Cancer immune therapy using engineered ?tail-flipping' nanoliposomes targeting alternatively activated macrophages.

Alternatively-activated, M2-like tumor-associated macrophages (TAM) strongly contribute to tumor growth, invasiveness and metastasis. Technologies to disable the pro-tumorigenic function of these TAMs are of high interest to immunotherapy research. Here we show that by designing engineered nanoliposomes bio-mimicking peroxidated phospholipids that are recognised and internalised by scavenger receptors, TAMs can be targeted. Incorporation of phospholipids possessing a terminal carboxylate group at the sn-2 position into nanoliposome bilayers drives their uptake by M2 macrophages with high specificity. Molecular dynamics simulation of the lipid bilayer predicts flipping of the sn-2 tail towards the aqueous phase, while molecular docking data indicates interaction of the tail with Scavenger Receptor Class B type 1 (SR-B1). In vivo, the engineered nanoliposomes are distributed specifically to M2-like macrophages and, upon delivery of the STAT6 inhibitor (AS1517499), zoledronic acid or muramyl tripeptide, these cells promote reduction of the premetastatic niche and/or tumor growth. Altogether, we demonstrate the efficiency and versatility of our engineered "tail-flipping" nanoliposomes in a pre-clinical model, which paves the way to their development as cancer immunotherapeutics in humans.

Differential uptake of nanoparticles by human M1 and M2 polarized macrophages: protein corona as a critical determinant.

AIM: To investigate the interaction behavior of M1- and M2-type macrophages with nanoparticles of different sizes with/without the presence of serum. MATERIALS & METHODS: THP-1 human monocytes were differentiated into M1 and M2 macrophages, and the uptake of silica nanoparticle (50-1000 nm) was studied using flow cytometry and different microscopies. RESULTS: Without serum, higher uptake of all-sized nanoparticles was observed by M1 compared with M2. With serum, uptake of nanoparticles (200-1000 nm) was dramatically increased by M2. Furthermore, serum proteins adsorbed (corona) by nanoparticles were found to be the ligands for receptors expressed by M2, as revealed by SDS-PAGE and gene profiling analyses. CONCLUSION: The observed differential uptake by M1 and M2 macrophages will help understand the fate of nanoparticles in vivo.

Microporous calcium phosphate ceramics driving osteogenesis through surface architecture.

The presence of micropores in calcium phosphate (CaP) ceramics has shown its important role in initiating inductive bone formation in ectopic sites. To investigate how microporous CaP ceramics trigger osteoinduction, we optimized two biphasic CaP ceramics (i.e., BCP-R and BCP-S) to have the same chemical composition, equivalent surface area per volume, comparable protein adsorption, similar ion (i.e., calcium and phosphate) exchange and the same surface mineralization potential, but different surface architecture. In particular, BCP-R had a surface roughness (Ra) of 325.4 ± 58.9 nm while for BCP-S it was 231.6 ± 35.7 nm. Ceramic blocks with crossing or noncrossing channels of 250, 500, 1000, and 2000 µm were implanted in paraspinal muscle of dogs for 12 weeks. The percentage of bone volume in the channels was not affected by the type of pores (i.e., crossing vs. closed) or their size, but it was greatly influenced by the ceramic type (i.e., BCP-R vs. BCP-S). Significantly, more bone was formed in the channels of BCP-R than in those of BCP-S. Since the two CaP ceramics differed only in their surface architecture, the results hereby demonstrate that microporous CaP ceramics may induce ectopic osteogenesis through surface architecture.

Microwell scaffolds for the extrahepatic transplantation of islets of Langerhans.

Allogeneic islet transplantation into the liver has the potential to restore normoglycemia in patients with type 1 diabetes. However, the suboptimal microenvironment for islets in the liver is likely to be involved in the progressive islet dysfunction that is often observed post-transplantation. This study validates a novel microwell scaffold platform to be used for the extrahepatic transplantation of islet of Langerhans. Scaffolds were fabricated from either a thin polymer film or an electrospun mesh of poly(ethylene oxide terephthalate)-poly(butylene terephthalate) (PEOT/PBT) block copolymer (composition: 4000PEOT30PBT70) and were imprinted with microwells, ∼400 µm in diameter and ∼350 µm in depth. The water contact angle and water uptake were 39±2° and 52.1±4.0 wt%, respectively. The glucose flux through electrospun scaffolds was three times higher than for thin film scaffolds, indicating enhanced nutrient diffusion. Human islets cultured in microwell scaffolds for seven days showed insulin release and insulin content comparable to those of free-floating control islets. Islet morphology and insulin and glucagon expression were maintained during culture in the microwell scaffolds. Our results indicate that the microwell scaffold platform prevents islet aggregation by confinement of individual islets in separate microwells, preserves the islet's native rounded morphology, and provides a protective environment without impairing islet functionality, making it a promising platform for use in extrahepatic islet transplantation.