Preparation and characterization of biodegradable poly(isobutylcyano acrylate) nanoparticles with the surface modified by the adsorption of proteins

The purpose of this work was to develop and characterize a biodegradable colloidal drug carrier which avoids uptake by the mononuclear phagocyte system. In order to imitate the cell surface, a sialic-acid-rich glycoprotein (human orosomucoid) was adsorbed onto poly(isobutylcyano acrylate) nanoparticles. The adsorption of human serum albumin and asialo-orosomucoid was also tested as a control. The adsorption was found to be dependent on the pH value and reached its maximum at a pH value close to the isoelectric point (pI) of each protein. The increase in the ionic strength due to the addition of NaCl generally resulted in an increase in the amount adsorbed. Considering the amounts of protein adsorbed (maximum of 4.5 mg m⁻²), the adsorption was assumed to be of the monolayer type. The adsorption kinetics performed at the pI of each protein showed that the equilibrium was reached within 1 h for albumin and within 8 h for the two glycoproteins. This significant difference suggested that conformational rearrangements could be much slower for the two glycoproteins than for the non-glycosylated albumin. The protein layer was found to be stable at pH 7 when the adsorption was performed beforehand at the pI, i.e. at an acidic pH. Finally, using hydrophobic interaction chromatography, the surface of the coated nanoparticles was found to be much more hydrophilic than the surface of the unmodified nanoparticles.     

Structural characterization of ultrasmall superparamagnetic iron oxide (USPIO) particles in aqueous suspension by energy dispersive X-ray diffraction (EDXD)

Ultrasmall superparamagnetic iron oxide (USPIO) particles were structurally characterized in situ in an aqueous dilute suspension by energy dispersive X-ray diffraction (EDXD) and ex situ as powders obtained by lyophilization of the suspension by angular dispersive X-ray diffraction (ADXD) at 20 degrees C. Structural parameters obtained by the Rietveld method on ADXD data were used as starting parameters for modeling the structure of the particles in suspension. Although each particle is a single crystal, as evidenced by conventional X-ray diffraction, our results indicate that the structural order, specific to a crystal, does not extend to the entire volume of the particle. In fact, each individual particle, averagely, has a crystalline structural extension ca. 4.0 nm smaller than the apparent dimensions obtained by both ADXD and TEM (ca. 8.0 nm).     

BioMOFs: Metal–Organic Frameworks for Biological and Medical Applications

The class of highly porous materials called metal–organic frameworks offer many opportunities for applications across biology and medicine. Their wide range of chemical composition makes toxicologically acceptable formulation possible, and their high level of functionality enables possible applications as imaging agents and as delivery vehicles for therapeutic agents. The challenges in the area encompass not only the development of new solids but also improvements in the formulation and processing of the materials, including tailoring the morphology and surface chemistry of the frameworks to fit the proposed applications.     

Squalenyl Hydrogen Sulfate Nanoparticles for Simultaneous Delivery of Tobramycin and an Alkylquinolone Quorum Sensing Inhibitor Enable the Eradication of P. aeruginosa Biofilm Infections

Elimination of pulmonary Pseudomonas aeruginosa (PA) infections is challenging to accomplish with antibiotic therapies, mainly due to resistance mechanisms. Quorum sensing inhibitors (QSIs) interfering with biofilm formation can thus complement antibiotics. For simultaneous and improved delivery of both active agents to the infection sites, self-assembling nanoparticles of a newly synthesized squalenyl hydrogen sulfate (SqNPs) were prepared. These nanocarriers allowed for remarkably high loading capacities of hydrophilic antibiotic tobramycin (Tob) and a novel lipophilic QSI at 30 % and circa 10 %, respectively. The drug-loaded SqNPs showed improved biofilm penetration and enhanced efficacy in relevant biological barriers (mucin/human tracheal mucus, biofilm), leading to complete eradication of PA biofilms at circa 16-fold lower Tob concentration than Tob alone. This study offers a viable therapy optimization and invigorates the research and development of QSIs for clinical use.     

Spontaneous association of hydrophobized dextran and poly-beta-cyclodextrin into nanoassemblies. Formation and interaction with a hydrophobic drug

New nanoassemblies were instantaneously prepared by mixing two aqueous solutions, one containing a beta-cyclodextrin polymer (pbetaCD), and the other a hydrophobically modified by alkyl chains dextran (MD). The formation mechanism and the inner structure of these nanoassemblies were analysed using surface tension measurements and (1)H NMR spectroscopy. The effect of a hydrophobic guest molecule, such as benzophenone (BZ), on the formation and stability of the nanoassemblies was also evaluated. MD exhibited the typical behaviour of a soluble amphiphilic molecule and adsorbed at the air/water interface. Whereas the injection of native beta-CDs in the solution beneath the adsorbed MD monolayer did not produce any change in the surface tension, that of the pbetaCD resulted in an increase in the surface tension, indicating the desorption of the polymer from the interface. This result accounts for a cooperative effect of beta-CDs linked together in the pbetaCD polymer on dextran desorption. The presence of benzophenone in the system hindered the sequestration of dextran alkyl moieties by beta-CD in the polymer without impeding the formation of associative nanoassemblies of 100-200 nm. (1)H NMR investigations demonstrated that, in the BZ-loaded nanoassemblies, the hydrophobic molecule was mainly located into the cyclodextrin cavities.     

Synthesis and physicochemical characterization of new squalenoyl amphiphilic gadolinium complexes as nanoparticle contrast agents

A family of novel amphiphilic gadolinium chelates was successfully obtained by coupling the hydrophilic DOTA ligand [1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane] to squalenoyl moieties. Thanks to the self-assembling properties of their squalenoyl lipophilic moieties, all these derivatives were able to form, without any adjuvant, micellar or liposome-like supramolecular nanoassemblies, endowed with high relaxivities (r(1) = 15-22 mM(-1) s(-1) at 20 MHz and 37 °C). The remarkably high payloads of Gd(3+) ions reached 10 to 17 wt %. Moreover, one of these derivatives interacted with human serum albumin (HSA) forming mixed micelles, which induced a remarkable increase in relaxivity. Liposome-like structures were obtained when the Gd(3+) complex of DOTA was coupled to two squalene units. These liposomal structures were characterized by a high loading of Gd(3+) (about 74,000 gadolinium ions per particle of 100 nm). The supramolecular architecture of these nano-objects has been investigated by electron microscopy and small-angle X-ray scattering. Squalenoylation of gadolinium derivatives offers a platform to conceive contrast agents (CAs) in mild conditions (no toxic solvents, no surfactants, no energy input). These new amphiphilic gadolinium chelates could also find potential applications in theranostics, by forming mixed systems with other squalenoylated drugs, or to delineate blood vessels owing to the interaction with HSA.     

Facile Synthesis of Multicompartment Micelles Based on Biocompatible Poly(3‐hydroxyalkanoate)

In this paper, a straightforward method to produce poly(3‐hydroxyalkanoate)‐based multicompartment micelles (MCMs) is presented. Thiol‐ene addition is used to graft sequentially perfluorooctyl chains and poly(ethylene glycol) oligomers onto poly(3‐hydroxyoctanoate‐co‐hydroxyundecenoate) oligomers backbone. Well‐defined copolymers are obtained as shown by ¹H NMR and size‐exclusion chromatography. After nanoprecipitation in water, novel PHA‐based MCMs are evidenced by cryo‐transmission electron microscopy. Moreover, the cytocompatibility of MCMs is demonstrated in vitro via cell viability assay.     

Compartmentalized Encapsulation of Two Antibiotics in Porous Nanoparticles: an Efficient Strategy to Treat Intracellular Infections

Combinatorial drug therapies emerge among the most promising strategies to treat complex pathologies such as cancer and severe infections. Biocompatible nanoparticles of mesoporous iron carboxylate metal–organic framework (nanoMOFs) are used here to address the challenging aspects related to the coincorporation of two antibiotics. Amoxicillin and potassium clavulanate, a typical example of drugs used in tandem, are efficiently coincorporated with payloads up to 36 wt%. Due to the occurrence of two distinct pore sizes/apertures within the MOF architecture, each drug is able to infiltrate the porous framework and localize within separate compartments. Molecular simulations predict drug loadings and locations consistent with experimental findings. Drug loaded nanoMOFs that are internalized by Staphylococcus aureus infected macrophages are able to colocalize with the pathogen, which in turn leads to an alleviation of bacterial infection. The data also reveal potential antibacterial properties of nanoMOFs alone as well as their ability to deliver a high payload of drugs to fight intracellular bacteria. These results pave the way toward the design of engineered “all‐in‐one” nanocarriers in which both the loaded drugs and their carrier play a role in fighting intracellular infections.     

Amphiphilic derivatives of dextran and related nanoparticles

Graft block copolymers of poly(?-caprolactone) containing various amounts of dextran [dextranpoly(?-caprolactone) copolymers] have been prepared and characterized. The methods of obtaining nanoparticles based on the dextran-poly(?-caprolactone) graft block copolymers have been elaborated and optimized. It has been demonstrated that the electrokinetic potential of nanoparticles may be varied relative to the composition of the polymer, the structure of nanoparticles, and the ionic strength of solution. Under physiological conditions, the nanoparticles behave as stable colloids. On the basis of the experimental evidence, conclusions concerning the structure of the nanoparticles have been made.