Innate and adaptive immune responses toward nanomedicines.

Since the commercialization of the first liposomes used for drug delivery, Doxil/Caelyx® and Myocet®, tremendous progress has been made in understanding interactions between nanomedicines and biological systems. Fundamental work at the interface of engineering and medicine has allowed nanomedicines to deliver therapeutic small molecules and nucleic acids more efficiently. While nanomedicines are used in oncology for immunotherapy or to deliver combinations of cytotoxics, the clinical successes of gene silencing approaches like patisiran lipid complexes (Onpattro®) have paved the way for a variety of therapies beyond cancer. In parallel, the global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has highlighted the potential of mRNA vaccines to develop immunization strategies at unprecedented speed. To rationally design therapeutic and vaccines, chemists, materials scientists, and drug delivery experts need to better understand how nanotechnologies interact with the immune system. This review presents a comprehensive overview of the innate and adaptative immune systems and emphasizes the intricate mechanisms through which nanomedicines interact with these biological functions.

Role of the complement cascade in the biological fate of liposomes in rodents.

Nanomedicines, including liposomes, have been used to improve the clinical efficacy and safety of drugs. In some liposomal formulations, a hydrophilic polymer coating of poly(ethylene glycol) (PEG) is used to increase the circulation time. Understanding the biological mechanisms responsible for the clearance of PEGylated and non-PEGylated nanomedicines is necessary to develop better-performing materials. The purpose of this work is to explore the role of complement in the elimination of intravenously administered liposomes (PEGylated and non-PEGylated) in mice and rats. Here, the complement cascade was depleted by intraperitoneal injections of cobra venom factor (CVF) 12 and 24 hours before the intravenous injection of radiolabeled liposomes. In both mice and rats, non-PEGylated liposomes showed faster elimination than PEGylated liposomes. At a lipid dose of 20 mg kg-1, the abrogation of the complement cascade (in CVF group) did not alter the circulation time of either PEGylated or non-PEGylated liposomes. In contrast, at lower doses (2 mg kg-1), animals treated with CVF had slightly higher levels of circulating liposomes, especially during the 24 hours pharmacokinetic studies. The complement cascade seems to govern the uptake of non-PEGylated liposomes by splenic B cells. Altogether, these results suggest that although PEGylated and non-PEGylated liposomes can activate complement, the impact of this cascade on their circulation time is minor and mostly perceivable at later phases of distribution. This work enlightens biological pathways responsible for in vivo clearance of liposomes and will help in orienting future research in elucidating the nano-bio interface.

Anti-polyethylene glycol antibodies alter the protein corona deposited on nanoparticles and the physiological pathways regulating their fate in vivo.

Multiple studies highlight the strong prevalence of anti-poly(ethylene glycol) (anti-PEG) antibodies in the general human population. As we develop therapeutic modalities using this polymer, it is increasingly relevant to assess the importance of anti-PEG antibodies on biological performances. Here, we show that the anti-PEG Immunoglobulin M (IgM) raised in mice following the injection of polymeric nanoparticles could have significant neutralizing effects on subsequent doses of PEGylated nanosystems in vivo. The circulation times of PEGylated nanoparticles and liposomes were strongly reduced in animals with circulating anti-PEG IgMs, irrespective of the PEG density or the surface properties of the system. In comparison, despite that anti-PEG IgMs could bind free methoxy-terminated PEG and PEGylated bovine serum albumin, the circulation kinetics of these systems remained unaltered in the presence of antibodies. The binding of IgMs to the PEGylated surface of nanoparticles alters the nature of the proteins adsorbed in the surrounding corona, notably due to the activation of the complement cascade. These changes are responsible for the observed differences in circulation times. In comparison, the PEG-BSA is unable to activate complement, even in the presence of anti-PEG IgMs. These results inform on how anti-PEG antibodies can affect the fate of PEGylated nanomaterials and highlight how the architecture of nanoparticles impacts the deposition of the protein corona.

Simultaneous determination of oral antidiabetic drugs in human plasma using microextraction by packed sorbent and high-performance liquid chromatography.

In this study, a simple method using microextraction by packed sorbent and high-performance liquid chromatography with ultraviolet detection for simultaneous determination of chlorpropamide, gliclazide and glimepiride in human plasma was developed and validated. A fractional factorial design and a complete factorial design were applied to evaluate the parameters which could affect the extraction and desorption steps, respectively. All parameters in the extraction step (pH, sample volume, sample dilution and number of aspiration/ejection cycles) and in the desorption step (percentage of acetonitrile in the elution solvent and number of aspirations of elution solvent through the device) were statistically significant (p>0.05) when recovery was used as response. The developed method allowed the use of small volumes of sample and solvents and rapid separation by using a fused core column (only 2.2min were needed). This method was fully validated showing selectivity, precision, accuracy and linearity over the range 1.0-50.0µgmL(-1) for chlorpropamide, 1.0-10.0µgmL(-1) for gliclazide and 0.1-1.0µgmL(-1) for glimepiride. Finally, the validated method was applied in the analysis of samples from volunteers containing the three tested analytes.