Sustained-release multiparticulates for oral delivery of a novel peptidic ghrelin agonist: Formulation design and in vitro characterization

Howick, Kenneth P.; Alam, Ryan M.; Chruścicka, Barbara; Kandil, Dalia; Fitzpatrick, Dara; Ryan, Aoife M.; Cryan, John F.; Schellekens, Harriët; Griffin, Brendan T.

doi:10.1016/j.ijpharm.2017.11.051

Cited by 14 publications

(13 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to the likely fragile nature of the peptide hydrolysate [ 26 ], we quantified the impact of the encapsulation processing conditions on bioactivity. Activity of CasHyd in the encapsulated pellets was determined relative to activity of non-encapsulated CasHyd peptide in the GHSR-1a overexpressing cells, as described above.…”

Section: Resultsmentioning

confidence: 99%

“…The dairy hydrolysate, CasHyd, dose-dependently and specifically increased intracellular Ca 2+ in HEK293A cells heterologously expressing the GHSR-1a. We have previously reported ghrelin agonistic effects of a whey-based protein derivative in the same in vitro system [ 26 ]. The CasHyd described here displays superior potency (0.27 mg/mL) compared to the whey derived fraction; however it is considerably less than the endogenous GHSR-1a ligand (0.25 µg/mL), ghrelin ( Figure 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, following IP injection of CasHyd (50 mg/kg dose), neither male nor female rats displayed a significant increase in food intake relative to control ( Figure 7 ). The apparent success of oral delivery of the bioactive peptide relative to injection may be reflective of the distribution of the GHSR-1a in vivo, which is heavily expressed in the gastrointestinal tract and involved in neuronal signalling to appetite centres in the brain [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Milk is one of the primary sources of bioactive fragments for nutraceuticals, many of which have purported health benefits in relation to appetite and metabolism. However, further bioactive identification, enrichment and incorporation into appropriate delivery systems is required [ 26 ]. Our screening platform revealed the dairy hydrolysate (CasHyd), a mixture of peptides produced by the enzymatic cleavage of casein, which potently activates the GHSR-1a in vitro.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A Dairy-Derived Ghrelinergic Hydrolysate Modulates Food Intake In Vivo

Howick

Wallace-Fitzsimons

Kandil

et al. 2018

IJMS

Self Cite

View full text Add to dashboard Cite

Recent times have seen an increasing move towards harnessing the health-promoting benefits of food and dietary constituents while providing scientific evidence to substantiate their claims. In particular, the potential for bioactive protein hydrolysates and peptides to enhance health in conjunction with conventional pharmaceutical therapy is being investigated. Dairy-derived proteins have been shown to contain bioactive peptide sequences with various purported health benefits, with effects ranging from the digestive system to cardiovascular circulation, the immune system and the central nervous system. Interestingly, the ability of dairy proteins to modulate metabolism and appetite has recently been reported. The ghrelin receptor (GHSR-1a) is a G-protein coupled receptor which plays a key role in the regulation of food intake. Pharmacological manipulation of the growth hormone secretagogue receptor-type 1a (GHSR-1a) receptor has therefore received a lot of attention as a strategy to combat disorders of appetite and body weight, including age-related malnutrition and the progressive muscle wasting syndrome known as cachexia. In this study, a milk protein-derivative is shown to increase GHSR-1a-mediated intracellular calcium signalling in a concentration-dependent manner in vitro. Significant increases in calcium mobilisation were also observed in a cultured neuronal cell line heterologously expressing the GHS-R1a. In addition, both additive and synergistic effects were observed following co-exposure of GHSR-1a to both the hydrolysate and ghrelin. Subsequent in vivo studies monitored standard chow intake in healthy male and female Sprague-Dawley rats after dosing with the casein hydrolysate (CasHyd). Furthermore, the provision of gastro-protected oral delivery to the bioactive in vivo may aid in the progression of in vitro efficacy to in vivo functionality. In summary, this study reports a ghrelin-stimulating bioactive peptide mixture (CasHyd) with potent effects in vitro. It also provides novel and valuable translational data supporting the potential role of CasHyd as an appetite-enhancing bioactive. Further mechanistic studies are required in order to confirm efficacy as a ghrelinergic bioactive in susceptible population groups.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Dairy-Derived Ghrelinergic Hydrolysate Modulates Food Intake In Vivo

Howick

Wallace-Fitzsimons

Kandil

et al. 2018

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Liposomal protection can shield ghrelin from metabolic enzymes in the nasal tissues and promote drug absorption. The dry-powdered form of the developed anionic liposomes coated with chitosan showed stronger adhesion to mucins, higher ghrelin entrapment efficiency, higher enzymatic protection against trypsin and lower ghrelin storage degradation at room temperature [ 95 ].…”

Section: Liposomesmentioning

confidence: 99%

Cachexia: Pathophysiology and Ghrelin Liposomes for Nose-to-Brain Delivery

Barros

Rios

Alves

et al. 2020

IJMS

View full text Add to dashboard Cite

Cachexia, a severe multifactorial condition that is underestimated and unrecognized in patients, is characterized by continuous muscle mass loss that leads to progressive functional impairment, while nutritional support cannot completely reverse this clinical condition. There is a strong need for more effective and targeted therapies for cachexia patients. There is a need for drugs that act on cachexia as a distinct and treatable condition to prevent or reverse excess catabolism and inflammation. Due to ghrelin properties, it has been studied in the cachexia and other treatments in a growing number of works. However, in the body, exogenous ghrelin is subject to very rapid degradation. In this context, the intranasal release of ghrelin-loaded liposomes to cross the blood-brain barrier and the release of the drug into the central nervous system may be a promising alternative to improve its bioavailability. The administration of nose-to-brain liposomes for the management of cachexia was addressed only in a limited number of published works. This review focuses on the discussion of the pathophysiology of cachexia, synthesis and physiological effects of ghrelin and the potential treatment of the diseased using ghrelin-loaded liposomes through the nose-to-brain route.

show abstract