PET imaging with copper-64 as a tool for real-time in vivo investigations of the necessity for cross-linking of polymeric micelles in nanomedicine.

Polymeric micelles in nanomedicine are often cross-linked to prevent disintegration in vivo. This typically requires clinically problematic chemicals or laborious procedures. In addition, cross-linking may interfere with advanced release strategies. Despite this, it is often not investigated whether cross-linking is necessary for efficient drug delivery. We used positron emission tomography (PET) imaging with 64 Cu to demonstrate general methodology for real-time in vivo investigations of micelle stability. Triblock copolymers with 4-methylcoumarin cores of ABC-type (PEG-PHEMA-PCMA) were functionalized in the handle region (PHEMA) with CB-TE2A chelators. Polymeric micelles were formed by dialysis and one half was core cross-linked (CL) by UV light and the other half was not (nonCL). Both CL and nonCL were radiolabeled with 64 Cu and compared in vivo in tumor-bearing mice, with free 64 Cu as control. Accumulation in relevant organs was quantified by region of interest analysis on PET images and ex vivo counting. It was observed that CL and nonCL showed limited differences in biodistribution from each other, whereas both differed markedly from control (free 64 Cu). This demonstrated that 4-methylcoumarin core micelles may form micelles that are stable in circulation even without cross-linking. The methodology presented here where individual unimers are radiolabeled is applicable to a wide range of polymeric micelle types.

Hyaluronic Acid Nanoparticles as Nanomedicine for Treatment of Inflammatory Diseases.

Owing to their unique biological functions, hyaluronic acid (HA) and its derivatives have been explored extensively for biomedical applications such as tissue engineering, drug delivery, and molecular imaging. In particular, self-assembled HA nanoparticles (HA-NPs) have been used widely as target-specific and long-acting nanocarriers for the delivery of a wide range of therapeutic or diagnostic agents. Recently, it has been demonstrated that empty HA-NPs without bearing any therapeutic agent can be used therapeutically for the treatment of inflammatory diseases via modulating inflammatory responses. In this review, we aim to provide an overview of the significant achievements in this field and highlight the potential of HA-NPs for the treatment of inflammatory diseases.

Shear stress regulated uptake of liposome-decorated microgels coated with a poly(dopamine) shell.

Advanced multicompartment drug delivery platforms ensure the co-localization of several drugs within the same carrier, thus making it possible to achieve a more effective and safe therapeutic outcome. Herein, we report a novel multicompartment architecture by combining two intrinsically different systems, i.e., polymeric microgels and liposomes, with the aim to achieve different release kinetics for model compounds. We assemble poly(N-isopropylacrylamide-co-acrylic acid) microgels decorated with liposomes which are subsequently coated with a protective poly(dopamine) shell and a poly(ethylene glycol) (PEG) layer. Since any intravenous administered drug delivery vehicle will get in contact with the dynamics of the blood flow, we evaluate the stealth properties of this novel multicompartment carrier towards protein adsorption and cellular uptake by three relevant cell lines (macrophages, endothelial and cancer cells) under physiological shear stress conditions. Our results demonstrate less protein adsorption for the PEGylated carriers and differences in the extent of internalized carriers depending on the presence of a PEG coating, the studied cell line and the intensity of the applied shear stress. Additionally, we demonstrate that, for all three tested cell lines, shear stress results in the activation of different cell entry pathways as compared to static conditions. All in all, we report a thorough study about the effect of shear stress on the cell association/uptake with a novel multicompartment carrier.

Differential toxicological response to positively and negatively charged nanoparticles in the rat brain.

We investigated the potential for systemic and local toxicity after administration of empty nanosized anionic and cationic PEGylated-micelles and non-PEGylated liposomes, without a ligand attached, intended for use in drug-delivery systems. The particles were administered to 5-6-week-old male rats by three intravenous (IV) administrations over a period of one week at a dose of 100 mg/kg bodyweight or after a single intracerebroventricular (ICV) injection at a dose of 50 µg. The particles were stable and well characterised with respect to size and zeta potential. ICV administration of cationic particles was associated with histological changes near the injection site (hippocampus). Here, we detected focal infiltration with phagocytic cells, loss of neurons and apoptotic cell death, which were not observed after administration of the vehicle. No significant difference was found after IV or ICV administration of the anionic micelles with regard to haematology, clinical chemistry parameters or at the pathological examinations, as compared to control animals. Our study suggests that ICV delivery of cationic particles to the brain tissue is associated with toxicity at the injection site.