Electrospun Poly(ε-caprolactone) Fiber Scaffolds Functionalized by the Covalent Grafting of a Bioactive Polymer: Surface Characterization and Influence on in Vitro Biological Response.

The purpose of this study is to present the poly(caprolactone) (PCL) functionalization by the covalent grafting of poly(sodium styrene sulfonate) on electrospun scaffolds using the "grafting from" technique and evaluate the effect of the coating and surface wettability on the biological response. The "grafting from" technique required energy (thermal or UV) to induce the decomposition of the PCL (hydro)peroxides and generate radicals able to initiate the polymerization of NaSS. In addition, UV irradiation was used to initiate the radical polymerization of NaSS directly from the surface (UV direct "grafting from"). The interest of these two techniques is their easiness, the reduction of the number of process steps, and its applicability to the industry. The selected parameters allow controlling the grafting rate (i.e., degree of functionalization). The aim of the study was to compare two covalent grafting in terms of surface functionalization and hydrophilicity and their effect on the in vitro biological responses of fibroblasts. The achieved results showed the influence of the sulfonate functional groups on the cell response. In addition, outcomes highlighted that the UV direct "grafting from" method allows to moderate the amount of sulfonate groups and the surface hydrophilicity presents a considerable interest for covalently immobilizing bioactive polymers onto electrospun scaffolds designed for tissue engineering applications using efficient post-electrospinning chemical modification.

Impact of simulated biological aging on physicochemical and biocompatibility properties of cyclic olefin copolymers.

We study the effect of simulated biological aging on the properties of cyclic olefin copolymers and particularly their biocompatibility. Already reported as biocompatible polymers according to ISO/EN 10993 guidelines, COC are good candidates for medical devices. The influence of two major additives (antioxidants and lubricants) was investigated and comparison with non-aging COC was done. Four in vitro simulated biological conditions were tested: 2 extreme pH (1 and 9) to simulate digestive tract environment; THP-1-derived macrophages contact and pro-oxidant medium with hypochlorite solution simulating the oxidative attack during the foreign body reaction. After one month of incubation with the different media at 37 °C, surface topography was studied by atomic force microscopy (AFM) and IR spectroscopy. Extracts of incubated media were also analysed in chromatography to investigate potential degradation products. Cytotoxicity (MTT and LDH) of the materials was evaluated using cell culture methods with L929 fibroblasts. Oxidative stress (ROS and SOD analysis) and two inflammatory biomarkers (Il-6 and TNF-α secretion) were explored on THP-1-derived macrophages in direct contact with aged COC. Surface topography of COC was modified by aging conditions with an influence of antioxidant presence and under some conditions. HPLC analysis realized on freeze-dried solutions issued from the different incubations showed the presence of traces of low molecular weight compounds issued from polyphenolic antioxidant and from COC degradation. GC-MS analysis carried out directly on the different incubated COC, showed no detectable leachable molecules. No cytotoxicity has been observed with the different aged COC. However, results show that the pH environment had an influence on the cytotoxicity tests with a protecting effect of antioxidant presence; and pro-oxidant incubating conditions decreased cellular viability on COC. pH 1 and pH 9 conditions also induced an increase of ROS production which was partially reduced for COC containing an antioxidant or a lubricant. Il-6 production was globally more important for aged COC compared with basal condition and particularly for oxidative simulated environment. Those results indicate that physiological factors like pH or oxidant conditions have an impact on surface topography and on COC interaction with the biological environment but without compromising their biocompatibility. Antioxidant or lubricant presence could modulate these variations pointing out the necessity of a thoroughly investigation for biocompatibility assessment of COC as a component of implantable devices. COCs show a good biocompatibility even after accelerated aging under extreme biological conditions.

Irradiation Effects on Polymer-Grafted Gold Nanoparticles for Cancer Therapy.

In the context of cancer treatment, gold nanoparticles (AuNPs) are considered as very promising radiosensitizers. Here, well-defined polymer-grafted AuNPs were synthesized and studied under gamma irradiation to better understand the involved radiosensitizing mechanisms. First, various water-soluble and well-defined thiol-functionalized homopolymers and copolymers were obtained through atom transfer radical polymerization. They were then used as ligands in the one-step synthesis of AuNPs, which resulted in stable hybrid metal-polymer nanoparticles. Second, these nano-objects were irradiated in solution by γ rays at different doses. Structures were fully characterized through size exclusion chromatography, small-angle X-ray scattering, and small-angle neutron scattering measurements, prior to and after irradiation. We were thus able to quantify and to localize radiation impacts onto the grafted polymers, revealing the production sites of reactive species around AuNPs. Both external and near-surface scissions were observed. Interestingly, the ratio between these two effects was found to vary according to the nature of polymer ligands. Medium-range and long-distance dose enhancements could not be identified from the calculated scission yields, but several mechanisms were considered to explain high yields found for near-surface scissions. Then cytotoxicity was shown to be equivalent for both nonirradiated and irradiated polymer-grafted NPs, which suggested that released polymer fragments were nontoxic. Finally, the potential to add bioactive molecules such as anticancer drugs has been explored by grafting doxorubicin onto the polymer corona. This may lead to nano-objects combining both radiosensitization and chemotherapy effects. This work is the first one to study in details the impact of radiation on radiosensitizing nano-objects combining physical, chemical, and biological analyses.

Biocompatibility of polymer-based biomaterials and medical devices - regulations, in vitro screening and risk-management.

Biomaterials play an increasing role in modern health care systems. Biocompatibility poses a significant challenge for manufacturers of medical devices and contemporary intelligent drug delivery technologies from materials development to market approval. Despite a highly regulated environment, biocompatibility evaluation of biomaterials for medical devices is a complex task related to various factors that include mainly chemical nature and physical properties of the material, the contact tissue and duration of contact. Although international standards, such as ISO 10993-1, are generally employed to prove regulatory compliance needed for market clearance or for initiating clinical investigations, they may not offer sufficient guidance, or risk-management perspective when it comes to choosing materials or appropriate in vitro biocompatibility screening methods when developing medical devices. The global normative approach towards the biocompatibility evaluation of medical devices is presented in this review, with a focus on in vitro studies. Indeed, a risk-management approach towards the judicial choice of in vitro tests throughout the development and production of medical devices and drug delivery systems will facilitate rapid regulatory approval, avoid unnecessary animal studies, and ultimately reduce risks for patients. A detailed overview towards the construction of a comprehensive biological evaluation plan is described herein, with a focus on polymer-based materials used in medical applications. Polymeric materials offer a broad spectrum of applications in the manufacturing of medical devices. They are extensively employed within both conventional and innovative drug delivery systems with superior attributes supporting robust, extended use capacity, capable of meeting specific requirement such as adhesion, drug release, and more. Various methods of biocompatibility assessment are detailed within, with an emphasis on scientific analysis. This review may be of interest to those involved in the design, manufacturing and in vitro testing of medical devices and innovative drug delivery technologies, specifically with respect to a risk-management approach towards the biocompatibility assessment of polymer-based devices.

Restructuration kinetics of amphiphilic intraocular lenses during aging.

Photooxidation and hydrolysis are the two primary aging factors of intraocular lenses. Opacifications, dislocations, glistening and yellowing of the implanted acrylic lenses, which are due to chain scissions and depolymerization, are the consequences of aging from the clinical perspective. The purpose of this study was to examine the consequence of the aging of intraocular lenses on chemical and surface properties. Acrylic lenses made of poly acrylic-co-polystyrene polymer were artificially aged by photooxidation and hydrolysis from 2 to 20 years. Degradation products were observed by Reverse-phase High-Performance Liquid Chromatography RP-HPLC and thermogravimetric analysis (TGA). The surface, which was analyzed by atomic force microscopy (AFM) and fibronectin adhesion kinetics, was chosen as an indicator of intraocular biocompatibility. Low-molecular-weight degradation products (LMWP) result from chain scission under both hydrolysis and photooxidation. The osmotic effects of water enable degradation products to migrate through the polymer. A portion of the degradation products exudate in the surrounding center, whereas a portion link with lateral chains of the polymer. At the same time, the surface roughness evolves to externalize the most hydrophilic chains. As a result, the fibronectin adhesion level decrease with time, which indicates the existence of a biocompatible kinetic for implanted intraocular lenses.

Biocompatibility assessment of cyclic olefin copolymers: Impact of two additives on cytotoxicity, oxidative stress, inflammatory reactions, and hemocompatibility.

This work reports the biocompatibility evaluation of cyclic olefin copolymers (COC) as candidates for implantable medical devices. The focus was to establish the influence of two major additives (antioxidant and lubricant) on the overall biocompatibility. The cytotoxicity was evaluated according to ISO 10993-5 guidelines using L929 fibroblasts, HUVEC, and THP-1-derived macrophages. Oxidative stress (ROS, GSH/GSSG, and SOD analysis) and pro-inflammatory cytokines (Il-6 and TNF-α secretion) were quantified using THP-1 cells in direct contact with films. Hemocompatibility was assessed through haemolysis testing, dynamic blood coagulation, platelet adhesion, and activation (membranous P-selectin expression). Results show that the different types of COC have successfully passed the in vitro biocompatibility tests. The presence of antioxidant induces however a slight decrease in ROS production in correlation with a high SOD activity and a modification in blood coagulation profile probably linked to antioxidant recrystallization phenomenon on the surface of COC. The lubricant presence reduced haemolysis, fibrinogen adhesion, and platelet activation. Surface nanotopography of COC highlights different types of needles and globules according to the present additive. Those primary results indicate that COC are promising biomaterial. However, additives influenced some biological parameters pointing out the necessity of a global approach of risk analysis for biocompatibility evaluation. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3333-3349, 2017.

Cationic lipids bearing succinic-based, acyclic and macrocyclic hydrophobic domains: Synthetic studies and in vitro gene transfer.

In this communication we describe the construction of four succinic-based cationic lipids, their formulation with plasmid DNA (pDNA), and an evaluation of their in vitro gene delivery into Chinese hamster ovarian (CHO-K1) cells. The cationic lipids employed in this work possess either a dimethylamine or trimethylamine headgroup, and a macrocyclic or an acyclic hydrophobic domain composed of, or derived from two 16-atom, succinic-based acyl chains. The synthesized lipids and a co-lipid of neutral charge, either cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), were formulated in an overall 3:2 cationic-to-neutral lipid molar ratio, then complexed with plasmid DNA (pDNA). The relative transfection performance was evaluated via a comparison between matched versus mismatched formulations defined by the rigidity relationship between the lipids employed. Gel electrophoresis was used to characterize the binding of the lipid formulations with plasmid DNA and the relative degree of plasmid degradation using a DNase I degradation assay. Small angle X-ray diffraction (SAXD) was employed to characterize the packing morphology of the lipid-DNA complexes. In general, the succinic unit embedded within the hydrophobic domain of the cationic lipids was found to improve lipid hydration. The transfection assays revealed a general trend in which mismatched formulations that employed a rigid lipid combined with a non-rigid (or flexible) lipid, outperformed the matched formulations. The results from this work suggest that the design of the cationic lipid structure and the composition of the lipoplex formulation play key roles in governing the transfection performance of nonviral gene delivery agents.

Cationic Lipid-Based Nucleic Acid Vectors.

The delivery of nucleic acids into cells remains an important laboratory cell culture technique and potential clinical therapy, based upon the initial cellular uptake, then translation into protein (in the case of DNA), or gene deletion by RNA interference (RNAi). Although viral delivery vectors are more efficient, the high production costs, limited cargo capacity, and the potential for clinical adverse events make nonviral strategies attractive. Cationic lipids are the most widely applied and studied nonviral vectors; however, much remains to be solved to overcome limitations of these systems. Advances in the field of cationic lipid-based nucleic acid (lipoplex) delivery rely upon the development of robust and reproducible lipoplex formulations, together with the use of cell culture assays. This chapter provides detailed protocols towards the formulation, delivery, and assessment of in vitro cationic lipid-based delivery of DNA.

Exudation of additives to the surface of medical devices: impact on biocompatibility in the case of polyurethane used in implantable catheters.

Surface state is one of the most important parameters determining the biocompatibility of an implantable medical device, any change on the surface once in contact with body tissues can impact the biological response (cytotoxicity, inflammation, irritation, thrombosis, etc.). In the present study, we use (Pellethane® ) catheter-based polyurethane (PU), because of its many applications in the field of medical devices, to evaluate the impact of additives blooming on the biocompatibility. Four different antioxidants and two anti-ultraviolet stabilizers were included in this study. A comprehensive study was conducted to evaluate the consequences of cellular exposure to theses additives in the following three forms: in dissolved form and after surface blooming, in amorphous and in crystalized ones, and finally in the overall biocompatibility of the native PU. Surface roughness was analyzed with atomic force microscopy. Endothelial cells' viability was studied in contact with all the three physical forms. A preliminary hemocompatibility evaluation was performed through the measurement of whole blood hemolysis, as well as platelet adhesion in contact with the different PU samples. The study of the proinflammatory IL-α and TNF-α production by macrophages in contact with these films is also reported. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2954-2967, 2016.

Next generation macrocyclic and acyclic cationic lipids for gene transfer: Synthesis and in vitro evaluation.

Previously we reported the synthesis and in vitro evaluation of four novel, short-chain cationic lipid gene delivery vectors, characterized by acyclic or macrocyclic hydrophobic regions composed of, or derived from, two 7-carbon chains. Herein we describe a revised synthesis of an expanded library of related cationic lipids to include extended chain analogues, their formulation with plasmid DNA (pDNA) and in vitro delivery into Chinese hamster ovarian (CHO-K1) cells. The formulations were evaluated against each other based on structural differences in the hydrophobic domain and headgroup. Structurally the library is divided into four sets based on lipids derived from two 7- or two 11-carbon hydrophobic chains, C7 and C11 respectively, which possess either a dimethylamine or a trimethylamine derived headgroup. Each set includes four cationic lipids based on an acyclic or macrocyclic, saturated or unsaturated hydrophobic domain. All lipids were co-formulated with the commercial cationic lipid 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC) in a 1:1 molar ratio, along with one of two distinct neutral co-lipids, cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in an overall cationic-to-neutral lipid molar ratio of 3:2. Binding of lipid formulations with DNA, and packing morphology associated with the individual lipid-DNA complexes were characterized by gel electrophoresis and small angle X-ray diffraction (SAXD), respectively. As a general trend, lipoplex formulations based on mismatched binary cationic lipids, composed of a shorter C7 lipid and the longer lipid EPC (C14), were generally associated with higher transfection efficiency and lower cytotoxicity than their more closely matched C11/EPC binary lipid formulation counterparts. Furthermore, the cyclic lipids gave transfection levels as high as or greater than their acyclic counterparts, and formulations with cholesterol exhibited higher transfection and lower cytotoxicity than those formulated with DOPE. A number of the lipid formulations with cholesterol as co-lipid performed as well as, or better than Lipofectamine 2000™ and EPC, the two positive controls employed in these studies. These results suggest that our novel cyclic and acyclic cationic lipid vectors are effective nonviral gene transfer agents that warrant further investigation.

Interaction of intraocular lenses with fibronectin and human lens epithelial cells: Effect of chemical composition and aging.

The aim of this study is to investigate in vitro interactions between hydrophobic acrylate intraocular lenses (IOLs) and their biological environment. The influence of lens chemical composition and aging on fibronectin (FN) adsorption and on IOLs cytotoxicity on human lens epithelial cells was examined. Cytotoxicity of acrylate monomers used in IOLs manufacture was also investigated. Four different IOLs were included in the study: Acrysof(®), Tecnis(®), EnVista(®), and iSert(®). Implants were artificially aged in a xenon arc chamber to simulate 2 years of light exposure. Fibronectin adsorption on IOL surface was quantified using ELISA and correlated to surface roughness determined with AFM. Direct contact cytotoxicity was determined with the MTT assay and cell morphology was observed with light microscopy. Results showed that fibronectin adsorption did not differ significantly among IOLs, whatever their chemical composition. Moreover, aging conditions did not impact fibronectin adsorption. All IOLs were biocompatible even after applying 2-year aging conditions, with cell viability higher than 70%. Five acrylate monomers appeared to be toxic in the range of concentrations tested, but no monomer release from the IOLs could be detected during accelerated 2-year incubation with saline solution. This study did not reveal an influence of chemical composition and aging on protein adsorption and on biocompatibility.

Polyene-based cationic lipids as visually traceable siRNA transfer reagents.

Cationic lipids are promising non-viral vectors for the cellular delivery of nucleic acids. Important considerations for the development of new delivery vectors are enhanced uptake efficiency, low toxicity and traceability. Traceable gene transfer systems however typically require the inclusion of a labeled excipient, and highly sensitive imaging instrumentation to detect the presence of the label. Recently, we reported the synthesis and characterization of colored, polyene cationic phospholipidoids composed of a rigid, polyenoic acid of predetermined dimension (C20:5 and C30:9) paired with flexible saturated alkyl chains of varying lengths (12:0, 14:0, 16:0, 18:0, 20:0 carbons). Herein, the potential of these cationic phospholipids as siRNA carriers was evaluated through standard liposomal formulations in combination with a neutral helper lipid DOPE. The polyene-based lipids were compared with a standard cationic lipid for siRNA-delivery into luciferase expressing HR5-CL11 cells. Within the series of lipids screened, knockdown results indicated that polyene cationic phospholipids paired with longer saturated alkyl chains are more effective as gene transfer agents, and perform comparably with the commercial lipid EPC. Furthermore, the chromophore associated with the polyene chain allowed tracking of the siRNA delivery using direct observation. The polyene lipoplexes were tracked on both a macroscopic and microscopic level either as a single-component or as a multi-component lipoplex formulation. When combined with a reference EPC, effective knockdown and tracking abilities were combined in a single preparation.

Novel cationic polyene glycol phospholipids as DNA transfer reagents--lack of a structure-activity relationship due to uncontrolled self-assembling processes.

Cationic glycol phospholipids were synthesized introducing chromophoric, rigid polyenoic C20:5 and C30:9 chains next to saturated flexible alkyl chains of variable lengths C6-20:0. Surface properties and liposome formation of the amphiphilic compounds were determined, the properties of liposome/DNA complexes (lipoplexes) were established using three formulations (no co-lipid, DOPE as a co-lipid, or cholesterol as a co-lipid), and the microstructure of the best transfecting compounds inspected using small angle X-ray diffraction to explore details of the partially ordered structures of the systems that constitute the series. Transfection and cytotoxicity of the lipoplexes were evaluated by DNA delivery to Chinese hamster ovary (CHO-K1) cells using the cationic glycerol phospholipid 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (EPC) as a reference compound. The uncontrollable self-association of the molecules in water resulted in aggregates and liposomes of quite different sizes without a structure-property relationship. Likewise, adding DNA to the liposomes gave rise to unpredictable sized lipoplexes, which, again, transfected without a structure-activity relationship. Nevertheless, one compound among the novel lipids (C30:9 chain paired with a C20:0 chain) exhibited comparable transfection efficiency and toxicity to the control cationic lipid EPC. Thus, the presence of a rigid polyene chain in this best performing achiral glycol lipid did not have an influence on transfection compared with the chiral glycerolipid reference ethyl phosphocholine EPC with two flexible saturated C14 chains.

Aspects of nonviral gene therapy: correlation of molecular parameters with lipoplex structure and transfection efficacy in pyridinium-based cationic lipids.

This study seeks correlations between the molecular structures of cationic and neutral lipids, the lipid phase behavior of the mixed-lipid lipoplexes they form with plasmid DNA, and the transfection efficacy of the lipoplexes. Synthetic cationic pyridinium lipids were co-formulated (1:1) with the cationic lipid 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC), and these lipids were co-formulated (3:2) with the neutral lipids 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) or cholesterol. All lipoplex formulations exhibited plasmid DNA binding and a level of protection from DNase I degradation. Composition-dependent transfection (beta-galactosidase and GFP) and cytotoxicity was observed in Chinese hamster ovarian-K1 cells. The most active formulations containing the pyridinium lipids were less cytotoxic but of comparable activity to a Lipofectamine 2000™ control. Molecular structure parameters and partition coefficients were calculated for all lipids using fragment additive methods. The derived shape parameter values correctly correlated with observed hexagonal lipid phase behavior of lipoplexes as derived from small-angle X-ray scattering experiments. A transfection index applicable to hexagonal phase lipoplexes derived from calculated parameters of the lipid mixture (partition coefficient, shape parameter, lipoplex packing) produced a direct correlation with transfection efficiency.

Synthesis, self-assembling and gene delivery potential of a novel highly unsaturated, conjugated cationic phospholipid.

The synthesis and self-assembling properties of a model compound in a new class of cationic phospholipids with a highly unsaturated conjugated fatty acid are described. In addition, the potential of this new lipid as a nucleic acid carrier was evaluated through lipoplex formulations employing 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as helper lipid with and without the polycationic peptide protamine, together with a plasmid DNA (pDNA). Lipoplexes composed of this novel unsaturated lipid exhibited pDNA binding and protection from DNase I degradation when formulated with protamine. The new cationic lipid revealed transfection efficiency comparable to the commercial reference 1,2-dimyristoyl-sn-glycero-3-ethylphophocholine (EPC) in Chinese hamster ovary-K1 (CHO-K1) cells and performed equally to the standard reference Lipofectamine 2000 when the formulation included protamine.

Novel macrocyclic and acyclic cationic lipids for gene transfer: synthesis and in vitro evaluation.

The synthesis and in vitro evaluation of four cationic lipid gene delivery vectors, characterized by acyclic or macrocyclic, and saturated or unsaturated hydrophobic regions, is described. The synthesis employed standard protocols, including ring-closing metathesis for macrocyclic lipid construction. All lipoplexes studied, formulated from plasmid DNA and a liposome composed of a synthesized lipid, 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC), and either 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or cholesterol as co-lipid, exhibited plasmid DNA binding and protection from DNase I degradation, and concentration dependent cytotoxicity using Chinese hamster ovary-K1 cells. The transfection efficiency of formulations with cholesterol outperformed those with DOPE, and in many cases the EPC/cholesterol control, and formulations with a macrocyclic lipid (+/- 10:1) outperformed their acyclic counterparts (+/- 3:1).

Synthesis and preliminary investigations of the siRNA delivery potential of novel, single-chain rigid cationic carotenoid lipids.

The success of nucleic acid delivery requires the development of safe and efficient delivery vectors that overcome cellular barriers for effective transport. Herein we describe the synthesis of a series of novel, single-chain rigid cationic carotenoid lipids and a study of their preliminary in vitro siRNA delivery effectiveness and cellular toxicity. The efficiency of siRNA delivery by the single-chain lipid series was compared with that of known cationic lipid vectors, 3ß-[N-(N',N'-dimethylaminoethane)carbamoyl]-cholesterol (DC-Chol) and 1,2-dimyristoyl-sn-glyceryl-3-phosphoethanolamine (EPC) as positive controls. All cationic lipids (controls and single-chain lipids) were co-formulated into liposomes with the neutral co-lipid, 1,2-dioleolyl-sn-glycerol-3-phosphoethanolamine (DOPE). Cationic lipid-siRNA complexes of varying (+/-) molar charge ratios were formulated for delivery into HR5-CL11 cells. Of the five single-chain carotenoid lipids investigated, lipids 1, 2, 3 and 5 displayed significant knockdown efficiency with HR5-CL11 cells. In addition, lipid 1 exhibited the lowest levels of cytotoxicity with cell viability greater than 80% at all (+/-) molar charge ratios studied. This novel, single-chain rigid carotenoid-based cationic lipid represents a new class of transfection vector with excellent cell tolerance, accompanied with encouraging siRNA delivery efficiency.

Preparation of E-selectin-targeting nanoparticles and preliminary in vitro evaluation.

Targeted delivery aims to concentrate therapeutic agents at their site of action and thereby enhance treatment and limit side-effects. E-selectin on endothelial cells is markedly up-regulated by cytokine stimulation of inflamed and some tumoral tissues, promoting the adhesion of leukocytes and metastatic tumor cells, thus making it an interesting molecular target for drug delivery systems. We report here the preparation of targeted nanoparticles from original amphiphilic block copolymers functionalized with an analog of sialyl Lewis X (SLEx), the physiological ligand of E-selectin. Nanoparticles, prepared by nanoprecipitation, caused no significant cytotoxicity. Ligand-functionalized nanoparticles were specifically recognized and internalized better by tumor necrosis factor α (TNF-α)-activated human umbilical vein endothelial cells (HUVECs) than control nanoparticles or HUVECs with low E-selectin expression. These nanoparticles are designed to carry the ligand at the end of a PEG spacer to improve accessibility. This system has potential for the treatment of inflammation, inhibition of tumor metastasis, and for molecular imaging.

E-selectin as a target for drug delivery and molecular imaging.

E-selectin, also known as CD62E, is a cell adhesion molecule expressed on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation and in the adhesion of metastatic cancer cells to the endothelium. E-selectin recognizes and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes. E-selectin has been chosen as a target for several therapeutic and medical imaging applications, based on its expression in the vicinity of inflammation, infection or cancer. These systems for drug delivery and molecular imaging include immunoconjugates, liposomes, nanoparticles, and microparticles prepared from a wide range of starting materials including lipids, synthetic polymers, polypeptides and organo-metallic structures. After a brief introduction presenting the selectin family and their implication in physiology and pathology, this review focuses on the formulation of these new delivery systems targeting E-selectin at a molecular level.