The challenges of oral drug delivery via nanocarriers

Figures & data

Figure 1. Anatomy of the small intestine and the implications for orally applied nanocarriers. Multiple consecutive close-ups are displayed. In order to enter the bloodstream, orally applied nanocarriers have to cross multiple borders of the human body. Especially the uptake and crossing of enterocytes in the small intestine mark a key challenge in oral drug delivery via nanocarriers.

Figure 2. Close-up of nanoparticles trapped in late endosomes/lysosomes. In this study, Caco-2 cells were incubated with 500 µg/mL polystyrene nanoparticles for 24 hours. The addition resulted in huge endolysosomal structures up to 2 µm in diameter as analyzed by (A) confocal laser scanning microscopy (scale bar =10 µm) and (B) transmission electron microscopy (Reinholz et al., 2018). Reprinted from J. Reinholz, C. Diesler, S. Schöttler, M. Kokkinopoulou, S. Ritz, K. Landfester, V. Mailänder, Protein Machineries defining Pathways of Nanocarrier Exocytosis and Transcytosis, Acta Biomaterialia, Copyright (2018) with permission from Elsevier.

Table 1. Uptake mechanisms of various nanomaterials in endo- and epithelial cell lines.

NP characterization	NP size	Uptake mechanism	Strategy	Cell line	Study
Positively charged PS-NP	50 and 100 nm	Clathrin-mediated, cholesterol-dependent, and macropinocytosis	Chlorpromazine, amiloride Methyl-β-cyclodextrin	Caco-2	(Bannunah et al., 2014)
Negatively charged PS-NP	50 and 100 nm	Lipid-raft-associated uptake (caveolae)	Genistein	Caco-2	(Bannunah et al., 2014)
PLGA-NP	80 nm	Co-mediation of clathrin, lipid raft/caveolae, and macropinocytosis	Methyl-β-cyclodextrin, EIPA, PAO, nystatin, indomethacin	Caco-2	(He et al., 2013)
WGA-PEG-NP	120 nm	Clathrin-mediated, depending on surface PEG length	Chlorpromazine	Caco-2	(Song et al., 2012)
PLGA-NP	100 nm	Clathrin-mediated, lipid-raft-mediated	Nystatin, hyperosmotic sucrose	MDCK	(He et al., 2013)
PS-NP	20 and 120 nm	Clathrin-mediated	Monodansylcadaverine for cLSM studies	MDCK	(Fazlollahi et al., 2011)
Positively charged PEG-PLGA	90 nm	Clathrin-mediated, partially macropinocytosis	Dominant-negative mutant polypeptides of clathrin, cLSM analysis	MDCK	(Harush-Frenkel et al., 2008)
Negatively charged PEG-PLGA	96 nm	Clathrin-mediated, partially macropinocytosis	Dominant-negative mutant polypeptides of clathrin, cLSM analysis	MDCK	(Harush-Frenkel et al., 2008)
BSA-coated NP	20, 40, and 100 nm	Caveolae-mediated	cLSM analysis	BLMVEC	(Wang et al., 2009)
Nano-Mg(OH)2 particles	70 nm	Caveolae-mediated	cLSM analysis	HUVEC	(Meng et al., 2015)
COOH-PS-NP	43 nm	Clathrin-mediated	Chlorpromazine	HUVEC	(Lai et al., 2007)
COOH-PS-NP	24 nm	Cholesterol-independent, non-clathrin-mediated, and non-caveolae-mediated	Various inhibitors	HUVEC	(Lai et al., 2007)
Gold NP	20 nm	Caveolae-mediated	Genistein	HMEC-1	(Landgraf et al., 2015)
Gold NP	40 nm	Clathrin-mediated and macropinocytosis	Chlorpromazine, wortmannin	HMEC-1	(Landgraf et al., 2015)
Gold NP	35 nm	Flotillin-dependent	cLSM analysis	hCMEC/D3	(Freese et al., 2013)

Figure 3. Transcytosis of 12 nm human serum albumin–gold nanoparticles across a hCMEC/D3 endothelial cell monolayer. In this study, the authors demonstrated a protocol for the in vitro determination of nanoparticle translocation across a cell monolayer using transmission electron microscopy. (a) Nanoparticles present in apical sorting vesicles within the cytosolic space. (b) Gold nanoparticles detected in different cytoplasmic regions. (c) Nanoparticles co-localizing with endosomes. (d) Nanoparticles co-localizing with lysosomes. (e) A single gold nanoparticle exits the basolateral cell membrane from a vesicle. (f) The nanoparticle is finally present in the basal compartment. EP: endocytic pit; ER: endoplasmic reticulum; EV: exocytic vesicle; E: endosome; L: lysosome; M: mitochondria; N: nucleus; TJ: tight junction (Ye et al., 2015). Reproduced from D. Ye, K.A. Dawson, I. Lynch, A TEM protocol for quality assurance of in vitro cellular barrier models and its application to the assessment of nanoparticle transport mechanisms across barriers, Analyst 140(1) (2015) 83-97 with permission of The Royal Society of Chemistry.

Figure 4. Putative pathways for endolysosomal escape and exocytosis of P22NPs in Caco-2 cells. The addition of hemagglutinin-2 and metformin led to an increase in endolysosomal escape and exocytosis of nanoparticles, overall resulting in an increase in transcytosis. The black arrows represent the pathways that were demonstrated by the authors (Cui et al., 2018). Reproduced from Y. Cui, W. Shan, R. Zhou, M. Liu, L. Wu, Q. Guo, Y. Zheng, J. Wu, Y. Huang, The combination of endolysosomal escape and basolateral stimulation to overcome the difficulties of ‘easy uptake hard transcytosis’ of ligand-modified nanoparticles in oral drug delivery, Nanoscale (2018) with permission of The Royal Society of Chemistry.

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 PubMed Web of Science ®Google Scholar

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