Dendrimers as anti-inflammatory agents

Dendrimers constitute an intriguing class of macromolecules which find applications in a variety of areas including biology. These hyperbranched macromolecules with tailored backbone and surface groups have been extensively investigated as nanocarriers for gene and drug delivery, by molecular encapsulation or covalent conjugation. Dendrimers have provided an excellent platform to develop multivalent and multifunctional nanoconjugates incorporating a variety of functional groups including drugs which are known to be anti-inflammatory agents. Recently, dendrimers have been shown to possess anti-inflammatory properties themselves. This unexpected and intriguing discovery has provided an additional impetus in designing novel active pharmaceutical agents. In this review, we highlight some of the recent developments in the field of dendrimers as nanoscale anti-inflammatory agents

In vivo proinflammatory activity of generations 0–3 (G0–G3) polyamidoamine (PAMAM) nanoparticles

International audienceThe aim of this study was to determine whether different generations (G) polyamidoamine (PAMAM) dendrimers possess proinflammatory activities in vivo. Several hundred female CD-1 mice were used to test four different PAMAM dendrimers using the murine air pouch model. Mice received appropriate negative and positive controls or G0-G3 PAMAM nanoparticles at 100 and 500 µg/ml into air pouches. Exudates were harvested after 3, 6, 24 and 48 h. Cell pellets and supernatants were used to determine the number of total leukocytes and neutrophils and to detect the production of several analytes by an antibody array approach, respectively. One-way analysis of variance was used for statistical analysis. PAMAM dendrimers rapidly increased a leukocyte influx after 3 h, the vast majority of cells being neutrophils. This was also observed after 6 and 24 h, and resolution of inflammation was noted after 48 h. In general, the increased production of a greater number of analytes detected in the exudates after 6 h correlated with the number of dendrimer generations (G3 > G2 > G1 > G0). PAMAM dendrimers devoid of any delivering molecules possess proinflammatory activities in vivo by themselves, probably via the production of different chemokines released by air pouch lining cells

Molecular modeling as a predictive tool for the development of solid dispersions

In this study molecular modeling is introduced as a novel approach for the development of pharmaceutical solid dispersions. A computational model based on quantum mechanical (QM) calculations was used to predict the miscibility of various drugs in various polymers by predicting the binding strength between the drug and dimeric form of the polymer. The drug/polymer miscibility was also estimated by using traditional approaches such as Van Krevelen/Hoftyzer and Bagley solubility parameters or Flory–Huggins interaction parameter in comparison to the molecular modeling approach. The molecular modeling studies predicted successfully the drug–polymer binding energies and the preferable site of interaction between the functional groups. The drug–polymer miscibility and the physical state of bulk materials, physical mixtures, and solid dispersions were determined by thermal analysis (DSC/MTDSC) and X-ray diffraction. The produced solid dispersions were analyzed by X-ray photoelectron spectroscopy (XPS), which confirmed not only the exact type of the intermolecular interactions between the drug–polymer functional groups but also the binding strength by estimating the N coefficient values. The findings demonstrate that QM-based molecular modeling is a powerful tool to predict the strength and type of intermolecular interactions in a range of drug/polymeric systems for the development of solid dispersions

Particulate Systems for Targeting of Macrophages: Basic and Therapeutic Concepts

Particulate systems in the form of liposomes, polymeric micelles, polymeric nano- and microparticles, and many others offer a rational approach for selective delivery of therapeutic agents to the macrophage from different physiological portals of entry. Particulate targeting of macrophages and intracellular drug release processes can be optimized through modifications of the drug carrier physicochemical properties, which include hydrodynamic size, shape, composition and surface characteristics. Through such modifications together with understanding of macrophage cell biology, targeting may be aimed at a particular subset of macrophages. Advances in basic and therapeutic concepts of particulate targeting of macrophages and related nanotechnology approaches for immune cell modifications are discussed