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 solubilization, protection against degradation, and increased access to pathological compartments. A key element for the success of drug-loaded nanocarriers 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, nanocarriers 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 tumor 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.

Cystic fibrosis (CF) patients are faced with chronic bacterial infections displaying persistent resistance if not eradicated during the first stage of the disease. Nanoantibiotics for pulmonary administration, such as liposomal ciprofloxacin or amikacin, have progressed through clinics thanks to their sustained release, prolonged lung residence time and low systemic absorption. In this work, we sought a nanoformulation of levofloxacin for the treatment of Pseudomonas aeruginosa. We prepared and compared PLA-g-PEG nanoparticles, as well as anionic and cationic liposomes for their size, charge and encapsulation efficiency. Cationic liposomes were unable to encapsulate any drug and were subsequently considered as a control formulation. Regarding the efficiency of the nanocarrier, anionic liposomes exhibited a prolonged release over 72 h and preserved the antibacterial activity of levofloxacin against 5 strains of Pseudomonas aeruginosa, whereas polymeric nanoparticles quickly released their entire payload and increased the minimal inhibitory concentration (MIC) of levofloxacin. Thus, only anionic liposomes were considered for further preclinical development. Anionic liposomes exhibited a suitable colloidal stability by Turbiscan analysis and crossed a layer of artificial mucus in under one hour in a Transwell setup. Despite their negative surface charge, liposomes still interacted with P. aeruginosa membrane in a dose-reponse manner, as demonstrated by flow cytometry. Viability assays confirmed that anionic liposomes, loaded or not, exhibited a good safety profile on A549 epithelial cells even at high concentrations. Finally, nebulization of anionic liposomes containing levofloxacin did not impact their colloidal stability and the droplet size distribution was suitable for deep lung deposition, where P. aeruginosa infection lies. Therefore, levofloxacin-loaded anionic liposomes exhibited suitable properties for the pulmonary treatment of P. aeruginosa in CF. This step-by-step study confirms the promising role of liposomes for lung administration of antibiotics, as recently seen in clinics, and fosters their development for several types of antibiotics.

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New symmetrically poly(ethylene glycol) (PEG)-decorated triglycerides of fatty acid are synthesized and proposed as drug-encapsulation systems. A method of effective grafting of PEG on secondary hydroxy groups located on long alkyl chains by the use of a short spacer represented by succinic acid is elaborated. Synthesis of new derivatives of triacylglycerols of fatty acids (TAG) based on the triolein standard and commercial olive oil, with PEG chains of different lengths (1000, 550, and 220 Da) is performed. MTT assay on the murine macrophage cell line RAW-262.7 shows the absence of cytotoxic effects caused by the obtained products. Encapsulation tests using itraconazole (ITZ) as a hydrophobic drug model are carried out. The infl uence of the PEG chain length, as well as of the presence of ITZ on the size of micelles, are studied by the dynamic light scattering (DLS) method. The reduced cytotoxicity observed on Candida albicans cells of ITZ formulated with the PEGdecorated TAG versus the free drug indicates that the systems may be promising to increase the duration of drug release and to reduce toxic side effects.

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