Exploring ex vivo peptideolysis of thymopentin and lipid-based nanocarriers towards oral formulations

Liu, Mengyang; Svirskis, Darren; Proft, Thomas; Loh, Jacelyn M. S.; Chen, Shuo; Dh, Kang; Wen, Jingyuan

doi:10.1016/j.ijpharm.2022.122123

Cited by 5 publications

(5 citation statements)

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“…As the concentration increased, there was an increase in proliferation until reaching 5.000 mg/mL, followed by similar cell viability when the concentration reached 10.000 mg/mL. This indicates that non-cytotoxicity can be observed in all TP5 solutions at three different time intervals (24,48, and 72 h). This is in correspondence with the results from the literature that TP5 is able to promote cell growth because TP5 can provide nutrition to Caco-2 and HT-29 cells due to its amino acid nature [43,44].…”

Section: Cytotoxicity Studymentioning

confidence: 70%

“…TP5 stock solution was prepared by dissolving TP5 in a cell culture medium, resulting in a final concentration of 10 mg/mL. TP5-PEG-niosomes were prepared and fabricated in two parts based on our previous research with particle size at 156 ± 36 nm [ 24 ]. In brief, it started with the conjugation of PEG600 and cholesterol.…”

Section: Methodsmentioning

confidence: 99%

“…In brief, it started with the conjugation of PEG600 and cholesterol. In the second part, TP5-PEG-niosomes were fabricated using a thin film hydration method [ 24 ]. In short, a 10 mL blend of methanol and chloroform (1:4, v / v ) comprising 2 μmoL DCP, 30 µmol cholesterol (including 22.5 µmol PEG600-cholesterol), and 120 µmol Span 60 was prepared.…”

Section: Methodsmentioning

confidence: 99%

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Cellular Uptake and Transport Mechanism Investigations of PEGylated Niosomes for Improving the Oral Delivery of Thymopentin

Liu,

Svirskis,

Proft

et al. 2024

Pharmaceutics

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Background: Although its immunomodulatory properties make thymopentin (TP5) appealing, its rapid metabolism and inactivation in the digestive system pose significant challenges for global scientists. PEGylated niosomal nanocarriers are hypothesized to improve the physicochemical stability of TP5, and to enhance its intestinal permeability for oral administration. Methods: TP5-loaded PEGylated niosomes were fabricated using the thin film hydration method. Co-cultured Caco-2 and HT29 cells with different ratios were screened as in vitro intestinal models. The cytotoxicity of TP5 and its formulations were evaluated using an MTT assay. The cellular uptake and transport studies were investigated in the absence or presence of variable inhibitors or enhancers, and their mechanisms were explored. Results and Discussion: All TP5 solutions and their niosomal formulations were nontoxic to Caco-2 and HT-29 cells. The uptake of TP5-PEG-niosomes by cells relied on active endocytosis, exhibiting dependence on time, energy, and concentration, which has the potential to significantly enhance its cellular uptake compared to TP5 in solution. Nevertheless, cellular transport rates were similar between TP5 in solution and its niosomal groups. The cellular transport of TP5 in solution was carried out mainly through MRP5 endocytosis and a passive pathway and effluxed by MRP5 transporters, while that of TP5-niosomes and TP5-PEG-niosomes was carried out through adsorptive- and clathrin-mediated endocytosis requiring energy. The permeability and transport rate was further enhanced when EDTA and sodium taurocholate were used as the penetration enhancers. Conclusions: This research has illustrated that PEG-niosomes were able to enhance the cellular uptake and maintain the cellular transport of TP5. This study also shows this formulation’s potential to serve as an effective carrier for improving the oral delivery of peptides.

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Section: Cytotoxicity Studymentioning

confidence: 70%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Cellular Uptake and Transport Mechanism Investigations of PEGylated Niosomes for Improving the Oral Delivery of Thymopentin

Liu,

Svirskis,

Proft

et al. 2024

Pharmaceutics

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“…[42] Due to the high lipid content of cell membranes, lipid NPs are considered advantageous for cellular uptake. [43] However, their lipophilicity poses a challenge to the encapsulation of hydrophilic proteins such as insulin. [44] SLNs and nanostructured lipid carriers (NLCs) are two major types of lipid NPs.…”

Section: Lipid-based Nanoparticlesmentioning

confidence: 99%

Advancements in oral insulin: A century of research and the emergence of targeted nanoparticle strategies

Han,

Spicer,

Huang

et al. 2024

Euro J Lipid Sci & Tech

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With the growing prevalence of diabetes, there is an urgent demand for a user‐friendly treatment option that minimizes side effects related to the use of subcutaneous injections. Scientists have dedicated over a century to developing an oral dosage form of insulin that can be administrated orally. The oral route of administration is the most desirable route for regularly dosed drugs in terms of safety and patient compliance. However, oral delivery of insulin remains a formidable challenge due to its intrinsically limited ability to cross the intestinal epithelium membrane and susceptibility to enzymatic degradation. This article reviews oral insulin research over the past decade, with a particular focus on surface modifications of nanoparticles (NPs). Various strategies involving controlling surface charges, utilizing protective proteins, and targeting specific receptors with ligands have been explored. Notably, surface modifications of the NPs for targeting specific intestinal receptors have shown promise in enhancing insulin oral absorption and bioavailability. Advanced technologies such as oral microneedles and gene therapy have also been developed, but their safety requires further assessment. Despite encouraging preclinical results across numerous strategies, the current clinical evidence is less optimistic. In summary, the present findings highlight the substantial journey that still lies ahead before achieving successful oral delivery of insulin.Practical Applications: This review provides a summary of recent progress in oral insulin delivery, particularly highlighting surface‐modified functional nanoparticles serving as an effective drug delivery system, which offers valuable information to the researchers. Due to the limited effectiveness of oral protein drugs caused by biological barriers, innovative technologies and drug delivery systems have been developed to overcome these obstacles and achieve therapeutic goals. This review concluded that surface modifications to nanoparticles can improve insulin stability and permeability, thereby enhancing oral bioavailability. It could assist researchers in developing more effective and patient‐friendly oral drug delivery systems.

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“…Optimized SLP formulations have been reported to maintain their physical integrity for at least three years [ 28 , 29 , 30 ]. Their physicochemical stability, low cost, and possibility for large-scale production, compared to liposomes, make SLPs highly suitable for further research as a delivery vehicle for oral delivery of proteins and peptides [ 31 , 32 ]. However, the safety profile and the mechanisms involved in the cellular uptake and transport of polymer-modified SLPs as vehicles for drug delivery have not undergone assessment.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Cellular Uptake and Transport of Bovine Lactoferrin Using Pectin- and Chitosan-Modified Solid Lipid Nanoparticles

Yao,

Bunt,

Liu

et al. 2023

Pharmaceutics

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Aim: The aim of this project is to use pectin- and chitosan-modified solid lipid nanoparticles for bovine lactoferrin to enhance its cellular uptake and transport. Methods: Solid lipid particles containing bovine lactoferrin (bLf) were formulated through the solvent evaporation technique, incorporating stearic acid along with either chitosan or pectin modification. bLf cellular uptake and transport were evaluated in vitro using the human adenocarcinoma cell line Caco-2 cell model. Results and Discussion: The bLf-loaded SLPs showed no significant effect on cytotoxicity and did not induce apoptosis within the eight-hour investigation. The use of confocal laser scanning microscopy confirmed that bLf follows the receptor-mediated endocytosis, whereas the primary mechanism for the cellular uptake of SLPs was endocytosis. The bLf-loaded SLPs had significantly more cellular uptake compared to bLf alone, and it was observed that this impact varied based on the time, temperature, and concentration. Verapamil and EDTA were determined to raise the apparent permeability coefficients (App) of bLf and bLf-loaded SLPs. Conclusion: This occurred because they hindered efflux by interacting with P-glycoproteins and had a penetration-enhancing influence. These findings propose the possibility of an additional absorption mechanism for SLPs, potentially involving active transportation facilitated by the P-glycoprotein transporter in Caco-2 cells. These results suggest that SLPs have the potential to be applied as effective carriers to improve the oral bioavailability of proteins and peptides.

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Exploring ex vivo peptideolysis of thymopentin and lipid-based nanocarriers towards oral formulations

Cited by 5 publications

References 44 publications

Cellular Uptake and Transport Mechanism Investigations of PEGylated Niosomes for Improving the Oral Delivery of Thymopentin

Cellular Uptake and Transport Mechanism Investigations of PEGylated Niosomes for Improving the Oral Delivery of Thymopentin

Advancements in oral insulin: A century of research and the emergence of targeted nanoparticle strategies

Enhanced Cellular Uptake and Transport of Bovine Lactoferrin Using Pectin- and Chitosan-Modified Solid Lipid Nanoparticles

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