Lung transporters and absorption mechanisms in the lungs
Anthony J. Hickey, Heidi M. Mansour in Inhalation Aerosols, 2019
Endocytosis is a form of active transport by which a molecule gains entry into the cell after being surrounded by an area of plasma membrane, which then buds off inside the cell forming a vesicle containing the ingested molecule. Transcytosis is a transcellular transport mechanism in which the internalized molecules are transported across the epithelial cells from one side to the opposite side. Among many endocytic pathways in mammalian cells, clathrin-dependent endocytosis and caveolar endocytosis are the most common and well-studied pathways. However, other pathways that use neither clathrin nor caveolae have been recognized (112).
Sonophoresis: Ultrasound-Enhanced Transdermal Drug Delivery
Richard H. Guy, Jonathan Hadgraft in Transdermal Drug Delivery, 2002
Langer and colleagues used a 1 MHz c.w. beam at 2 W cm−2 in order to enhance the penetration of a wide range of compounds through human epidermis in vitro (Mitragotri et al., 1995b). Large improvements in transdermal delivery were obtained for three out of the seven investigated compounds. Powerful evidence that the enhanced delivery was due to cavitation was derived from the fact that drug penetration was radically reduced by raising the frequency to 3 MHz, or by using deaerated or compressed epidermis. Furthermore, confocal microscopy of fluorescein-stained keratinocytes showed that following sonication at 1 MHz, there was bleaching of fluorescein in the keratinocytes but not in the intercellular lipids. Fluorescein is bleached in the presence of hydrogen peroxide, which is formed from the free radicals generated by transient cavitation. Significantly, 3 MHz ultrasound did not cause any bleaching. This data indicates that transient cavitation occurring in the keratinocytes somehow permeabilizes the stratum corneum. In sequential in vitro work (Mitragotri et al., 1996), this group found that employing very low frequency ultrasound (0.02 MHz) induced greater cavitational activity within the stratum corneum, thus facilitating even more efficacious phonophoresis. Electrical resistance measurements, indicative of the integrity of the stratum corneum lipid bilayers, decreased 25-fold as result of sonication. From this and other theoretical considerations, the authors proposed that cavitation disorders the intercellular lipid bilayers of the stratum corneum, allowing aqueous channels to form within the lipid domains. Together with keratinocytes, the perturbed bilayers constitute a new transcellular transport pathway that permits the rapid ingress of permeant molecules. The mechanism is illustrated in Fig. 5.
Evaluation Methods for Conditioned Hair
E. Desmond Goddard, James V. Gruber in Principles of Polymer Science and Technology in Cosmetics and Personal Care, 1999
Intercellular, as opposed to transcellular, transport is especially important for the incorporation of larger molecules such as polymeric materials into the cuticle, or even more so for diffusion into the cortex. The intercellular cement is thought to contain nonkeratinous, low-sulfur proteins, which are high in polar amino acids and are assumed to swell
Overview of intranasally delivered peptides: key considerations for pharmaceutical development
Published in Expert Opinion on Drug Delivery, 2018
Wisam Al Bakri, Maureen D. Donovan, Maria Cueto, Yunhui Wu, Chinedu Orekie, Zhen Yang
Along with MW, the size and shape of peptide molecules also affect the uptake of peptides across the nasal mucosa. McMartin et al. reported that cyclic molecules with smaller molecular radii have an improved absorption compared with linear molecules. The same investigators suggested that the transport of polar molecules could occur in three possible ways: 1) transcytosis, which involves uptake into vesicles formed along the cell membrane; 2) transcellular transport, which includes passive partitioning and carrier-mediated transport across the cell membrane; and 3) paracellular transport through the tight junctions [13,42]. Endocytotic vesicles range in size from about 60 nm (600 Å) to a few microns [43,44], and therefore can participate in the uptake of large molecules such as peptides. Richard et al. reported that wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) (MW 38,000 Da) delivered intranasally is endocytosed by the olfactory neurons [45]. Balin et al. observed that WGA-HRP administered intranasally passes freely through the paracellular spaces within 45–90 min [46]. McMartin suggested that paracellular transport through the tight junctions is one of the most important uptake pathways through which peptides are absorbed across the nasal epithelium [13].
Evaluating the safety profile of focused ultrasound and microbubble-mediated treatments to increase blood-brain barrier permeability
Published in Expert Opinion on Drug Delivery, 2019
Dallan McMahon, Charissa Poon, Kullervo Hynynen
Currently, strategies to circumvent the BBB for the delivery of therapeutics rely on altering paracellular transport (e.g. hyperosmotic solutions [8]), transcellular transport (e.g. carrier protein-mediated transport [9]), or on utilizing delivery routes outside of the circulatory system (e.g. intracranial injections [10], intranasal delivery [11], hydrogels [12]). Although hyperosmotic solutions may be helpful for neurological diseases that require treating large volumes of brain tissue, the use of such reagents can lead to structural alterations to neurons, lesions, macrophage accumulation, and glial activation [13]. Other strategies for bypassing the BBB suffer from their invasive nature, non-targeted delivery, or non-therapeutically relevant concentrations of drug delivery.
Silica nanoparticles on the oral delivery of insulin
Published in Expert Opinion on Drug Delivery, 2018
Xinyi Tan, Xiaolin Liu, Yan Zhang, Hongjuan Zhang, Xiaoyang Lin, Chenguang Pu, Jingxin Gou, Haibing He, Tian Yin, Yu Zhang, Xing Tang
With the help of SNs, insulin can be absorbed and enter into bodies (Figure 4a), and thus absorption of SNs is important for the delivery of insulin. The absorption can be achieved by paracellular or transcellular transport from the intestine. For paracellular transport, tight junctions (TJs) between adjacent epithelial cells are often the obstacle of oral absorption. The narrow paracellular entrance, below 1 and 0.4 nm in rats and humans, respectively [69,70], places a limit of 1.5 nm (ca. 3.5 kDa) as the largest hydrodynamic size of insulin [42,71,72]. Additionally, the net charges of insulin can further limit their paracellular diffusion, and the threshold value is then further restricted to 100–200 Da [73]. Thus, various permeability enhancers based on transient opening or loosening of the TJs are commonly used. Some enhancers include zonula occludens toxin (Zot) and methacrylate derivatives that can target specific TJ proteins [74]. Represented by sodium caprate [75], fatty acids can remove TJ proteins like tricellulin. Chelating agents such as ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA) [76–78] or their derivatives can eliminate ions and inhibit the redistribution of TJ [71]. Bile salt and other surfactants can also contribute to paracellular transport. It is worth noting that these enhancers are often multi-mechanism, and not merely TJ openers. For SNs, only dissolved or fragmented particles can pass through paracellular gap, due to the size limit and the limited proportion of the intestinal area (ca. 0.01–0.1% [79]) [76]. However, safety in regards to this should be considered due to the potential danger of invasive toxins and pathogens.
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