Molecular Design, Synthesis, and Properties of Surface-Active Comb-Like PEG-Containing Polymers and Derived Supramolecular Structures for Drug Delivery

Mitina, Nataliya; Riabtseva, Anna; Paiuk, Olena; Finiuk, Nataliya; Šlouf, Miroslav; Pavlová, Ewa; Kobylinska, Lesya; Lesyk, Roman; Hevus, Orest; Garamus, V. M.; Stoika, Rostyslav; Zaichenko, Alexander

doi:10.1007/978-3-030-76235-3_2

Cited by 2 publications

(5 citation statements)

References 43 publications

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“…As shown in Figure 5 b, PEG-niosomes were not toxic in most concentrations from 0.01 to 2.00 × 10 12 /mL for 24, 48, and 72 h. As the niosome numbers increased, there was a light increase in cell growth until the niosomes’ number reached 2.000 × 10 12 /mL, followed by a decreased cell viability after the concentration reached 5.00 × 10 12 /mL. It may be due to the weak toxicity of surfactants used in PEG-niosomes [ 45 , 46 ]. Because the higher numbers of niosomes contain a higher drug loading, the cellular uptake and transport of TP5 can be increased.…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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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“…Synthesis of the comb-like copolymer was conducted, as described earlier. − In Figure , a scheme of its conjugation with the SPC tripeptide is presented.…”

Section: Resultsmentioning

confidence: 99%

“…Procedures, described earlier, − were used to obtain a micelle-forming surface-active copolymer consisting of the backbone of the PEGylated comb-like polymer and the terminal fragment of the SPC tripeptide.…”

Section: Methodsmentioning

confidence: 99%

“…A mixture of PEGMA (3.8 mL, 8.0 mmol) and DMM (0.13 mL, 0.9 mmol) and 10 mL of the CGE (0.03 mL, 0.3 mmol) was prepared; after that, an AIBN (0.1 g, 0.61 mmol) solution in the dioxane (Acros, USA) was added to the mixture. Monomer conversion was controlled via dilatometric study . After polymerization was finished, the polymer was purified by precipitation and dried under vacuum until constant weight .…”

Section: Methodsmentioning

confidence: 99%

“…Monomer conversion was controlled via dilatometric study. 9 After polymerization was finished, the polymer was purified by precipitation and dried under vacuum until constant weight. 10 A residual PEGMA was removed by dialysis using dialysis bags with pore sizes MWCO 6 kDa (Sigma-Aldrich, USA).…”

Section: Methodsmentioning

confidence: 99%

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Covalent Conjugate of Ser-Pro-Cys Tripeptide with PEGylated Comb-Like Polymer as Novel Killer of Human Tumor Cells

et al. 2022

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Recently, we detected a previously unknown Ser-Pro-Cys (SPC) tripeptide in the blood serum of multiple sclerosis patients. Its role as a biomarker of the autoimmune disease was suggested, although its origin and real biological activity remained unclear. Here, we created a biocompatible PEGylated comb-like polymer that was used as a platform for covalent immobilization of the SPC, which provided a possibility to explore the biological activity of this tripeptide. This macromolecular conjugate was synthesized via a reaction of the terminal epoxide group of the biocompatible copolymer of dimethyl maleate (DMM) and polyethylene glycol methyl ether methacrylate (PEGMA) with the amino group of the SPC tripeptide. Unexpectedly, the resulting conjugate containing SPC demonstrated anticancer activity in vitro. It possessed pro-apoptotic action toward human tumor cells, while there was no cytotoxic effect of that conjugate toward normal lymphocytes of human peripheral blood. The detected biological effects of the created conjugate inspired us to carry out a thorough study of structural and colloidal-chemical characteristics of this surface-active copolymer containing side PEG chains and a terminal nontoxic synthetic fragment. The copolymer composition, in particular, the content of the peptide fragment, was determined via elemental analysis and NMR spectroscopy. At CMC, it formed polymeric micelle-like structures with a hydrodynamic diameter of 180 ± 60 nm. The conjugation of the peptide fragment to the initial comb-like copolymer caused a change of zeta-potential of the formed micelle-like structures from −0.15 to 0.32 mV. Additional structural modification of the created polymeric nanoplatform was performed via attachment of fluorescein isothiocianate (FITC) dye that permitted monitoring of the behavior of the bioactive SPC-functionalized conjugate in the treated tumor cells. Its penetration into those cells and localization in their cytoplasm were revealed. The principal novelty of this study consists in finding that covalent conjugation of two nontoxic compoundsSPC tripeptide and comb-like PEGylated polymerled to an unexpected synergy which appeared in the distinct cytotoxic action of the macromolecular complex toward human tumor cells. A potential role of peculiarities of the colloidal-chemical properties of the novel conjugate in its cytotoxic effect are discussed. Thus, synthesized comb-like PEGylated polymers can provide a prospective nanoplatform for drug delivery in anticancer chemotherapy.

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Molecular Design, Synthesis, and Properties of Surface-Active Comb-Like PEG-Containing Polymers and Derived Supramolecular Structures for Drug Delivery

Cited by 2 publications

References 43 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

Covalent Conjugate of Ser-Pro-Cys Tripeptide with PEGylated Comb-Like Polymer as Novel Killer of Human Tumor Cells

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