A nanoemulsion/micelles mixed nanosystem for the oral administration of hydrophobically modified insulin

Santalices, Irene; Vázquez–Vázquez, C.; Santander-Ortega, Manuel J.; Lozano, Victoria; Araújo, Francisca; Sarmento, Bruno; Shrestha, Neha; Préat, Véronique; Chenlo, Miguel; Álvarez, Clara V.; Benetti, Federico; Cuñarro, Juan; Tovar, Sulay; Torres, Dolores; Alonso, María José

doi:10.1007/s13346-021-00920-x

Cited by 16 publications

(5 citation statements)

References 82 publications

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“…Fortunately, in vitro cellular assays are now available, for example, with insulin receptor-expressing hepatic HepG2 − and murine fat cells, , to investigate the physiological activity of insulin. These assays provide an affordable, robust, and reproducible platform to investigate the bioactivity of insulin.…”

Section: Future Perspectivesmentioning

confidence: 99%

Amyloid Fibrillation of Insulin: Amelioration Strategies and Implications for Translation

Fagihi

Bhattacharjee

2022

ACS Pharmacol. Transl. Sci.

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Insulin is a therapeutically relevant molecule with use in treating diabetes patients. Unfortunately, it undergoes a range of untoward and often unpredictable physical transformations due to alterations in its biochemical environment, including pH, ionic strength, temperature, agitation, and exposure to hydrophobic surfaces. The transformations are prevalent in its physiologically active monomeric form, while the zinc cationcoordinated hexamer, although physiologically inactive, is stable and less susceptible to fibrillation. The resultant molecular reconfiguration, including unfolding, misfolding, and hydrophobic interactions, often results in agglomeration, amyloid fibrillogenesis, and precipitation. As a result, a part of the dose is lost, causing a compromised therapeutic efficacy. Besides, the amyloid fibrils form insoluble deposits, trigger immunologic reactions, and harbor cytotoxic potential. The physical transformations also hold back a successful translation of non-parenteral insulin formulations, in addition to challenges related to encapsulation, chemical modification, purification, storage, and dosing. This review revisits the mechanisms and challenges that drive such physical transformations in insulin, with an emphasis on the observed amyloid fibrillation, and presents a critique of the current amelioration strategies before prioritizing some future research objectives.

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Section: Future Perspectivesmentioning

confidence: 99%

Amyloid Fibrillation of Insulin: Amelioration Strategies and Implications for Translation

Fagihi

Bhattacharjee

2022

ACS Pharmacol. Transl. Sci.

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“…Regrettably, there are no quick ways to quantify or predict the bioactivity of an (agglomerated) insulin preparation. In vitro assays were used to ascertain such bioactivity, − although these assays need further refinement, acceptable reproducibility, set standard operating protocols, and a better interpretation. Fluorophore-labeled insulin, similar to the FITC-labeled insulin used here, could expand the scope of these in vitro assays.…”

Section: Discussionmentioning

confidence: 99%

An Investigation into the Acidity-Induced Insulin Agglomeration: Implications for Drug Delivery and Translation

Fagihi,

Premathilaka,

O’Neill

et al. 2023

ACS Omega

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Insulin undergoes agglomeration with (subtle) changes in its biochemical environment, including acidity, application of heat, ionic imbalance, and exposure to hydrophobic surfaces. The therapeutic impact of such unwarranted insulin agglomeration is unclear and needs further evaluation. A systematic investigation was conducted on recombinant human insulinwith or without labeling with fluorescein isothiocyanatewhile preparing insulin suspensions (0.125, 0.25, and 0.5 mg/mL) at pH 3. The suspensions were incubated (37 °C) and analyzed at different time points (t = 2, 4, 24, 48, and 72 h). Transmission electron microscopy and nanoparticle tracking analysis identified colloidally stable (zeta potential 15 ± 5 mV) spherical agglomerates of unlabeled insulin (100–500 nm). Circular dichroism established the preservation of insulin’s secondary structure rich in α-helices despite exposure to an acidic environment (pH 3) for 72 h. Furthermore, fluorescence lifetime imaging microscopy illustrated an acidic core inside these spherical agglomerates, while the acidity gradually lessened toward the periphery. Some of these smaller agglomerates fused to form larger chunks with discrete zones of acidity. The data indicated a primary nucleation-driven mechanism of acid-induced insulin agglomeration under physiologically relevant conditions.

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“…In addition, it exhibited a high interaction with cell monocultures (Caco -2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and cocultures (C2BBe1 human colon carcinoma Caco-2 clone/HT29-MTX cells). Overall, this information underlined the crucial steps to address the intestinal barriers associated with the oral delivery of peptide-based nanoformulations [80].…”

Section: Nanoemulsionmentioning

confidence: 95%

Emerging Treatment Strategies for Diabetes Mellitus and Associated Complications: An Update

et al. 2021

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The occurrence of diabetes mellitus (DM) is increasing rapidly at an accelerating rate worldwide. The status of diabetes has changed over the last three generations; whereas before it was deemed a minor disease of older people but currently it is now one of the leading causes of morbidity and mortality among middle-aged and young people. High blood glucose-mediated functional loss, insulin sensitivity, and insulin deficiency lead to chronic disorders such as Type 1 and Type 2 DM. Traditional treatments of DM, such as insulin sensitization and insulin secretion cause undesirable side effects, leading to patient incompliance and lack of treatment. Nanotechnology in diabetes studies has encouraged the development of new modalities for measuring glucose and supplying insulin that hold the potential to improve the quality of life of diabetics. Other therapies, such as β-cells regeneration and gene therapy, in addition to insulin and oral hypoglycemic drugs, are currently used to control diabetes. The present review highlights the nanocarrier-based drug delivery systems and emerging treatment strategies of DM.

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A nanoemulsion/micelles mixed nanosystem for the oral administration of hydrophobically modified insulin

Cited by 16 publications

References 82 publications

Amyloid Fibrillation of Insulin: Amelioration Strategies and Implications for Translation

Amyloid Fibrillation of Insulin: Amelioration Strategies and Implications for Translation

An Investigation into the Acidity-Induced Insulin Agglomeration: Implications for Drug Delivery and Translation

Emerging Treatment Strategies for Diabetes Mellitus and Associated Complications: An Update

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