Drug-loaded nanocarriers : passive targeting and crossing of biological barriers

Poor bioavailability and poor pharmacokinetic characteristics are some of the leading causes of drug development failure. Therefore, poorly-soluble drugs, fragile proteins or nucleic acid products may benefit from their encapsulation in nanosized vehicles, providing enhanced solubilisation, protection against degradation, and increased access to pathological compartments. A key element for the success of drug-loaded nanocarriers (NC) is their ability to either cross biological barriers themselves or allow loaded drugs to traverse them to achieve optimal pharmacological action at pathological sites. Depending on the mode of administration, NC may have to cross different physiological barriers in their journey towards their target. In this review, the crossing of biological barriers by passive targeting strategies will be presented for intravenous delivery (vascular endothelial lining, particularly for tumour vasculature and blood-brain barrier targeting), oral administration (gastrointestinal lining) and upper airway administration (pulmonary epithelium). For each specific barrier, background information will be provided on the structure and biology of the tissues involved as well as available pathways for nano-objects or loaded drugs (diffusion and convection through fenestration, transcytosis, tight junction crossing, etc.). The determinants of passive targeting − size, shape, surface chemistry, surface patterning of nanovectors − will be discussed in light of current results. Perspectives on each mode of administration will be presented. The focus will be on polymeric nanoparticles and dendrimers although advances in liposome technology will be also reported as they represent the largest body in the drug delivery literature

Nanoparticle heterogeneity : an emerging structural parameter 2 influencing particle fate in biological media?

Drug nanocarriers’ surface chemistry is often presumed to be uniform. For instance, the polymer surface coverage and distribution of ligands on nanoparticles are described with averaged values obtained from quantification techniques based on particle populations. However, these averaged values may conceal heterogeneities at different levels, either because of the presence of particle sub-populations or because of surface inhomogeneities, such as patchy surfaces on individual particles. The characterization and quantification of chemical surface heterogeneities are tedious tasks, which are rather limited by the currently available instruments and research protocols. However, heterogeneities may contribute to some non-linear effects observed during the nanoformulation optimization process, cause problems related to nanocarrier production scale-up and correlate with unexpected biological outcomes. On the other hand, heterogeneities, while usually unintended and detrimental to nanocarrier performance, may, in some cases, be sought as adjustable properties that provide NPs with unique functionality. In this review, results and processes related to this issue are compiled, and perspectives and possible analytical developments are discussed

Effect of polymer architecture on Curcumin 1 encapsulation and release from PEGylated polymer nanoparticles: toward a drug delivery nano-platform to the CNS

We developed a nanoparticles (NPs) library from poly(ethylene glycol)–poly lactic acid comb-like polymers with variable amount of PEG. Curcumin was encapsulated in the NPs with a view to develop a delivery platform to treat diseases involving oxidative stress affecting the CNS. We observed a sharp decrease in size between 15 and 20% w/w of PEG which corresponds to a transition from a large solid particle structure to a “micelle-like” or “polymer nano-aggregate” structure. Drug loading, loading efficacy and release kinetics were determined. The diffusion coefficients of curcumin in NPs were determined using a mathematical modeling. The higher diffusion was observed for solid particles compared to “polymer nano-aggregate” particles. NPs did not present any significant toxicity when tested in vitro on a neuronal cell line. Moreover, the ability of NPs carrying curcumin to prevent oxidative stress was evidenced and linked to polymer architecture and NPs organization. Our study showed the intimate relationship between the polymer architecture and the biophysical properties of the resulting NPs and sheds light on new approaches to design efficient NP-based drug carriers

Unified scaling of the structure and loading of nanoparticles formed via diffusion-limited coalescence

The present study establishes the scaling laws describing the structure of spherical nanoparticles formed by diffusion-limited coalescence. We produced drug-loaded nanoparticles from a poly(ethylene glycol)-poly(d,l-lactic acid) diblock polymer (PEG-b-PLA) by the nanoprecipitation method using different types of micromixing chambers to explore multiple mixing regimes and characteristic times. We first show that the drug loading of the nanoparticles is not controlled by the mixing time but solely by the drug-to-polymer ratio (D:P) in the feed and the hydrophobicity of the drug scaled via the partition coefficient P. We then procure compelling evidence that particles formed via diffusion/coalescence exhibit a relative distribution of PEG blocks between the particle core and its shell that depends only on mixing conditions (not on D:P). Scaling laws of PEG relative distribution and chain surface density were derived in different mixing regimes and showed excellent agreement with experimental data. In particular, results made evident that PEG blocks entrapment in the core of the particles occurs in the slow-mixing regime and favors the overloading (above the thermodynamic limit) of the particles with hydrophilic drugs. The present analysis compiles effective guidelines for the scale up of nanoparticles structure and properties with mixing conditions, which should facilitate their future translation to medical and industrial settings

Functional polylactide via ring-opening copolymerisation with allyl, benzyl and propargyl glycidyl ethers.

A versatile and simple strategy is presented to synthesize reactive polylactide derivatives and their block copolymers with polyethylene glycol. Commercially available glycidyl ethers with an allyl, benzyl or propargyl functional group were copolymerised with D,L-lactide. Tin(II)-2- ethylhexanoate-catalysis produced polymers with up to 4.6, 5.9 and 2.3 allyl, benzyl or propargyl groups per chain, respectively. In contrast, less than one reactive group per chain was obtained with the organocatalyst 1,5,7-triazabicyclo[4.4.0]dec-5-ene. By increasing the polymerisation feed ratio in glycidyl ether polymers with a higher number of reactive groups per chain were obtained, however a decrease in molar mass was observed. An azidocoumarin was conjugated to the propargylated polymers via copper-catalysed azide-alkyne cycloaddition. These dye-labelled polymers produced nanospheres with fluorescent properties and diameters in the 100-nm sizerange, as characterised by asymmetric flow field flow fractionation hyphenated with fluorescence, static and dynamic light scattering detection. The functionalised polymers were obtained at gram-scale in one step from commercially available reagents; therefore providing a robust and easy to implement approach for the production of multifunctional nanomaterials

Selectins Ligand Decorated Drug Carriers for Activated Endothelial Cell Targeting

New active particulate polymeric vectors based on branched polyester copolymers of hydroxy-acid and allyl glycidyl ether were developed to target drugs to the inflammatory endothelial cell surface. The hydroxyl and carboxyl derivatives of these polymers allow grafting of ligand molecules on the polyester backbones at different densities. A known potent nonselective selectin ligand was selected and synthesized using a new scheme. This synthesis allowed the grafting of the ligand to the polyester polymers, preserving its binding activity as assessed by docking simulations. Selectin expression on human umbilical cord vascular endothelial cells (HUVEC) was induced with the pro-inflammatory bacterial lipopolysaccharide (LPS) or with the nonselective inhibitor of nitric oxide synthase L-NAME. Strong adhesion of the ligand decorated nanoparticles was evidenced in Vitro on activated HUVEC. Binding of nanoparticles bearing ligand molecules could be efficiently inhibited by prior incubation of cells with free ligand, demonstrating that adhesion of the nanoparticles is mediated by specific interaction between the ligand and the selectin receptors. These nanoparticles could be used for specific drug delivery to the activated vascular endothelium, suggesting their application in the treatment of diseases with an inflammatory component such as rheumatoid arthritis and cancer

Synthesis and characterization of 3-methyl-6-[(propynyloxy)methyl]-1,4-dioxane-2,5-dione

The number of known asymmetrically substituted hemilactides, important precursors for obtaining regular derivatives of polylactide polymers, is still limited and structural characterization of most of them is incomplete. In the title racemic 1,4-dioxane-2,5-dione derivative, C9H10O5, the hemilactide heterocycle exhibits a twist-boat conformation. The bulkier propynyloxymethyl group is in an axial position with a gauche conformation for the CH2–O–CH2–C segment. In the crystal, molecules are linked by pairs of C—H...O hydrogen bonds, forming inversion dimers. The dimers are linked by further C—H...O contacts, forming a three-dimensional structure

Compatibilité de l’acétylcystéine injectable lors de son administration en Y avec d’autres médicaments usuels

RésuméObjectif : Il n’existe que peu de données publiées sur la compatibilité de l’acétylcystéine intraveineuse avec d’autres médicaments. Le but de ce travail vise à dresser une liste de médicaments compatibles avec l’acétylcystéine lorsqu’ils lui sont mélangés.Méthode : Les tests de compatibilité visuelle effectués consistaient en des vérifications de la présence ou non de précipitation dans des mélanges de 1 mL d’acétylcystéine injectable et de plusieurs autres médicaments.Résultats : Nous notons une incompatibilité visuelle de l’acétylcystéine avec l’acyclovir, l’amphotéricine B, la céfazoline, la cyclosporine, l’érythromycine, l’insuline et la méthylprednisolone. Les tests concernant l’adrénaline, l’aminophylline, la céfuroxime, la chlorpromazine, la cloxacilline, la dexaméthasone, le dextrose à 50 % et le métronidazole laissent planer quelques doutes, le mélange de ces substances à l’acétylcystéine n’est donc pas recommandé. Plusieurs autres médicaments sont toutefois visuellement compatibles avec l’acétylcystéine lors d’une administration en Y.Conclusion : Ce protocole a permis d’établir de nombreuses données de compatibilité entre l’acétylcystéine et plusieurs médicaments. Toutefois, ces données ne sont que des observations visuelles, et des tests physico chimiques formels confirmant les résultats seraient requis.AbstractObjectives: Few published data on the compatibility of intravenous acetylcysteine with other drugs are available. The aim of this research was to prepare a list of drugs compatible with acetylcysteine.Method: The visual compatibility tests performed consisted in checking whether or not precipitation occurred in mixtures of 1 mL of injectable acetylcysteine and a number of other drugs.Results: We observed visual incompatibility of acetylcysteine with acyclovir, amphotericin B, cefazolin, cyclosporine, erythromycin, insulin and methylprednisolone. The tests involving adrenaline, aminophylline, cefuroxime, chlorpromazine, cloxacillin, dexamethasone, 50% dextrose and metronidazole left some uncertainly. Mixing these substances with acetylcysteine is therefore not recommended. A number of other drugs were, however, visually compatible with acetylcysteine during Y-site administration.Conclusion: This research has provided new information on the compatibility of acetylcysteine with other drugs. However, these data are based only on visual observations. Formal physicochemical tests are needed to confirm these findings

Assessment of PEG on Polymeric Particles Surface, a Key Step in Drug Carrier Translation

Injectable drug nanocarriers have greatly benefited in their clinical development from the addition of a superficial hydrophilic corona to improve their cargo pharmacokinetics. The most studied and used polymer for this purpose is poly(ethylene glycol), PEG. However, in spite of its wide use for over two decades now, there is no general consensus on the optimum PEG chain coverage-density and size required to escape from the mononuclear phagocyte system and to extend the circulation time. Moreover, cellular uptake and active targeting may have conflicting requirements in terms of surface properties of the nanocarriers which complicates even more the optimization process. These persistent issues can be largely attributed to the lack of straightforward characterization techniques to assess the coverage-density, the conformation or the thickness of a PEG layer grafted or adsorbed on a particulate drug carrier and is certainly one of the main reasons why so few clinical applications involving PEG coated particle-based drug delivery systems are under clinical trial so far. The objective of this review is to provide the reader with a brief description of the most relevant techniques used to assess qualitatively or quantitatively PEG chain coverage-density, conformation and layer thickness on polymeric nanoparticles. Emphasis has been made on polymeric particle (solid core) either made of copolymers containing PEG chains or modified after particle formation. Advantages and limitations of each technique are presented as well as methods to calculate PEG coverage-density and to investigate PEG chains conformation on the NP surface