy, spectrofluorimetry (measuring quenching of intrinsic peptide fluorescence) and MTT-cytotoxicity assay, were applied to characterize interactions of cationic phosphorus-containing dendrimers of generation 3 and generation 4 (CPDG3, CPDG4) with the fragment of amyloid peptide (Aβ(1-28)) and MAP-Tau protein. We have demonstrated that CPDs are able to affect β-amyloid and MAP-Tau aggregation processes. A neuro-2a cell line (N2a) was used to test cytotoxicity of formed fibrils and intermediate products during the Aβ(1-28) aggregation. It has been shown that CPDs might have a beneficial effect by reducing the system toxicity. Presented results suggest that phosphorus dendrimers may be used in the future as agents regulating the fibrilization processes in Alzheimer's disease.
Layer-by-layer (LbL) deposition of polyelectrolytes within nanopores in terms of the pore size and the ionic strength was experimentally studied. Anodic aluminum oxide (AAO) membranes, which have aligned, cylindrical, nonintersecting pores, were used as a model nanoporous system. Furthermore, the AAO membranes were also employed as planar optical waveguides to enable in situ monitoring of the LbL process within the nanopores by optical waveguide spectroscopy (OWS). Structurally well-defined N,N-disubstituted hydrazine phosphorus-containing dendrimers of the fourth generation, with peripherally charged groups and diameters of approximately 7 nm, were used as the model polyelectrolytes. The pore diameter of the AAO was varied between 30-116 nm and the ionic strength was varied over 3 orders of magnitude. The dependence of the deposited layer thickness on ionic strength within the nanopores is found to be significantly stronger than LbL deposition on a planar surface. Furthermore, deposition within the nanopores can become inhibited even if the pore diameter is much larger than the diameter of the G4-polyelectrolyte, or if the screening length is insignificant relative to the dendrimer diameter at high ionic strengths. Our results will aid in the template preparation of polyelectrolyte multilayer nanotubes, and our experimental approach may be useful for investigating theories regarding the partitioning of nano-objects within nanopores where electrostatic interactions are dominant. Furthermore, we show that the enhanced ionic strength dependence of polyelectrolyte transport within the nanopores can be used to selectively deposit a LbL multilayer atop a nanoporous substrate.
Spin-probe and spin-label techniques were used to study the interactions of the Abeta 1-28 peptide involved in Alzheimer disease and the PrP 106-126 peptide suspected to be preferentially involved in spongiform encephalopathies with three different types of dendrimers. A computer-aided EPR analysis of a positively charged and a neutral spin probe was performed by comparing the pure dendrimer and peptide systems with the dendrimer-peptide ones. Also spin-labeled PAMAM dendrimers were used to test the interactions. The results show the interactions between dendrimer and peptide monomer to be stronger for Abeta 1-28 than for PrP 106-126. PAMAM dendrimers perturb the aggregation of the peptides more than PPI dendrimers do.
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