Various lipid anchors on amphiphilic polyoxazolines to reach efficient intracellular delivery.

This work aimed at evaluating the potential of amphiphilic polyoxazolines bearing lipid chain called lipopolyoxazolines to reach efficient intracellular delivery. Four lipid chains: linear saturated, linear unsaturated and two branched one of various length were associated to poly(2-methyl-2-oxazoline) block. The evaluation of their physicochemical features and their impact on cell viability and internalization capacity indicated that the linear saturated gathered the highest cell internalization with a good cell viability. Its intracellular delivery capacity was compared to the PEG reference (DSPE-PEG) after being formulated in liposomes and loaded with fluorescent probe. Both POxylated and PEGylated liposomes showed similar characteristics regarding size distribution, drug loading and cell viability. However, their intracellular delivery was dramatically different, with an improved delivery by 30 folds for the POxylated ones. This significantly better performance highlighted the difficulty of PEGylated liposomes to enter the cells by endocytosis, contrary to POxylated liposomes. This study promotes the value of lipopoly(oxazoline) as a lipopoly(ethylene glycol) alternative for effective intracellular delivery and holds great promises for development of nanoformulations for intravenous administration.

Interactions of amphiphilic polyoxazolines formulated or not in lipid nanocapsules with biological systems: Evaluation from membrane models up to in vivo mice epidermis.

In this study, we evaluated the potential of amphiphilic polyoxazolines (POx) to interact with biological membranes thanks to models of increasing complexity, from a simple lipid bilayer using giant unilamellar vesicles (GUV), to plasma membranes of three different cell types, fibroblasts, keratinocytes and melanocytes, which are found in human skin. Upon assessing an excellent penetration into GUV membranes and cultured cells, we addressed POx's potential to penetrate the murine skin within an in vivo model. Exposure studies were made with native POx and with POx encapsulated within lipid nanocapsules (LNC). Our findings indicate that POx's interactions with membranes tightly depend on the nature of the alkyl chain constituting the POx. Saturated C16POx insert rapidly and efficiently into GUV and plasma membranes, while unsaturated C18:2POx insert to a smaller extent. The high amount of membrane-inserted saturated C16POx impacts cell viability to a greater extent than the unsaturated C18:2POx. The in vivo study, performed on mice, showed an efficient accumulation of both POx types in the stratum corneum barrier, reaching the upper epidermis, independently of POx's degree of saturation. Furthermore, the formulation of POx into lipid nanocapsules allowed delivering an encapsulated molecule, the quercetin, in the upper epidermis layers of murine skin, proving POx's efficacy for topical delivery of active molecules. Overall, POx proved to be an excellent choice for topical delivery, which might in turn offer new possibilities for skin treatments in diseases such as psoriasis or melanomas.

Recent advances and prospects in nano drug delivery systems using lipopolyoxazolines.

Facing the growing demand in nano drug delivery systems (nDDS), hybrid excipients based on natural molecules and well-defined synthetic polymers are intensively investigated. Lipopolyoxazolines (LipoPOx) composed of a polyoxazoline block (POx) and a lipid or lipid-like derivative are detailed in this review. The nature of lipids used, the route to synthesize LipoPOx and their advantages for the formulation of drugs are reported. The place of POx family in nanomedicine is discussed compared to PEG, considered as the gold standard of hydrophilic polymers. LipoPOx nanoformulations including liposomes, mixed micelles, lipid nanocapsules are provided alongside discussion of the nDDS for intravenous or topical administration.

Polyoxazolines based lipid nanocapsules for topical delivery of antioxidants.

Nano-sized lipid formulations offer a great potential for topical delivery of active compounds to treat and prevent human skin damages. Of particular importance is the high loading of hydrophobic molecules, the long-term stability and the auspicious penetration capacity especially reached when using lipid nanocapsules (LNC). Unfortunately, their formation currently relies on a phase inversion process that only operates when using a poly(ethylene glycol) (PEG) based surfactant belonging to the controversial PEG family that was subject of clinical awareness. The present study proposes an alternative to this overused polymer in formulations by designing LNC made of harmless amphiphilic polyoxazolines (POx). Implementing a short sonication step in the process allowed well-defined spherical nanoparticles of ~30 nm to be obtained. The structure of the so called LNC POx was composed of an oily core surrounded by a rigid shell of phospholipids and POx, which ensures a high stability over time, temperature, centrifugation and freezing. Encapsulation of the natural quercetin antioxidant led to a drug loading three times higher than for LNC constituted of PEG (LNC PEG). The antioxidant activity of loaded LNC POx was tested on mice fibroblasts and human keratinocytes after exposure to free radicals from peroxides and UVB irradiation, respectively. The radical scavenging capacity of quercetin loaded in the LNC POx was preserved and even slightly enhanced compared to LNC PEG, highlighting the POx value in nanoformulations.

Polyoxazolines based mixed micelles as PEG free formulations for an effective quercetin antioxidant topical delivery.

This study aims to prove the value of the polyoxazolines polymer family as surfactant in formulations for topical application and as an alternative to PEG overuse. The amphiphilic polyoxazolines (POx) were demonstrated to have less impact on cell viability of mice fibroblasts (NIH3T3) than their PEG counterparts. Mixed micelles, made of POx and phosphatidylcholine, were manufactured using thin film and high pressure homogenizer process. The mixed micelles were optimized to produce nanosized vesicles of about 20 nm with a spherical shape and stable over 28 days. The natural lipophilic antioxidant, quercetin, was successfully encapsulated (encapsulation efficiency 94 ±â€¯4% and drug loading 3.6 ±â€¯0.2%) in the mixed micelles with no morphological variation. Once loaded in the formulation, the quercetin impact on cell viability of NIH3T3 was decreased while its antioxidant activity remained unchanged. This work highlights the capacity of amphiphilic POx to create, in association with phospholipids, stable nanoformulations which show promise for topical delivery of antioxidant and ensure skin protection against oxidative stress.

Physicochemical properties of pH-controlled polyion complex (PIC) micelles of poly(acrylic acid)-based double hydrophilic block copolymers and various polyamines.

The physicochemical properties of polyion complex (PIC) micelles were investigated in order to characterize the cores constituted of electrostatic complexes of two oppositely charged polyelectrolytes. The pH-sensitive micelles were obtained with double hydrophilic block copolymers containing a poly(acrylic acid) block linked to a modified poly(ethylene oxide) block and various polyamines (polylysine, linear and branched polyethyleneimine, polyvinylpyridine, and polyallylamine). The pH range of micellization in which both components are ionized was determined for each polyamine. The resulting PIC micelles were characterized using dynamic light scattering and small-angle X-ray scattering experiments (SAXS). The PIC micelles presented a core-corona nanostructure with variable polymer density contrasts between the core and the corona, as revealed by the analysis of the SAXS curves. It was shown that PIC micelle cores constituted by polyacrylate chains and polyamines were more or less dense depending on the nature of the polyamine. It was also determined that the density of the cores of the PIC micelles depended strongly on the nature of the polyamine. These homogeneous cores were surrounded by a large hairy corona of hydrated polyethylene oxide block chains. Auramine O (AO) was successfully entrapped in the PIC micelles, and its fluorescence properties were used to get more insight on the core properties. Fluorescence data confirmed that the cores of such micelles are quite compact and that their microviscosity depended on the nature of the polyamine. The results obtained on these core-shell micelles allow contemplating a wide range of applications in which the AO probe would be replaced by various cationic drugs or other similarly charged species to form drug nanocarriers or new functional nanodevices.

Kinetics of protein diffusion from a poly(D,L-lactide) reservoir system.

The release kinetics of albumin diffusion from a poly(D,L-lactide) reservoir system was investigated with the long-term aim of developing a multidose pulsatile delivery system. Albumin pellets were coated with polylactide of varying viscosity-average molecular weight, Mv, and concentration, and incubated in aqueous solution. The albumin release profile was approximated by zero-order release kinetics, with release rates ranging from 3 to 1800 mg/day. The permeability of the poly(D,L-lactide) membranes to albumin diffusion ranged from 1 x 10(-9) to 100 x 10(-9) cm2/S, and was found to decrease with increasing membrane thickness (18 to 1400 microns) and density (300 to 3000 mg/cm3). The initiation of albumin release from the pellets could be delayed from a few hours to more than one month by increasing the Mv of the polylactide from 6.2 x 10(3) to 140 x 10(3) and raising the concentration of the polymer coating solution from 50 to 100 mg/mL. The diversity in delayed-release effect and the variations in membrane permeabilities were attributed to changes in membrane porosity and polymer morphology.