Oral delivery of protein-based therapeutics: Gastroprotective strategies, physiological barriers and in vitro permeability prediction

Wright, Leah; Barnes, Timothy J.; Prestidge, Clive A.

doi:10.1016/j.ijpharm.2020.119488

Cited by 24 publications

(20 citation statements)

References 122 publications

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“…The stomach is the second compartment where encapsulates are exposed to harsh conditions. This organ is responsible for breaking down food into smaller and more assimilable molecules [14]. This occurs under an acidic environment, which, when in contact with bioactive compounds, will induce protonation of some pendant groups such as phospholipids, amino and carboxyl groups [6], and the decrease of cell cytoplasmic pH.…”

Section: Introductionmentioning

confidence: 99%

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Gelatin-Graphene Oxide Nanocomposite Hydrogels for Kluyveromyces lactis Encapsulation: Potential Applications in Probiotics and Bioreactor Packings

et al. 2021

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Nutraceutical formulations based on probiotic microorganisms have gained significant attention over the past decade due to their beneficial properties on human health. Yeasts offer some advantages over other probiotic organisms, such as immunomodulatory properties, anticancer effects and effective suppression of pathogens. However, one of the main challenges for their oral administration is ensuring that cell viability remains high enough for a sustained therapeutic effect while avoiding possible substrate inhibition issues as they transit through the gastrointestinal (GI) tract. Here, we propose addressing these issues using a probiotic yeast encapsulation strategy, Kluyveromyces lactis, based on gelatin hydrogels doubly cross-linked with graphene oxide (GO) and glutaraldehyde to form highly resistant nanocomposite encapsulates. GO was selected here as a reinforcement agent due to its unique properties, including superior solubility and dispersibility in water and other solvents, high biocompatibility, antimicrobial activity, and response to electrical fields in its reduced form. Finally, GO has been reported to enhance the mechanical properties of several materials, including natural and synthetic polymers and ceramics. The synthesized GO-gelatin nanocomposite hydrogels were characterized in morphological, swelling, mechanical, thermal, and rheological properties and their ability to maintain probiotic cell viability. The obtained nanocomposites exhibited larger pore sizes for successful cell entrapment and proliferation, tunable degradation rates, pH-dependent swelling ratio, and higher mechanical stability and integrity in simulated GI media and during bioreactor operation. These results encourage us to consider the application of the obtained nanocomposites to not only formulate high-performance nutraceuticals but to extend it to tissue engineering, bioadhesives, smart coatings, controlled release systems, and bioproduction of highly added value metabolites.

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Section: Introductionmentioning

confidence: 99%

“…Mucus provides a physical barrier since it is formed by a negatively charged fibrous mesh. For this reason, electrostatic interactions with bioactive compounds might still be possible and even help them to remain attached to the intestinal lumen as they start diffusing across the mucus layer [14].…”

Section: Introductionmentioning

confidence: 99%

Gelatin-Graphene Oxide Nanocomposite Hydrogels for Kluyveromyces lactis Encapsulation: Potential Applications in Probiotics and Bioreactor Packings

et al. 2021

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“…Numerous materials have been utilised for protein encapsulation and facilitation of systemic delivery of macromolecular therapeutics, including mesoporous silica and polymeric systems such as chitosan and PLGA. 10 Despite this, few studies have systematically compared nanocarrier type and chemistry on the mechanisms and efficacy of mediating epithelial transport for biologics.…”

Section: Introductionmentioning

confidence: 99%

A Comparison of Chitosan, Mesoporous Silica and Poly(lactic-co-glycolic) Acid Nanocarriers for Optimising Intestinal Uptake of Oral Protein Therapeutics

Wright

Joyce

Barnes

et al. 2021

Journal of Pharmaceutical Sciences

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Efficacious oral delivery of therapeutic proteins remains challenging and nanoparticulate approaches are gaining interest for enhancing their permeability. In this study, we explore the ability for three comparably sized nanocarriers, with diverse physicochemical properties [i.e., chitosan (CSNP), mesoporous silica nanoparticles (MSNP) and poly(lactic-co-glycolic) acid (PLGA-NP)], to successfully facilitate epithelial uptake of a model protein, ovalbumin (OVA). We report the effect of nanoparticle surface chemistry and nanostructure on protein release, cell toxicity and the uptake mechanism in a Madin Darby Canine Kidney (MDCK) cell model of the intestinal epithelium. All nanocarriers exhibited bi-phasic OVA release kinetics with sustained and incomplete release after 4 days, and more pronounced release from MSNP than either polymeric nanocarriers. CSNP and MSNP displayed the highest cellular uptake, however CSNP was prone to significant dose-dependent toxicity attributed to the cationic surface charge. Approximately 25% of MSNP uptake was governed by a clathrin-independent endocytic mechanism, while CSNP and PLGA-NP uptake was not controlled via any endocytic mechanisms investigated herein. Furthermore, endosomal localisation was observed for CSNP and MSNP, but not for PLGA-NP. These findings may assist in the optimal choice and engineering of nanocarriers for specific intestinal permeation enhancement for oral protein delivery.

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“…Despite the above-mentioned advantages, oral drug delivery is confronted with multiple challenges. The harsh gastrointestinal environment owing to secretion of gastric acid, various surfactants and enzymes tends to degrade or inactivate certain labile entities including both small molecular drugs and biomacromolecules 9 , 10 , 11 , 12 . Some therapeutic compounds are stable and absorbable in the GIT, but are susceptible to first-pass hepatic metabolism and suffer from extremely low bioavailability 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

An update on oral drug delivery via intestinal lymphatic transport

Zi-chen

Lü

et al. 2021

Acta Pharmaceutica Sinica B

113

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Orally administered drug entities have to survive the harsh gastrointestinal environment, penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation. Whereas the gastrointestinal stability can be well maintained by taking proper measures, hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism. The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway. Intestinal lymphatic transport is emerging as a promising pathway to this end. In this review, we intend to provide an updated overview on the rationale, strategies, factors and applications involved in intestinal lymphatic transport. There are mainly two pathways for peroral lymphatic transport—the chylomicron and the microfold cell pathways. The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications.

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Oral delivery of protein-based therapeutics: Gastroprotective strategies, physiological barriers and in vitro permeability prediction

Cited by 24 publications

References 122 publications

Gelatin-Graphene Oxide Nanocomposite Hydrogels for Kluyveromyces lactis Encapsulation: Potential Applications in Probiotics and Bioreactor Packings

Gelatin-Graphene Oxide Nanocomposite Hydrogels for Kluyveromyces lactis Encapsulation: Potential Applications in Probiotics and Bioreactor Packings

A Comparison of Chitosan, Mesoporous Silica and Poly(lactic-co-glycolic) Acid Nanocarriers for Optimising Intestinal Uptake of Oral Protein Therapeutics

An update on oral drug delivery via intestinal lymphatic transport

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