Online citations, reference lists, and bibliographies.
← Back to Search

Multifunctional Nanoparticles Enable Efficient Oral Delivery Of Biomacromolecules Via Improving Payload Stability And Regulating The Transcytosis Pathway.

Yaxian Zheng, Jiawei Wu, Wei Shan, L. Wu, Rui Zhou, Mengshuai Liu, Y. Cui, Minglu Zhou, Zhi-Rong Zhang, Yuan Huang
Published 2018 · Materials Science, Medicine

Cite This
Download PDF
Analyze on Scholarcy
Share
In oral delivery of biomacromolecules, ligand-modified nanoparticles (NPs) have emerged as a promising tool to improve the epithelial uptake of the loaded protein/peptide. Unfortunately, the stability and the transport mechanisms of the biotherapeutics during the intracellular transportation still remained unclear, leading to the poor transepithelial efficiency. Additionally, developing novel approaches to simultaneously monitor the payload bioactivity during the transport processes is veritably benefit for keeping their bioactivity. In the present study, EGP peptide (KRKKKGKGLGKKRDPCLRKYK), a ligand with high affinity to heparan sulfate proteoglycans (HSPGs), was found remarkably increasing the cellular uptake (4.5-fold) and also surprisingly achieving high transcytosis efficiency (4.2-fold) of poly(lactide- co-glycolide) NPs on Caco-2 cell monolayer. Compared with unmodified NPs (C NPs), EGP modified NPs (EGP NPs) exhibited more desirable colloidal stability within epithelia. In the subsequent study, the bioactivity of encapsulated insulin during the cellular transportation was innovatively monitored by a glucose consumption assay. Inspiringly, EGP NPs could mostly retain the bioactivity of loaded insulin whereas insulin from INS-C NPs was significantly degraded. Then the detailed mechanism study revealed that the binding of EGP to HSPGs played a vital role on NP transportation. Unlike C NPs being delivered in the endo/lysosomal pathway, EGP NPs were involved in caveolae-mediated transport, which contributes to the efficient avoidance of the lysosomal entrapment and sequentially facilitates the direct apical-to-basolateral transcytosis. The enhanced absorption of EGP NPs was confirmed in in situ intestinal loop models. Most importantly, oral administrated INS-EGP NPs generated a strong hypoglycemic response on diabetic rats with 10.2-fold and 2.6-fold increase in bioavailability compared with free insulin and INS-C NPs, respectively. The work provided an innovative strategy to monitor the payload bioactivity during the transport processes and proposed a novel aspect to increase oral bioavailability of biomacromolecules via improving payload stability and regulating the transcytosis pathway of nanocarriers.
This paper references
10.1016/j.addr.2016.04.014
Mechanisms of transport of polymeric and lipidic nanoparticles across the intestinal barrier.
A. Beloqui (2016)
10.1083/JCB.63.2.430
PROTEIN DEGRADATION IN CULTURED CELLS
M. Wibo (1974)
10.1016/j.jconrel.2017.07.045
Bioinspired butyrate-functionalized nanovehicles for targeted oral delivery of biomacromolecular drugs.
Lei Wu (2017)
10.1016/j.biomaterials.2017.10.022
Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery.
W. Fan (2018)
10.1039/C6TB01199C
Core-shell stability of nanoparticles plays an important role for overcoming the intestinal mucus and epithelium barrier.
M. Liu (2016)
10.1002/iub.485
Delivery of nanoparticle‐complexed drugs across the vascular endothelial barrier via caveolae
Zhenjia Wang (2011)
10.1002/ADFM.201505000
Sub‐50 nm Nanoparticles with Biomimetic Surfaces to Sequentially Overcome the Mucosal Diffusion Barrier and the Epithelial Absorption Barrier
X. Zhu (2016)
10.1016/j.jconrel.2014.06.038
Insight into nanoparticle cellular uptake and intracellular targeting.
Basit Yameen (2014)
10.1083/JCB.132.3.487
Heparan sulfate expression in polarized epithelial cells: the apical sorting of glypican (GPI-anchored proteoglycan) is inversely related to its heparan sulfate content
G. Mertens (1996)
10.1039/c7nr06063g
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.
Y. Cui (2018)
10.1039/C7TB02450A
Iron-mimic peptide converts transferrin from foe to friend for orally targeting insulin delivery.
M. Liu (2018)
10.1053/META.2002.34715
Effects of berberine on glucose metabolism in vitro.
J. Yin (2002)
10.1038/sj.gt.3300843
Factors affecting blood clearance and in vivo distribution of polyelectrolyte complexes for gene delivery
P. R. Dash (1999)
10.1002/smll.201202623
Nanoparticle transport in epithelial cells: pathway switching through bioconjugation.
R. Fowler (2013)
10.1016/j.biomaterials.2013.04.053
The transport mechanisms of polymer nanoparticles in Caco-2 epithelial cells.
Bing He (2013)
10.1021/acsami.8b00507
Novel Solid Lipid Nanoparticle with Endosomal Escape Function for Oral Delivery of Insulin.
Yining Xu (2018)
10.1016/j.jconrel.2011.02.027
Enhanced gene transfection efficiency in CD13-positive vascular endothelial cells with targeted poly(lactic acid)-poly(ethylene glycol) nanoparticles through caveolae-mediated endocytosis.
C. Liu (2011)
Mechanisms of transport of polymeric and lipidic nanoparticles across the intestinal barrier
A. Beloqui (2016)
10.1016/j.addr.2016.02.004
Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials.
T. A. Aguirre (2016)
10.1038/ncb3325
Godzilla-dependent transcytosis promotes Wingless signalling in Drosophila wing imaginal discs
Yasuo Yamazaki (2016)
10.1016/j.metabol.2008.01.013
Efficacy of berberine in patients with type 2 diabetes mellitus.
J. Yin (2008)
10.1016/j.addr.2016.10.005
Oral delivery of peptides: opportunities and issues for translation.
D. Brayden (2016)
10.1111/j.1365-2796.2006.01620.x
Mechanotransduction and the glycocalyx
J. Tarbell (2006)
10.1038/nature03866
Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae
L. Pelkmans (2005)
10.1021/acsami.7b16524
Biomimetic Viruslike and Charge Reversible Nanoparticles to Sequentially Overcome Mucus and Epithelial Barriers for Oral Insulin Delivery.
Jiawei Wu (2018)
10.1021/acsami.7b19153
Intestinal Mucin Induces More Endocytosis but Less Transcytosis of Nanoparticles across Enterocytes by Triggering Nanoclustering and Strengthening the Retrograde Pathway.
D. Yang (2018)
10.1016/0026-0495(89)90197-2
A rapid ELISA for measuring insulin in a large number of research samples.
M. MacDonald (1989)
10.1002/ADFM.201103059
Multicomponent Organic Nanoparticles for Fluorescence Studies in Biological Systems
T. McDonald (2011)
10.1002/anie.201509183
Polymeric Nanoparticles Amenable to Simultaneous Installation of Exterior Targeting and Interior Therapeutic Proteins.
Xi Zhu (2016)
10.1016/j.ijpharm.2016.01.028
The transport mechanism of integrin αvβ3 receptor targeting nanoparticles in Caco-2 cells.
Yining Xu (2016)
10.1002/smll.201800462
Engineered Multifunctional Albumin-Decorated Porous Silicon Nanoparticles for FcRn Translocation of Insulin.
J. P. Martins (2018)
10.1016/j.cell.2004.09.003
Caveolin-Stabilized Membrane Domains as Multifunctional Transport and Sorting Devices in Endocytic Membrane Traffic
L. Pelkmans (2004)
10.1016/j.jconrel.2015.12.008
Efficient mucus permeation and tight junction opening by dissociable "mucus-inert" agent coated trimethyl chitosan nanoparticles for oral insulin delivery.
Mengshuai Liu (2016)
10.1002/jgm.237
Side‐effects of a systemic injection of linear polyethylenimine–DNA complexes
P. Chollet (2002)
10.3233/JAD-2010-100462
Apical-to-basolateral transport of amyloid-β peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein.
P. Candela (2010)
10.1016/j.jconrel.2016.07.051
Role of nanoparticle size, shape and surface chemistry in oral drug delivery.
Amrita Banerjee (2016)
10.1021/bm401580k
Improved stability and antidiabetic potential of insulin containing folic acid functionalized polymer stabilized multilayered liposomes following oral administration.
A. Agrawal (2014)
10.1016/S0968-0004(03)00031-8
Heparan sulfate proteoglycan as a plasma membrane carrier.
M. Belting (2003)
10.1083/JCB.122.4.933
Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate
S. Higashiyama (1993)
10.1021/mp400685v
Mechanism study of cellular uptake and tight junction opening mediated by goblet cell-specific trimethyl chitosan nanoparticles.
J. Zhang (2014)
10.1016/j.addr.2012.10.007
Nanoparticles for oral delivery: targeted nanoparticles with peptidic ligands for oral protein delivery.
Yeonhee Yun (2013)
10.1128/MCB.23.24.9389-9404.2003
Caveolin-1 Maintains Activated Akt in Prostate CancerCells through Scaffolding Domain Binding Site Interactions with andInhibition of Serine/Threonine Protein Phosphatases PP1 andPP2A
Likun Li (2003)
10.1073/pnas.1518634113
Highly efficient delivery of functional cargoes by the synergistic effect of GAG binding motifs and cell-penetrating peptides
James E. Dixon (2016)
10.1016/J.BBAMCR.2005.06.009
Secrets of caveolae- and lipid raft-mediated endocytosis revealed by mammalian viruses.
L. Pelkmans (2005)



This paper is referenced by
10.1208/s12249-020-01648-6
Lyophilisation Improves Bioactivity and Stability of Insulin-Loaded Polymeric-Oligonucleotide Nanoparticles for Diabetes Treatment
Chun Y Wong (2020)
10.1002/adma.201903793
A Probiotic Spore-Based Oral Autonomous Nanoparticles Generator for Cancer Therapy.
Qingling Song (2019)
10.1016/j.ijpharm.2019.118720
Bio-nanotechnological advancement of orally administered insulin nanoparticles: Comprehensive review of experimental design for physicochemical characterization.
Chun Y Wong (2019)
10.1002/adfm.201907170
Biomaterial Approaches for Understanding and Overcoming Immunological Barriers to Effective Oral Vaccinations
H. Frizzell (2020)
10.1016/j.biomaterials.2020.120323
Tailored elasticity combined with biomimetic surface promotes nanoparticle transcytosis to overcome mucosal epithelial barrier.
Yaxian Zheng (2020)
10.1080/10717544.2020.1831104
Engineered biomaterial strategies for controlling growth factors in tissue engineering
Na Guan (2020)
10.1080/1061186X.2020.1726356
Cellular assays and applied technologies for characterisation of orally administered protein nanoparticles: a systematic review
Chun Y Wong (2020)
10.1039/c9tb02860a
Nanoparticles with surface features of dendritic oligopeptides as potential oral drug delivery systems.
Yuli Bai (2020)
10.1038/s41573-019-0053-0
Advances in oral peptide therapeutics
Daniel J. Drucker (2019)
10.3390/pharmaceutics12050462
Enhanced Intestinal Absorption of Insulin by Capryol 90, a Novel Absorption Enhancer in Rats: Implications in Oral Insulin Delivery
Hiroki Ukai (2020)
10.1016/j.biomaterials.2020.119902
Tumor extravasation and infiltration as barriers of nanomedicine for high efficacy: The current status and transcytosis strategy.
Q. Zhou (2020)
10.1002/adma.201901935
Oral Delivery of Biologics for Precision Medicine.
M. Durán‐Lobato (2019)
10.1016/j.jddst.2020.101738
Formulation and characterisation of insulin-loaded chitosan nanoparticles capable of inducing glucose uptake in skeletal muscle cells in vitro
Chun Y Wong (2020)
10.1080/1061186x.2020.1817042
Fabrication techniques for the preparation of orally administered insulin nanoparticles.
Chun Y Wong (2020)
10.1080/1061186X.2020.1759078
Current status and applications of animal models in pre-clinical development of orally administered insulin-loaded nanoparticles
Chun Y Wong (2020)
10.1039/c9nr03802g
An oral drug delivery system with programmed drug release and imaging properties for orthotopic colon cancer therapy.
Qingling Song (2019)
Semantic Scholar Logo Some data provided by SemanticScholar