Oral administration of peptides still remains a challenging issue. We previously pointed out the possibility to target intestinal PepT1 transporter with functionalized PLA-PEG nanoparticles (NPs) formulated by nanoprecipitation, and to improve drug-loaded intestinal permeability. Nevertheless, alternative manufacturing processes exist and the impact on the intestinal transporter targeting could be interesting to study. Our objective is consequently to assess the ability of functionalized NPs to target PepT1 according to the manufacturing process, and the possibility to improve peptide absorption. PLA-PEG-Valine NPs were formulated by nanoprecipitation, double and simple emulsion with median particle size <200 nm. Using Caco-2 cells, the competition between PLA-PEG-Val NPs formulated by the different manufacturing processes, and [3H]Glycylsarcosine, a well-known substrate of PepT1, was observed to evaluate the impact of the process on the intestinal transporter PepT1 targeting. Simultaneously, PLA-PEG-Val NPs were labeled with fluorescein (FITC) to evaluate PepT1 targeting and to observe the behavior of the NPs close to the cell according to the manufacturing process by confocal imaging. Finally, oxytocin peptide (OXY) was encapsulated in Val-NPs according to the most relevant process and the transport of the drug was assessed in vitro and in vivo, and compared to free drug. It was possible to observe by TEM imaging a better organization and expression of the ligand at the surface for NPs formulated by emulsion processes. Furthermore, the competition between functionalized NPs and [3H]Glycylsarcosine revealed a better transport inhibition of [3H]Glycylsarcosine for NPs formulated by double emulsion (≈ 67%). These results were confirmed by fluorescence measurements, comparing the amount of fluorescence linked to the cells after incubation with fluorescent Val-NPs for the 3 processes (≈ 39% for double emulsion). Additionally, confocal microscopy confirmed the ability of Val-NPs prepared by double emulsion to target the cell membrane and even to reach the intracellular space. OXY was then encapsulated by double emulsion in Val-NPs with a drug load of ≈ 4%. It was thus shown in vitro that drug transport was doubled compared to free drug. In vivo, OXY plasma concentration after oral administration were significantly increased when encapsulated in Val-NPS obtained by double emulsion compared to free drug. These results demonstrated that NPs prepared by double emulsion allowed a better PepT1 targeting and is a promising approach for oral peptide delivery.

Targeting intestinal di- and tri-peptide transporter PepT1 with prodrugs is a successful strategy to improve oral drug bioavailability, as demonstrated with valacyclovir, a prodrug of acyclovir. The aim of this new drug delivery strategy is to over-concentrate a poorly absorbed drug on the intestinal membrane surface by targeting PepT1 with functionalized polymer nanoparticles. In the present study, poly(lactic acid)-poly(ethylene glycol)-ligand (PLA-PEG-ligand) nanoparticles were obtained by nanoprecipitation. A factorial experimental design allowed us to identify size-influent parameters and to obtain optimized ≈30 nm nanoparticles. Valine, Glycylsarcosine, Valine-Glycine, and Tyrosine-Valine were chemically linked to PLA-PEG. In Caco-2 cell monolayer model, competition between functionalized nanoparticles and [3H]Glycylsarcosine, a strong substrate of PepT1, reduced [3H]Glycylsarcosine transport from 22 to 46%. Acyclovir was encapsulated with a drug load of ≈10% in valine-functionalized nanoparticles, resulting in a 2.7-fold increase in permeability as compared to the free drug. An in vivo pharmacokinetic study in mice compared oral absorption of acyclovir after administration of 25 mg/kg of valacyclovir, free or encapsulated acyclovir in functionalized nanoparticles. Acyclovir encapsulation did not statistically modify AUC or Cmax, but increased t1/2 and MRT 1.3-fold as compared to free acyclovir. This new strategy is promising for poorly absorbed drugs by oral administration.

During the course of our study on the innovative ligand for nicotinic acetylcholinergic receptors, LNAChR, and in order to assess activity and toxicity profiles of the drug’s metabolites, synthesis of the main metabolites was undertaken. This synthesis work was done in parallel by organic chemistry and by biotransformation of LNAChR. Filamentous fungus Aspergillus alliaceus (NRRL 315) neatly afforded three of the main metabolites, one of which arose from a very unexpected and very uncommon rearrangement.

To improve solubilization of a water insoluble anticancer drug, novel surfactants were synthesized. All surfactants derived from lysine, with a so-called nitrilo triacetic acid (NTA) polar head, and differed from the length and saturation degree of their hydrophobic moieties: C19:0-NTA, C20:4-NTA, C25:0-NTA and C25:4-NTA. Self-assembling properties and critical micellar concentration (CMC) values were determined using pyrene fluorescence and cytotoxicity using MTT and LDH assays on endothelial cells. Surfactant haemolytic activity and drug solubilization capacity were also evaluated. All surfactants self-assemble with low CMC values from 0.012 to 0.430 mg/mL. Cytotoxicity assays showed that C20:4-NTA and C25:0-NTA were less cytotoxic than polysorbate 80. Unsaturations and alkane chain length have a marked influence on toxicity. Saturated surfactants had a similar haemolytic activity, explained by their low CMC values and the linear configuration of their hydrophobic tail. C20:4-NTA and C25:4-NTA were less haemolytic than polysorbate 80. Furthermore, C19:0-NTA, C25:0-NTA and C25:4-NTA increased drug solubility from <0.15 μg/mL up to 7 mg/mL, with 46% (w/w) drug loading, due to their linear and flexible hydrophobic chain configuration, as evidenced by molecular modelling. Although these solubilizers are promising, a compromise between drug solubilization and toxicity remains to be found.

This concept article summarizes our recent findings regarding photopolymerized micelles obtained from the self-assembly of diacetylene-containing amphiphiles. Their synthesis and characterization are presented as well as some biomedical applications, such as tumor imaging and drug delivery. Finally, ongoing studies and future challenges are briefly discussed.

Novel surfactants made of diglutamic acid (DG) polar head linked to lithocholic, arachidonic, linoleic or stearic acids were designed for drug solubilization.

To overcome poor water-solubility of new drug candidates, four innovative surfactants based on naturally-occuring hydrophilic and hydrophobic moities were designed and synthesized: cholesteryl-glutamic acid, cholesteryl-poly[N-2-hydroxyethyl-l-glutamine] (PHEG), ursodeoxycholanyl-PHEG (UDCA-PHEG) and ursodeoxycholanyl-poly-l-glutamic acid (UDCA-PGA). Their self-assembling capacity was evaluated using pyrene fluorescence measurements which allow to determine their critical aggregation concentration (CAC). Size measurements were carried out using dynamic light scattering (DLS). Surfactant cytotoxicity was investigated on human umbilical vein endothelial cells (HUVEC) by determining tetrazolium salt (MTT) activity and lactate dehydrogenase (LDH) release. In addition, surfactant haemolytic activity was assessed using rat red blood cells (RBCs). Finally, the ability of these surfactants to solubilize a model poorly soluble drug was quantified. Surfactant self-assembly, cytotoxicity and solubilization properties were compared to those obtained with polysorbate 80, a model solubilizer. Except for cholesteryl-glutamic acid, surfactants were water-soluble. UDCA-PGA was not able to self-assemble or to increase significantly drug solubility. Results showed that cholesteryl-PHEG and UDCA-PHEG were self-assembling with low CAC values (17 and 120μg/ml) into nano-structures with mean diameters of 13 and 250nm, respectively. Cholesteryl-PHEG was the most efficient surfactant in increasing drug solubility (2mg/ml) but exhibited a similar or higher toxicity than polysorbate 80. UDCA-PHEG did not present any cytotoxicity but was far less efficient to solubilize the drug (0.2mg/ml). These results evidence interesting properties of cholesteryl-PHEG and UDCA-PHEG as novel solubilizers.

A new drug carrier system based on self-assembly and polymerization of polydiacetylenic amphiphiles is described. Although classical amphiphiles can help in solubilizing hydrophobic molecules upon self-arrangement into a variety of nanometric structures, a greater effect on drug loading was observed for our polymerized micelles as compared to the non-polymerized analogues. This permitted higher aqueous solubilization of lipophilic drugs with low micelle concentration. (14)C labeling of a model drug on one side and of the amphiphile on the other side permitted assessment, after intravenous injection, of biodistribution and excretion profiles of the drug cargo.

Over the past few years, health and medicine have been domains where nanotechnologies have shown great promise, in particular in the area of drug carriers and drug targeting. Many active substances suffer from poor solubility, instability in biological medium and low bioavailability. Inaccurate distribution and accumulation of the drug in the body could lead to some side effects possibly detrimental to drug development. With the advent of nanosciences applied to medicine, new tools are becoming available, giving rise to a whole range of drug carriers with different properties and functionalities. Nanocarriers should play a crucial role in the controlled and sustained delivery of drugs. Various types of functional nanosystems are currently being explored and the aim of this review is to give an overview of the most recent advances in the field of nanometric drug carriers, including future strategies and perspectives.

The synthesis of ring opening metathesis, polymer (ROMPgel) supported naphthalene and biphenyl reagents was carried out. These reagents were utilized for catalytic lithiation reactions of aryl and alkyl chlorides and for the reductive deprotection of benzyl and allyl ethers.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A novel ROMPgel immobilized active ester for the purification free synthesis of Mosher amides is described.

Allylboration of various aldehydes was carried out by a ROMPgel supported allylboronate. Filtration and evaporation gave the corresponding homoallylic alcohols in high yield and purity (>95%).

Four consecutive ring closing metathesis reactions could be run with almost no loss of activity using the second generation recyclable 'boomerang' polymer supported catalyst 4.

[reaction: see text] Grubbs catalyst, Cl2(Cy3P)2Ru=CHPh, was found to catalyze the cross-metathesis of monosubstituted allenes to 1,3-disubstituted allenes in varying yields.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.