Revealing the importance of carrier-cargo association in delivery of insulin and lipidated insulin

Diedrichsen, Ragna Guldsmed; Rønholt, Stine; Ulrich, Werner; Besenius, Melissa; Leberer, Ekkehard; Kristensen, M; Nielsen, Hanne Mørck

doi:10.1016/j.jconrel.2021.07.030

Cited by 23 publications

(30 citation statements)

References 44 publications

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“…Tat and Penetratin are among the most studied CPPs, which have been employed as a vector to improve intracellular delivery of various drug compounds, including oligonucleotides ( Brown & Graham, 2010 ) and proteins ( Harada et al, 2002 ; Liang & Yang, 2005 ; Kamei et al, 2008 ; Khafagy et al, 2009 ). Besides that, both Tat and Penetratin have been shown to promote permeation through tight junction modulation ( Bai et al, 2008 ; Kristensen et al, 2020 ; Diedrichsen et al, 2021 ). However, results from our study showed that Tat and Penetratin had no permeabilizing effect in the Caco-2 monolayer setup at 100 µM.…”

Section: Discussionmentioning

confidence: 99%

“…Tight junctions are responsible for closing intercellular gaps, thereby determining the paracellular permeability and epithelial barrier integrity ( Johnson & Quay 2005 ; Deli, 2009 ). To overcome these permeability challenges for improving drug uptake, several strategies have been explored, including the use of medium chain fatty acids ( Izgelov et al, 2020 ), biosurfactants ( Perinelli et al, 2017 ), ingestible capsules ( Abramson et al, 2019 ) and cell-penetrating peptides (CPPs) ( Kristensen and Nielsen, 2016a ; Rehmani and Dixon, 2018 ; Diedrichsen et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Paracellular spaces are aqueous filled channels through which these drugs prefer to diffuse ( Salamat-Miller and Johnston, 2005 ; Patel and Misra, 2011 ). Several studies have reported that some CPPs can also promote permeation of various cellular barriers through paracellular route both in vitro and in vivo ( Ohtake et al, 2002 ; Bai et al, 2008 ; Kristensen and Nielsen, 2016a ; Kristensen and Nielsen, 2016b ; Kristensen et al, 2020 ; Diedrichsen et al, 2021 ; Ragupathy et al, 2021 ; Frøslev et al, 2022 ). This could be either due to the high local concentration of the CPPs, influencing the dynamics of the tight junction proteins or due to cell-penetrating tendency of CPPs, targeting intracellular proteins which are involved in regulation of opening and closing of tight junctions ( Taverner et al, 2015 ; Kristensen and Nielsen, 2016a ).…”

Section: Introductionmentioning

confidence: 99%

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Screening for effective cell-penetrating peptides with minimal impact on epithelial cells and gut commensals in vitro

Gelli

Vazquez-Uribe²,

Sommer³

2022

Front. Pharmacol.

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One of the biggest challenges for oral drug absorption is the epithelial barrier of the gastrointestinal tract. The use of cell-penetrating peptides (CPPs) to modulate the epithelial barrier function is known to be an effective strategy to improve drug absorption and bioavailability. In this study we compare side-by-side, 9 most promising CPPs to study their cytotoxicity (Cytotox Red dye staining) and cell viability (AlamarBlue staining) on epithelial cells and their effects on paracellular permeability of the intestinal barrier in vitro in a differentiated Caco-2 epithelial monolayer model. The data revealed that 4 out of 9 well-studied CPPs significantly improved Caco-2 paracellular permeability without compromising on cellular health. To assess the impact of CPPs on the human microbiota we studied the antimicrobial effects of the 4 effective CPPs from our permeation studies against 10 representative strains of the gut microbiota in vitro using microbroth dilution. Our data revealed that these 4 CPPs affected the growth of almost all tested commensal strains. Interestingly, we found that two synthetic CPPs (Shuffle and Penetramax) outperformed all the other CPPs in their ability to increase intestinal paracellular permeability at 50 µM and had only a small to moderate effect on the tested gut commensal strains. Based on these data Shuffle and Penetramax represent relevant CPPs to be further characterized in vivo for safe delivery of poorly absorbed therapeutics while minimizing negative impacts on the gut microbiota.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Screening for effective cell-penetrating peptides with minimal impact on epithelial cells and gut commensals in vitro

Gelli

Vazquez-Uribe²,

Sommer³

2022

Front. Pharmacol.

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“…Amphipathic and cationic CPPs have been used as carrier proteins to enhance the intracellular delivery of hydrophilic therapeutic peptides. Diedrichsen et al ( 2021 ) prepared CPP-insulin composites and studied their drug efficacy. The CPP-insulin composite was a few hundred nanometers in hydrodynamic size.…”

Section: Application Of the Cpp-based Delivery Systemmentioning

confidence: 99%

Recent advances in selective and targeted drug/gene delivery systems using cell-penetrating peptides

2023

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Biological cell membranes are a natural barrier for living cells. In the last few decades, the cell membrane has been the main hurdle in the efficient delivery of bioactive and therapeutic agents. To increase the drug efficacy of these agents, additional mediators have been considered. Cell-penetrating peptides (CPPs), a series of oligopeptides composed of mostly hydrophobic and/or positively charged side chains, can increase the interaction with the cell membrane. CPP-based delivery platforms have shown great potential for the efficient and direct cytosol delivery of various cargos, including genes, proteins, and small molecule drugs. Bypassing endocytosis allows the CPP-based delivery systems greater defense against the degradation of protein-based drugs than other drug delivery systems. However, the delivery of CPPs exhibits intrinsically non-specific targeting, which limits their medical applications. To endow CPPs with specific targeting ability, the conjugation of pH-sensitive, enzyme-specific cleavable, and multiple targeting ligands has been reported. Optimization of the length and sequence of CPPs is still needed for various drugs of different sizes and surface charges. Toxicity issues in CPP-based delivery systems should be addressed carefully before clinical use.

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“…Although effective in short periods, frequent injection cannot mimic the normal physiological INS secretion pattern upon variation in the BGL [ 13 , 14 , 15 , 16 ]. Even with the combinations of short- and long-term INS releasing systems, complications, such as intermittent hypoglycemic periods of excessive INS and hyperglycemic periods with a lack of INS, may occur if the doses and timings of INS are imprecise [ 17 , 18 , 19 , 20 ]. Ideally, INS therapy should provide an appropriate quantity of INS to restore the BGL [ 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

A Closed-Loop Autologous Erythrocyte-Mediated Delivery Platform for Diabetic Nephropathy Therapy

Feng

Huang

et al. 2022

Nanomaterials

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Failure to control blood glucose level (BGL) may aggravate oxidative stress and contribute to the development of diabetic nephropathy (DN). Using erythrocytes (ERs) as the carriers, a smart self-regulatory insulin (INS) release system was constructed to release INS according to changes in BGLs to improve patients’ compliance and health. To overcome the limited sources of ERs and decrease the risk of transmitting infections, we developed an in vitro, closed-loop autologous ER-mediated delivery (CAER) platform, based on a commercial hemodialysis instrument modified with a glucose-responsive ER-based INS delivery system (GOx-INS@ER). After the blood was drained via a jugular vein cannula, some of the blood was pumped into the CAER platform. The INS was packed inside the autologous ERs in the INS reactor, and then their surface was modified with glucose oxidase (GOx), which acts as a glucose-activated switch. In vivo, the CAER platform showed that the BGL responsively controlled INS release in order to control hyperglycemia and maintain the BGL in the normal range for up to 3 days; plus, there was good glycemic control without the added burden of hemodialysis in DN rabbits. These results demonstrate that this closed-loop extracorporeal hemodialysis platform provides a practical approach for improving diabetes management in DN patients.

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Revealing the importance of carrier-cargo association in delivery of insulin and lipidated insulin

Cited by 23 publications

References 44 publications

Screening for effective cell-penetrating peptides with minimal impact on epithelial cells and gut commensals in vitro

Screening for effective cell-penetrating peptides with minimal impact on epithelial cells and gut commensals in vitro

Recent advances in selective and targeted drug/gene delivery systems using cell-penetrating peptides

A Closed-Loop Autologous Erythrocyte-Mediated Delivery Platform for Diabetic Nephropathy Therapy

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