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The 4-trifluoromethyl analog 4c shown moderate activity against Pim-1, but was surprisingly effective when tested against Pim-3 (residual activities 51% and 24%, respectively) The overall yield for the preparation of the C8 methyl derivative 17 from the common aldehyde starting material was 18%

Sonophoresis is mainly caused by acoustic cavitation, i.e. than the NANs or genes also have to enter the nucleus. In this review we will focus on the extracellular barriers encountered by pulmonary delivered NANs on their way to epithelial cells, pneumocytes and lung macrophages. It is not the goal of this review to discus the other barriers mentioned above or to summarize the outcome of all experiments Pyrindamycin B or clinical trials in the field of respiratory gene therapy. The latter has been covered by some recent reviews [1], [3], [4]. To allow the reader to gain insights into the mechanism by which extracellular fluids in Pyrindamycin B the lungs may Pyrindamycin B affect the performance of NANs we will start the review with a brief introduction to the biochemical and physical properties of especially respiratory mucus and alveolar fluid. This part will be followed with an overview and discussion of the scientific papers that deal with the behavior of NANs in the different extracellular secretions present in the respiratory tract. Most of the efforts in respiratory gene therapy have focused on CF gene therapy. Therefore, special attention will be given to the extracellular barriers in CF gene therapy. CF is the most common lethal autosomal-recessive disorder in Caucasians, affecting approximately 1 in 2000 newborns, and is characterized by the presence of tenacious mucus in the lungs, intestines and vagina [11]. However, fifteen years of pre-clinical and clinical research, using both viral and non-viral NANs, has revealed that the delivery of the CFTR gene to the lung epithelium of CF patients is a very difficult task. Extracellular barriers play an important role in the failure of CF gene therapy. In the last part of this review we will discuss the strategies that have been evaluate to overcome the different extracellular barriers in respiratory gene therapy. Additionally, we will also suggest new strategies that may enhance the success of respiratory gene therapy. 2.?Biochemical and physical aspects of respiratory secretions 2.1. Respiratory mucus The air we daily inhale contains besides gas also dust, toxic substances and pathogens. Therefore, the lungs have developed ingenious mechanisms to remove and/or neutralize these alien materials. One of the most important defense mechanism against these inhaled materials is respiratory mucus, which lines the respiratory epithelium from the nose to the terminal bronchioles [12]. This mucus layer lays on the tips of the cilia which bath in a periciliary fluid layer. Inhaled materials are captured in this blanket of mucus and are together with the mucus continuously transported by the cilia to the esophagus. The physical properties of respiratory mucus determines the efficiency of this mucociliary clearance mechanism [13]. Indeed, in lung diseases characterized by very tenacious mucus the mucociliary clearance is impaired and elimination of mucus occurs via coughing [14], [15]. The thickness of the mucus layer depends on the location in the airways and the presence of bHLHb27 a pathologic condition. Although very difficult to determine, it has been reported that in non-pathological conditions the thickness varies between 10 and 30?m in the trachea and between 2 and 5?m in the bronchi [16], [17]. However, other reports claim that the Pyrindamycin B thickness of the mucus layer can vary between 5 and 260?m [18]. In CF and other respiratory diseases the mucus layer is much thicker [19]. Respiratory mucus is mainly composed of a three-dimensional network of cross-linked mucin chains which gives the mucus viscoelastic properties [20], [21], [22]. The Globlet cells and submucosal glands are the producers of these mucins. Mucins are built up by 4 to 5 subunits which are bound together head-to-tail by intramolecular disulfide bridges (Fig. 1 ) [23]. The subunits, which have a length of about 500?nm, consist of a highly glycosylated protein backbone with non-glycosylated ends [24]. The molecular weight of mucins varies from 2 to 16 MDa. Mucins are negatively charged due to the presence of entrapment of the NANs in the mucus, aggregation of the NANs due to neutralization of their surface charges, release of therapeutic DNA/RNA from non-viral NANs, an inefficient cell binding of the NANs due to shielding of their positive charges or their receptor binding ligands, and endosomal entrapment of NANs. All these effects will strongly impede the gene transfer efficiency of NANs in the presence of mucus. Information on the interactions of NANs with.