Biomedical Nanoparticles: Overview of Their Surface Immune-Compatibility

Diagnostic- and therapeutic release-aimed nanoparticles require the highest degree of biocompatibility. Some physical and chemical characteristics of such nanomaterials are often at odds with this requirement. For instance, metals with specific features used as contrast agents in magnetic resonance imaging need particular coatings to improve their blood solubility and increase their biocompatibility. Other examples come from the development of nanocarriers exploiting the different characteristics of two or more materials, i.e., the ability to encapsulate a certain drug by one core-material and the targeting capability of a different coating surface. Furthermore, all these “human-non-self” modifications necessitate proofs of compatibility with the immune system to avoid inflammatory reactions and resultant adverse effects for the patient. In the present review we discuss the molecular interactions and responses of the immune system to the principal nanoparticle surface modifications used in nanomedicine

The obesity and inflammatory marker haptoglobin attracts monocytes via interaction with chemokine (C-C motif) receptor 2 (CCR2)

<p>Abstract</p> <p>Background</p> <p>Obesity is a chronic low inflammatory state. In the obesity condition the white adipose tissue (WAT) is massively infiltrated with monocytes/macrophages, and the nature of the signals recruiting these inflammatory cells has yet to be fully elucidated. Haptoglobin (Hp) is an inflammatory marker and its expression is induced in the WAT of obese subjects. In an effort to elucidate the biological significance of Hp presence in the WAT and of its upregulation in obesity we formulated the hypothesis that Hp may serve as a macrophage chemoattractant.</p> <p>Results</p> <p>We demonstrated by chemotaxis assay that Hp is able to attract chemokine (C-C motif) receptor 2 (CCR2)-transfected pre-B lymphocytes and monocytes in a dose-dependent manner. Moreover, Hp-mediated migration of monocytes is impaired by CCR2-specific inhibition or previous cell exposure to monocyte chemoattractant protein 1 (MCP1) (also known as CCR2 ligand or chemokine (C-C motif) ligand 2 (CCL2)). Downstream effects of Hp/CCR2 interaction were also investigated: flow cytometry proved that monocytes treated with Hp show reduced CCR2 expression on their surface; Hp interaction induces calcium release that is reduced upon pretreatment with CCR2 antagonist; extracellular signal-regulated kinase (ERK)1/2, a signal transducer activated by CCR2, is phosphorylated following Hp treatment and this phosphorylation is reduced when cells are pretreated with a specific CCR2 inhibitor. Consistently, blocking the ERK1/2 pathway with U0126, the selective inhibitor of the ERK upstream mitogen-activated protein (MAP)-ERK kinase (MEK), results in a dramatic reduction (by almost 100%) of the capability of Hp to induce monocyte migration.</p> <p>Conclusions</p> <p>Our data show that Hp is a novel monocyte chemoattractant and that its chemotactic potential is mediated, at least in part. by its interaction with CCR2.</p

“Metabolic consequences of Hp deficiency:detailed study of the Hp -/- mice white adipose tissue”

INTRODUCTION— Haptoglobin (Hp) is an inflammatory and adiposity marker, its expression during obesity being specifically induced in the white adipose tissue (WAT). The low chronic inflammatory state, caused by massive adipose tissue macrophage (ATM) infiltration found in obesity, and low adiponectin have been implicated in the development of insulin resistance and hepatosteatosis. The aim of this project was to get further insights into Hp function in WAT and to investigate whether and how Hp interferes with the onset of obesity-associated complications. To this end, we metabolically profiled and analyzed the histology and the gene expression of the WAT in the Hp deficient model both in standard and obesity conditions. To get further insights into Hp function in the adipocyte, the adipogenic potential of Hp−/− mouse embryonic fibroblasts (MEFs) was also evaluated. MATERIALS AND METHODS— Hp null (Hp−/−) and wild type (WT) mice were metabolically profiled under chow food diet (CFD) and high fat diet (HFD) feeding, by assessing physical parameters, glucose tolerance, insulin sensitivity, insulin response to glucose load, liver triglyceride content, plasma levels of leptin, insulin, glucose and adiponectin. ATM content and adipocyte size were evaluated by using immunohistochemistry. Adiponectin expression was measured in Hp-treated, cultured 3T3-L1 and human adipocytes. Primary MEFs were isolated from embryos of WT and Hp−/− embryos at 15 days post coitum and induced to progress to adipose conversion using an adipogenic hormonal cocktail. RESULTS— Metabolic profiling did not reveal any genotype-related difference in CFD animals. HFD Hp−/− mice showed significantly higher glucose tolerance, insulin sensitivity, glucose-stimulated insulin secretion, adiponectin expression and reduced hepatomegaly / steatosis compared with HFD WT mice. The WAT of HFD Hp−/− mice showed higher activation of insulin signaling cascade, lower ATM and higher adiponectin expression. Hp was able to inhibit adiponectin expression in cultured adipocytes. Average size and percentage of very large adipocytes were respectively smaller and reduced in HFD Hp−/− mice as compared to HFD WT. Lean adult Hp−/− showed significantly larger adipocytes and lower subcutaneous WAT expression of aP2 and LPL with respect to WT. Morphometric analysis of adipocytes in lean and obese mice revealed an attenuation of obesity-related changes in Hp−/− mice compared to WT. MEFs from Hp−/− mice were less capable to accumulate triglycerides and exhibited lower expression of PPARgamma, aP2, FAS, LPL, Leptin. CONCLUSIONS— We demonstrated that, in the absence of Hp, obesity-associated insulin resistance and hepatosteatosis are attenuated, this being consistent with reduced ATM content, increased plasma adiponectin and higher WAT insulin sensitivity. Moreover, Hp deficiency tends to blunt the diet effect on the size of adipocytes, which show less susceptibility to develop hypertrophy upon obesity; in addition Hp deficiency impacts negatively on adipogenesis

Targeted drug delivery across biological barriers using polymer nanoparticles

The systemic administration of pharmacological agents generally shows some important limitations related to the biodistribution of active agents in the body such as the lack of affinity of pharmaceuticals toward the site of pathology, the nonspecific therapeutic effects on health cells, the necessity to administrate large doses to obtain an efficient local concentration and the side effects arising after the administration of high drug doses. An emerging technology to overcome these limitations is represented by the targeted drug delivery, or rather, the development of medicaments able to control the delivery kinetics and, in addition, functionalized to hit specific sites thus reducing side effects and unwanted high doses. Drug targeting can be performed in two different ways: the first is the functionalization of drugs or the preparations of prodrugs but with the possibility to decrease the pharmacological activity of the active molecule; the second is based on the use of nanocarriers to entrap, protect and transport the active agent in the desired site. Nanocarriers can be obtained by inorganic (e.g., metallic) or organic materials; organic nanoparticulate systems can be prepared using natural (e.g., liposomes and polysaccharides) or synthetic (e.g., polymers) materials. Based on the desired functional properties of nanocarrier materials, the site of the pathology to treat and the entity of the disease, the correct choice of the material constituting the carrier is fundamental in its setup. This chapter will discuss the possibility of targeting a drug in some different body organs by using polymeric nanocarriers. Mechanisms of drug targeting will be explained and a list of smart polymer systems currently employed or under investigation is reported