Cross-Linked Thiolated Hydroxypropil-β-Cyclodextrin for Pulmonary Drug Delivery
Abstract
:1. Introduction
2. Results
2.1. Synthesis and Characterization of HP-β-CD-SH-NP
2.2. Determination of the Association Constant for Cyclodextrins/DMS and Cyclodextrins/OLE-GS
2.3. Cytotoxicity Studies
2.4. Dimensional Analysis and Zeta Potential of Drug-Loaded Formulations
2.5. DMS Permeation through Monolayer
2.6. Evaluation of the Protective Effect from Oxidative Stress of OLE-GS Nebulized on the Monolayer
3. Materials and Methods
3.1. Materials
3.2. Synthesis and Purification of Thiolated Hydroxypropyl-β-Cyclodextrin (HP-β-CD-SH)
3.3. Synthesis and Purification of Nanoparticles Based on HP-β-CD-SH (HP-β-CD-SH-NP)
3.4. Determination of the Association Constant for Cyclodextrins/DMS and Cyclodextrins/OLE-GS
3.5. Preparation of Drug-Loaded HP-β-CD, HP-β-CD-SH, or HP-β-CD-SH-NP Samples
3.6. Biological Investigation
3.6.1. Cell Viability Assay
- 0.25 mg/mL DMS containing 10 mg/mL of HP-β-CD (code HP-β-CD/DMS);
- 0.25 mg/mL DMS containing 10 mg/mL of HP-β-CD-SH (code HP-β-CD-SH/DMS);
- 0.25 mg/mL DMS containing 10 mg/mL of HP-β-CD-SH-NP (code HP-β-CD-SH-NP/DMS);
- 0.3 mg/mL OLE-GS containing 10 mg/mL of HP-β-CD (code HP-β-CD/OLE-GS);
- 0.3 mg/mL OLE-GS containing 10 mg/mL of HP-β-CD-SH (code HP-β-CD-SH/OLE-GS);
- 0.3 mg/mL OLE-GS containing 10 mg/mL of HP-β-CD-SH-NP (code HP-β-CD-SH-NP/OLE-GS).
3.6.2. In Vitro Air–Liquid Interface (ALI) Model
3.6.3. Permeation of Nebulized DMS Formulations through ALI Lung Model
3.6.4. Protective Effect of Nebulized OLE-GS Formulations on H2O2-Stressed ALI Lung Model
3.7. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Levy, M.L.; Carroll, W.; Izquierdo Alonso, J.L.; Keller, C.; Lavorini, F.; Lehtimäk, L. Understanding Dry Powder Inhalers: Key Technical and Patient Preference Attributes. Adv. Ther. 2019, 36, 2547–2557. [Google Scholar] [CrossRef]
- Perinel, S.; Pourchez, J.; Leclerc, L.; Avet, J.; Durand, M.; Prévôt, N.; Cottier, M.; Vergnon, J.M. Development of an ex vivo human-porcine respiratory model for preclinical studies. Sci. Rep. 2017, 7, 43121. [Google Scholar] [CrossRef] [PubMed]
- Respiratory Diseases Statistics—European Commission. 2024. Available online: https://ec.europa.eu/eurostat/statistics-explained/index.php?title=Respiratory_diseases_statistics (accessed on 25 August 2024).
- Guo, Y.; Bera, H.; Shi, C.; Zhang, L.; Cun, D.; Yang, M. Pharmaceutical strategies to extend pulmonary exposure of inhaled medicines. Acta Pharm. Sin. B 2021, 11, 2565–2584. [Google Scholar] [CrossRef] [PubMed]
- Qin, L.; Cui, Z.; Wu, Y.; Wang, H.; Zhang, X.; Guan, J.; Mao, S. Challenges and Strategies to Enhance the Systemic Absorption. of Inhaled Peptides and Proteins. Pharm. Res. 2023, 40, 1037–1055. [Google Scholar] [CrossRef] [PubMed]
- Schwarz, D.H.; Engelke, A.; Wenz, G. Solubilizing steroidal drugs by β-cyclodextrin derivatives. Int. J. Pharm. 2017, 531, 559–567. [Google Scholar] [CrossRef]
- Bueva, V.V.; Blynskaja, E.V.; Alekseev, K.V.; Minaev, S.V.; Eremin, V.A. Advanced taste-masking methods of solid dosage form. Pharm. Chem. J. 2023, 57, 1494–1498. [Google Scholar] [CrossRef]
- Miyajima, K.; Sawada, M.; Nakagaki, M. Viscosity B-cofficients, apparent molar volumes, and activity coefficients for α- and γ-cyclodextrins in aqueous solutions. Bull. Chem. Soc. Jpn. 1983, 56, 3556–3560. [Google Scholar] [CrossRef]
- Calleja, P.; Espuelas, S.; Corrales, L.; Pio, R.; Irache, J.M. Pharmacokinetics and antitumor efficacy of paclitaxel–cyclodextrin complexes loaded in mucus-penetrating nanoparticles for oral administration. Nanomedicine 2014, 14, 2109–2121. [Google Scholar] [CrossRef]
- Loftsson, T.; Jansook, P.; Stefansson, E. Topical drug delivery to the eye: Dorzolamide. Acta Ophthalmol. 2012, 90, 603–608. [Google Scholar] [CrossRef]
- Loftsson, T.; Saokham, P.; Sa Couto, A.R. Self-association of cyclodextrin and cyclodextrin complexes in aqueous solutions. Int. J. Pharm. 2019, 560, 228–234. [Google Scholar] [CrossRef]
- Grassiri, B.; Knoll, P.; Fabiano, A.; Piras, A.M.; Zambito, Y.; Bernkop-Schnürch, A. Thiolated Hydroxypropyl-β-cyclodextrin: A Potential Multifunctional Excipient for Ocular Drug Delivery. Int. J. Mol. Sci. 2022, 23, 2612. [Google Scholar] [CrossRef] [PubMed]
- Grassiri, B.; Cesari, A.; Balzano, F.; Migone, C.; Kali, G.; Bernkop-Schnürch, A.; Uccello-Barretta, G.; Zambito, Y.; Piras, A.M. Thiolated 2-Methyl-β-Cyclodextrin as a Mucoadhesive Excipient for Poorly Soluble Drugs: Synthesis and Characterization. Polymers 2022, 14, 3170. [Google Scholar] [CrossRef] [PubMed]
- Trotta, V.; Scalia, S. Pulmonary delivery systems for polyphenols. Drug Dev. Ind. Pharm. 2017, 43, 1043–1052. [Google Scholar] [CrossRef] [PubMed]
- Rouibah, Z.; Ben Mensour, A.; Rekik, O.; Boumendjel, M.; Taibi, F.; Bouaziz, M.; El Feki, A.; Messarah, M.; Boumendjel, A. Chemical composition, antioxidant activities, in an allergic asthma model, of Olea europaea L. leaf extracts from Collo (Skikda, Algeria). Drug Chem. Toxicol. 2022, 45, 197–208. [Google Scholar] [CrossRef]
- Elgebaly, H.A.; Mosa, N.M.; Allach, M.; El-Massry, K.F.; El-Ghorab, A.H.; Al Hroob, A.M.; Mahmoud, A.M. Olive oil and leaf extract prevent fluoxetine-induced hepatotoxicity by attenuating oxidative stress, inflammation and apoptosis. Biomed. Pharmacother. 2018, 98, 446–453. [Google Scholar] [CrossRef]
- Silva, S.; Bicker, J.; Falcão, A.; Fortuna, A. Air-liquid interface (ALI) impact on different respiratory cell cultures. Eur. J. Pharm. Biopharm. 2023, 184, 62–82. [Google Scholar] [CrossRef]
- Loftsson, T.; Stefánsson, E. Cyclodextrins in eye drop formulations: Enhanced topical delivery of corticosteroids to the eye. Acta Ophthalmol. Scand. 2002, 80, 144–150. [Google Scholar] [CrossRef]
- Sa Couto, A.R.; Ryzhakov, A.; Lambertsen, L.K.; Loftsson, T. Interaction of native Cyclodextrin and their hydroxypropylated derivatives with carbamazepine in aqueous solution. Evaluation of inclusion complexes and aggregates formation. ACS Omega 2019, 4, 1460–1469. [Google Scholar] [CrossRef]
- Partis, M.D.; Griffiths, D.G.; Roberts, G.C.; Beechey, R.B. Cross-linking of protein by ω-maleimido alkanoyl N-hydroxysuccinimido esters. J. Prot. Chem. 1983, 2, 263–277. [Google Scholar] [CrossRef]
- Smyth, D.G.; Blumenfeld, O.O.; Konigsberg, W. Reactions of N-ethylmaleimide with peptides and amino acids. Biochem. J. 1964, 91, 589–595. [Google Scholar] [CrossRef]
- Akbulut, O.; Mace, C.R.; Martinez, R.V.; Kumar, A.A.; Nie, Z.; Patton, M.R.; Whitesides, G.M. Separation of Nanoparticles in Aqueous Multiphase System through Centrifugation. Nano Lett. 2012, 12, 4060–4064. [Google Scholar] [CrossRef]
- Benesi, H.A.; Hildebrand, J.H. A Spectrophotometric Investigation of the Interaction of Iodine with Aromatic Hydrocarbons. J. Am. Chem. Soc. 1949, 71, 2703–2707. [Google Scholar] [CrossRef]
- Cesari, A.; Recchimurzo, A.; Fabiano, A.; Balzano, F.; Rossi, N.; Migone, C.; Uccello-Barretta, G.; Zambito, Y.; Piras, A.M. Improvement of Peptide Affinity and Stability by Complexing to Cyclodextrin-Grafted Ammonium Chitosan. Polymers 2020, 12, 474. [Google Scholar] [CrossRef]
- Kesavan, K.; Kant, S.; Singh, P.N.; Pandit, J.K. Effect of Hydroxypropyl-β-cyclodextrin on the ocular bioavailability of Dexamethasone from a pH-induced mucoadhesive hydrogel. Curr. Eye Res. 2011, 36, 918–929. [Google Scholar] [CrossRef] [PubMed]
- Coleman, A.W.; Nicolis, L.; Keller, N.; Dalbiez, J.P. Aggregation of cyclodextrins: An explanation of the abnormal solubility of beta-cyclodextrin. J. Incl. Phenom. Mol. Recognit. Chem. 1992, 13, 139–143. [Google Scholar] [CrossRef]
- Messner, M.; Kurkov, S.V.; Jansook, P.; Loftsson, T. Self-assembled cyclodextrin aggregates and nanoparticles. Int. J. Pharm. 2010, 387, 199–208. [Google Scholar] [CrossRef]
- Rabanel, J.M.; Hildgen, P.; Banquy, X. Assessment of PEG on polymeric particles surface, a key step in drug carrier translation. J. Control. Release 2014, 185, 71–87. [Google Scholar] [CrossRef]
- Bernkop-Schnürch, A.; Weithaler, A.; Albrecht, K.; Greimel, A. Thiomers: Preparation and in vitro evaluation of a mucoadhesive nanoparticulate drug delivery system. Int. J. Pharm. 2006, 317, 76–81. [Google Scholar] [CrossRef]
- Wong, P.S.; Vogel, C.F.; Kokosinski, K.; Matsumura, F. Arylhydrocarbon receptor activation in NCI-H441 cells and C57BL/6 mice: Possible mechanisms for lung dysfunction. Am. J. Respir. Cell Mol. Biol. 2010, 42, 210–217. [Google Scholar] [CrossRef]
- Asim, M.H.; Ijaz, M.; Mahmood, A.; Knoll, P.; Jalil, A.; Arshad, S.; Bernkop-Schnürch, A. Thiolatd cyclodextrins: Mucoadhesive and permeation enhancing excipients for ocular drug delivery. Int. J. Pharm. 2021, 599, 120451. [Google Scholar] [CrossRef]
- Zambito, Y.; Piras, A.M.; Fabiano, A. Bergamot essential oil: A method for introducing it in solid dosage form. Foods 2022, 11, 3860. [Google Scholar] [CrossRef] [PubMed]
- Cerri, L.; Parri, S.; Dias, M.C.; Fabiano, A.; Romi, M.; Cai, G.; Cantini, C.; Zambito, Y. Olive leaf extract from three Italian cultivars exposed to drought stress differentially protect cells against oxidative stress. Antioxidants 2024, 13, 77. [Google Scholar] [CrossRef] [PubMed]
- Migone, C.; Mattii, L.; Giannasi, M.; Moscato, S.; Cesari, A.; Zambito, Y.; Piras, A.M. Nanoparticles Based on Quaternary Ammonium Chitosan-methyl-β-cyclodextrin Conjugate for the Neuropeptide Dalargin Delivery to the Central Nervous System: An In Vitro Study. Pharmaceutics 2021, 13, 5. [Google Scholar] [CrossRef]
- Vizzoni, L.; Migone, C.; Grassiri, B.; Zambito, Y.; Ferro, B.; Roncucci, P.; Mori, F.; Salvatore, A.; Ascione, E.; Crea, R.; et al. Biopharmaceutical Assessment of Mesh Aerosolised Plasminogen, a Step towards ARDS Treatment. Pharmaceutics 2023, 15, 1618. [Google Scholar] [CrossRef] [PubMed]
- Zambito, Y.; Fogli, S.; Zaino, C.; Stefanelli, F.; Breschi, M.C.; Di Colo, G. Synthesis, Characterization and Evaluation of Thiolated Quaternary Ammonium-Chitosan Conjugates for Enhanced Intestinal Drug Permeation. Eur. J. Pharm. Sci. 2009, 38, 112–120. [Google Scholar] [CrossRef]
- Cesare, M.M.; Felice, F.; Conti, V.; Cerri, L.; Zambito, Y.; Romi, M.; Cai, G.; Cantini, C.; Di Stefano, R. Impact of Peels Extracts from an Italian Ancient Tomato Variety Grown under Drought Stress Conditions on Vascular Related Dysfunction. Molecules 2021, 26, 4289. [Google Scholar] [CrossRef]
Drug | HP-β-CD (M−1) | HP-β-CD-SH (M−1) | HP-β-CD-SH-NP (M−1) |
---|---|---|---|
DMS | 480.1 ± 1.1 | 1573.9 ± 4.2 | 639.0 ± 0.5 |
OLE-GS | 233.1 ± 1.2 | 1418.0 ± 13.9 | 900.0 ± 6.0 |
Formulation | Z Average (nm) | PDI | ζ-Potential (mV) |
---|---|---|---|
HP-β-CD | 152.4 ± 5.4 | 0.408 ± 0.040 | −8.05 ± 0.61 |
HP-β-CD-SH | 196.8 ± 3.4 | 0.275 ± 0.030 | −6.89 ± 0.49 |
HP-β-CD-SH-NP | 431.5 ± 7.1 | 0.443 ± 0.061 | −5.33 ± 0.37 |
HP-β-CD/DMS | 200.7 ± 9.4 | 0.460 ± 0.075 | −10.00 ± 0.78 |
HP-β-CD-SH/DMS | 301.4 ± 1.6 | 0.424 ± 0.064 | −6.53 ± 1.14 |
HP-β-CD-SH-NP/DMS | 492.2 ± 5.5 | 0.461 ± 0.092 | −4.51 ± 1.54 |
HP-β-CD/OLE-GS | 165.1 ± 5.1 | 0.424 ± 0.013 | −7.64 ± 0.41 |
HP-β-CD-SH/OLE-GS | 189.3 ± 3.2 | 0.369 ± 0.029 | −9.22 ± 1.25 |
HP-β-CD-SH-NP/OLE-GS | 397.3 ± 6.1 | 0.473 ± 0.022 | −5.66 ± 0.56 |
Formulation | Flux (µg cm−2 h−1) | L (h) | T2.5h (µg cm−2) |
---|---|---|---|
DMS | 1.43± 0.04 | 0.53± 0.03 | 2.91± 0.09 |
HP-β-CD/DMS | 1.33± 0.09 | 0.04± 0.01 | 3.21± 0.15 |
HP-β-CD-SH/DMS | 2.30± 0.11 * | −0.04± 0.02 a | 5.39± 0.48 *** |
HP-β-CD-SH-NP/DMS | 1.92± 0.02 | 0.13± 0.01 ** | 4.48± 0.55 *** |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Cerri, L.; Migone, C.; Vizzoni, L.; Grassiri, B.; Fabiano, A.; Piras, A.M.; Zambito, Y. Cross-Linked Thiolated Hydroxypropil-β-Cyclodextrin for Pulmonary Drug Delivery. Int. J. Mol. Sci. 2024, 25, 9394. https://doi.org/10.3390/ijms25179394
Cerri L, Migone C, Vizzoni L, Grassiri B, Fabiano A, Piras AM, Zambito Y. Cross-Linked Thiolated Hydroxypropil-β-Cyclodextrin for Pulmonary Drug Delivery. International Journal of Molecular Sciences. 2024; 25(17):9394. https://doi.org/10.3390/ijms25179394
Chicago/Turabian StyleCerri, Luca, Chiara Migone, Lucia Vizzoni, Brunella Grassiri, Angela Fabiano, Anna Maria Piras, and Ylenia Zambito. 2024. "Cross-Linked Thiolated Hydroxypropil-β-Cyclodextrin for Pulmonary Drug Delivery" International Journal of Molecular Sciences 25, no. 17: 9394. https://doi.org/10.3390/ijms25179394