Caracterización fisicoquímica de péptidos sintéticos monoméricos y diméricos derivados de la Lactoferricina Bovina con actividad anticancerígena comprobada

ilustraciones, diagramas

Autores:
González López, Nicolás Mateo
Tipo de recurso:
Fecha de publicación:
2023
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/84397
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/84397
https://repositorio.unal.edu.co/
Palabra clave:
540 - Química y ciencias afines::543 - Química analítica
500 - Ciencias naturales y matemáticas::502 - Miscelánea
610 - Medicina y salud::615 - Farmacología y terapéutica
540 - Química y ciencias afines::542 - Técnicas, procedimientos, aparatos, equipos, materiales
Péptidos sintéticos
Synthetic peptides
CANCER-TRATAMIENTO
Cancer-treatment
Péptidos Anticancerígenos
Lactoferricina Bovina
Metodologías Analíticas
Farmacopea
Caracterización Analítica
Propiedades Fisicoquímicas
Anticancer Peptides
Bovine Lactoferricin
Analytical Methodologies
Pharmacopoeia
Analytical Characterization
Physicochemical Properties
Rights
openAccess
License
Atribución-NoComercial-SinDerivadas 4.0 Internacional
id UNACIONAL2_ba27f884096f1f100bdd03c42f7bbe9b
oai_identifier_str oai:repositorio.unal.edu.co:unal/84397
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Caracterización fisicoquímica de péptidos sintéticos monoméricos y diméricos derivados de la Lactoferricina Bovina con actividad anticancerígena comprobada
dc.title.translated.eng.fl_str_mv Physicochemical characterization of monomeric and dimeric synthetic peptides derived from Bovine Lactoferricin with proven anticancer activity
title Caracterización fisicoquímica de péptidos sintéticos monoméricos y diméricos derivados de la Lactoferricina Bovina con actividad anticancerígena comprobada
spellingShingle Caracterización fisicoquímica de péptidos sintéticos monoméricos y diméricos derivados de la Lactoferricina Bovina con actividad anticancerígena comprobada
540 - Química y ciencias afines::543 - Química analítica
500 - Ciencias naturales y matemáticas::502 - Miscelánea
610 - Medicina y salud::615 - Farmacología y terapéutica
540 - Química y ciencias afines::542 - Técnicas, procedimientos, aparatos, equipos, materiales
Péptidos sintéticos
Synthetic peptides
CANCER-TRATAMIENTO
Cancer-treatment
Péptidos Anticancerígenos
Lactoferricina Bovina
Metodologías Analíticas
Farmacopea
Caracterización Analítica
Propiedades Fisicoquímicas
Anticancer Peptides
Bovine Lactoferricin
Analytical Methodologies
Pharmacopoeia
Analytical Characterization
Physicochemical Properties
title_short Caracterización fisicoquímica de péptidos sintéticos monoméricos y diméricos derivados de la Lactoferricina Bovina con actividad anticancerígena comprobada
title_full Caracterización fisicoquímica de péptidos sintéticos monoméricos y diméricos derivados de la Lactoferricina Bovina con actividad anticancerígena comprobada
title_fullStr Caracterización fisicoquímica de péptidos sintéticos monoméricos y diméricos derivados de la Lactoferricina Bovina con actividad anticancerígena comprobada
title_full_unstemmed Caracterización fisicoquímica de péptidos sintéticos monoméricos y diméricos derivados de la Lactoferricina Bovina con actividad anticancerígena comprobada
title_sort Caracterización fisicoquímica de péptidos sintéticos monoméricos y diméricos derivados de la Lactoferricina Bovina con actividad anticancerígena comprobada
dc.creator.fl_str_mv González López, Nicolás Mateo
dc.contributor.advisor.none.fl_str_mv García Castañeda, Javier Eduardo
Martínez Ramírez, Jorge Ariel
dc.contributor.author.none.fl_str_mv González López, Nicolás Mateo
dc.contributor.researchgroup.spa.fl_str_mv Síntesis y Aplicación de Moléculas Peptídicas
dc.contributor.orcid.spa.fl_str_mv Nicolás Mateo González López [0000-0003-0009-1347]
dc.subject.ddc.spa.fl_str_mv 540 - Química y ciencias afines::543 - Química analítica
500 - Ciencias naturales y matemáticas::502 - Miscelánea
610 - Medicina y salud::615 - Farmacología y terapéutica
540 - Química y ciencias afines::542 - Técnicas, procedimientos, aparatos, equipos, materiales
topic 540 - Química y ciencias afines::543 - Química analítica
500 - Ciencias naturales y matemáticas::502 - Miscelánea
610 - Medicina y salud::615 - Farmacología y terapéutica
540 - Química y ciencias afines::542 - Técnicas, procedimientos, aparatos, equipos, materiales
Péptidos sintéticos
Synthetic peptides
CANCER-TRATAMIENTO
Cancer-treatment
Péptidos Anticancerígenos
Lactoferricina Bovina
Metodologías Analíticas
Farmacopea
Caracterización Analítica
Propiedades Fisicoquímicas
Anticancer Peptides
Bovine Lactoferricin
Analytical Methodologies
Pharmacopoeia
Analytical Characterization
Physicochemical Properties
dc.subject.agrovoc.spa.fl_str_mv Péptidos sintéticos
dc.subject.agrovoc.eng.fl_str_mv Synthetic peptides
dc.subject.lemb.spa.fl_str_mv CANCER-TRATAMIENTO
dc.subject.lemb.eng.fl_str_mv Cancer-treatment
dc.subject.proposal.spa.fl_str_mv Péptidos Anticancerígenos
Lactoferricina Bovina
Metodologías Analíticas
Farmacopea
Caracterización Analítica
Propiedades Fisicoquímicas
dc.subject.proposal.eng.fl_str_mv Anticancer Peptides
Bovine Lactoferricin
Analytical Methodologies
Pharmacopoeia
Analytical Characterization
Physicochemical Properties
description ilustraciones, diagramas
publishDate 2023
dc.date.accessioned.none.fl_str_mv 2023-08-01T17:34:10Z
dc.date.available.none.fl_str_mv 2023-08-01T17:34:10Z
dc.date.issued.none.fl_str_mv 2023
dc.type.spa.fl_str_mv Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv Text
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/TM
status_str acceptedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unal.edu.co/handle/unal/84397
dc.identifier.instname.spa.fl_str_mv Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv https://repositorio.unal.edu.co/
url https://repositorio.unal.edu.co/handle/unal/84397
https://repositorio.unal.edu.co/
identifier_str_mv Universidad Nacional de Colombia
Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv spa
language spa
dc.relation.references.spa.fl_str_mv American Cancer Society. Datos y Estadísticas Sobre El Cáncer Entre Los Hispanos/Latinos 2018-2020; Atlanta, 2018.
Ministerio de Salud. Plan Nacional de Cuidados Integrales Del Cáncer (2020 - 2024); Lima, 2021.
Tattersall, M. H. N.; Thomas, H. Recent Advances: Oncology. BMJ 1999, 318, 1–4.
Xie, M.; Liu, D.; Yang, Y. Anti-Cancer Peptides: Classification, Mechanism of Action, Reconstruction and Modification. Open Biol 2020, 10 (7), 1–10. https://doi.org/10.1098/rsob.200004.
Schirrmacher, V. From Chemotherapy to Biological Therapy: A Review of Novel Concepts to Reduce the Side Effects of Systemic Cancer Treatment (Review). Int J Oncol 2019, 54 (2), 407–419. https://doi.org/10.3892/ijo.2018.4661.
Wefel, J. S.; Kayl, A. E.; Meyers, C. A. Neuropsychological Dysfunction Associated with Cancer and Cancer Therapies: A Conceptual Review of an Emerging Target. Br J Cancer 2004, 90 (9), 1691–1696. https://doi.org/10.1038/sj.bjc.6601772.
Guerra, J. R.; Cárdenas, A. B.; Ochoa-Zarzosa, A.; Meza, J. L.; Umaña Pérez, A.; Fierro-Medina, R.; Rivera Monroy, Z. J.; García Castañeda, J. E. The Tetrameric Peptide LfcinB (20-25)4 Derived from Bovine Lactoferricin Induces Apoptosis in the MCF-7 Breast Cancer Cell Line. RSC Adv 2019, 9 (36), 20497–20504. https://doi.org/10.1039/c9ra04145a.
Liscano, Y.; Oñate-Garzón, J.; Delgado, J. P. Peptides with Dual Antimicrobial–Anticancer Activity: Strategies to Overcome Peptide Limitations and Rational Design of Anticancer Peptides. Molecules 2020, 25 (18), 1–20. https://doi.org/10.3390/molecules25184245.
Vergote, V.; Burvenich, C.; van de Wiele, C.; de Spiegeleer, B. Quality Specifications for Peptide Drugs: A Regulatory-Pharmaceutical Approach. Journal of Peptide Science 2009, 15 (11), 697–710. https://doi.org/10.1002/psc.1167.
Hilchie, A. L.; Doucette, C. D.; Pinto, D. M.; Patrzykat, A.; Douglas, S.; Hoskin, D. W. Pleurocidin-Family Cationic Antimicrobial Peptides Are Cytolytic for Breast Carcinoma Cells and Prevent Growth of Tumor Xenografts. Breast Cancer Research 2011, 13 (5), 1–16. https://doi.org/10.1186/bcr3043.
Felício, M. R.; Silva, O. N.; Gonçalves, S.; Santos, N. C.; Franco, O. L. Peptides with Dual Antimicrobial and Anticancer Activities. Front Chem 2017, 5 (5), 1–9. https://doi.org/10.3389/fchem.2017.00005.
Hao, Y.; Yang, N.; Teng, D.; Wang, X.; Mao, R.; Wang, J. A Review of the Design and Modification of Lactoferricins and Their Derivatives. BioMetals 2018, 31 (3), 331–341. https://doi.org/10.1007/s10534-018-0086-6.
Gibbons, J. A.; Kanwar, R. K.; Kanwar, J. R. Lactoferrin and Cancer in Different Cancer Models. Frontiers in Bioscience 2011, 3, 1080–1088.
Mader, J. S.; Salsman, J.; Conrad, D. M.; Hoskin, D. W. Bovine Lactoferricin Selectively Induces Apoptosis in Human Leukemia and Carcinoma Cell Lines. Molecular Cancer Therapy 2005, 4 (4), 612–624.
Boohaker, R. J.; Lee, M. W.; Vishnubhotla, P.; Perez, J. M.; Khaled, A. R. The Use of Therapeutic Peptides to Target and to Kill Cancer Cells. Curr Med Chem 2012, 19, 3794–3804.
Huang, K. Y.; Tseng, Y. J.; Kao, H. J.; Chen, C. H.; Yang, H. H.; Weng, S. L. Identification of Subtypes of Anticancer Peptides Based on Sequential Features and Physicochemical Properties. Sci Rep 2021, 11 (1), 1–13. https://doi.org/10.1038/s41598-021-93124-9.
D’Aloisio, V.; Dognini, P.; Hutcheon, G. A.; Coxon, C. R. PepTherDia: Database and Structural Composition Analysis of Approved Peptide Therapeutics and Diagnostics. Drug Discov Today 2021, 26 (6), 1409–1419. https://doi.org/10.1016/j.drudis.2021.02.019.
Henninot, A.; Collins, J. C.; Nuss, J. M. The Current State of Peptide Drug Discovery: Back to the Future? J Med Chem 2018, 61 (4), 1382–1414. https://doi.org/10.1021/acs.jmedchem.7b00318.
Wang, L.; Wang, N.; Zhang, W.; Cheng, X.; Yan, Z.; Shao, G.; Wang, X.; Wang, R.; Fu, C. Therapeutic Peptides: Current Applications and Future Directions. Signal Transduct Target Ther 2022, 7 (1), 1–27. https://doi.org/10.1038/s41392-022-00904-4.
Lau, J. L.; Dunn, M. K. Therapeutic Peptides: Historical Perspectives, Current Development Trends, and Future Directions. Bioorg Med Chem 2018, 26 (10), 2700–2707. https://doi.org/10.1016/j.bmc.2017.06.052.
Charoenkwan, P.; Chiangjong, W.; Lee, V. S.; Nantasenamat, C.; Hasan, M. M.; Shoombuatong, W. Improved Prediction and Characterization of Anticancer Activities of Peptides Using a Novel Flexible Scoring Card Method. Sci Rep 2021, 11 (1), 1–13. https://doi.org/10.1038/s41598-021-82513-9.
Gaspar, D.; Salomé Veiga, A.; Castanho, M. A. R. B. From Antimicrobial to Anticancer Peptides. A Review. Front Microbiol 2013, 4, 1–16. https://doi.org/10.3389/fmicb.2013.00294.
Paredes-Gamero, E. J.; Martins, M. N. C.; Cappabianco, F. A. M.; Ide, J. S.; Miranda, A. Characterization of Dual Effects Induced by Antimicrobial Peptides: Regulated Cell Death or Membrane Disruption. Biochim Biophys Acta 2012, 1820 (7), 1062–1072. https://doi.org/10.1016/j.bbagen.2012.02.015.
Zhang, Y.; Lima, C. F.; Rodrigues, L. R. Anticancer Effects of Lactoferrin: Underlying Mechanisms and Future Trends in Cancer Therapy. Nutr Rev 2014, 72 (12), 763–773. https://doi.org/10.1111/nure.12155.
Jiang, R.; Lonnerdal, B. Bovine Lactoferrin and Lactoferricin Exert Antitumor Activities on Human Colorectal Cancer Cells (HT-29) by Activating Various Signaling Pathways. Biochem Cell. Biol. 2017, 95 (1), 1–42.
Pei, J.; Xiong, L.; Chu, M.; Guo, X.; Yan, P. Effect of Intramolecular Disulfide Bond of Bovine Lactoferricin on Its Molecular Structure and Antibacterial Activity against Trueperella Pyogenes Separated from Cow Milk with Mastitis. BMC Vet Res 2020, 16 (1), 1–10. https://doi.org/10.1186/s12917-020-02620-z.
Yan, D.; Chen, D.; Shen, J.; Xiao, G.; van Wijnen, A. J.; Im, H. J. Bovine Lactoferricin, an Antimicrobial Peptide Is Anti-Inflammatory and Anti-Catabolic in Human Articular Cartilage and Synovium. J Cell Physiol 2013, 228 (2), 447–456. https://doi.org/10.1002/jcp.24151.
Vorland, L. H.; Ulvatne, H.; Andersen, J.; Haukland, H. H.; Rekdal, Ø.; Svendsen, J. S.; Gutteberg, T. J.; Vorland, L. H. Lactoferricin of Bovine Origin Is More Active than Lactoferricins of Human, Murine and Caprine Origin. Scand J Infect Dis 1998, 30, 513–517.
Fang, B.; Guo, H. Y.; Zhang, M.; Jiang, L.; Ren, F. Z. The Six Amino Acid Antimicrobial Peptide BLFcin6 Penetrates Cells and Delivers SiRNA. FEBS Journal 2013, 280 (4), 1007–1017. https://doi.org/10.1111/febs.12093.
Huertas, N. de J.; Monroy, Z. J. R.; Medina, R. F.; Castañeda, J. E. G. Antimicrobial Activity of Truncated and Polyvalent Peptides Derived from the FKCRRQWQWRMKKGLA Sequence against Escherichia Coli ATCC 25922 and Staphylococcus Aureus ATCC 25923. Molecules 2017, 22 (6), 1–11. https://doi.org/10.3390/molecules22060987.
Barragán-Cárdenas, A.; Insuasty-Cepeda, D. S.; Niño-Ramírez, V. A.; Umaña-Pérez, A.; Ochoa-Zarzosa, A.; López-Meza, J. E.; Rivera-Monroy, Z. J.; García-Castañeda, J. E. The Nonapeptide RWQWRWQWR: A Promising Molecule for Breast Cancer Therapy. ChemistrySelect 2020, 5 (31), 9691–9700. https://doi.org/10.1002/slct.202002101.
Solarte, V. A.; Conget, P.; Vernot, J. P.; Rosas, J. E.; Rivera, Z. J.; García, J. E.; Arango-Rodríguez, M. L. A Tetrameric Peptide Derived from Bovine Lactoferricin as a Potential Therapeutic Tool for Oral Squamous Cell Carcinoma: A Preclinical Model. PLoS One 2017, 12 (3), 1–17. https://doi.org/10.1371/journal.pone.0174707.
Insuasty-Cepeda, D. S.; Barragán-Cárdenas, A. C.; Ochoa-Zarzosa, A.; López-Meza, J. E.; Fierro-Medina, R.; García-Castañeda, J. E.; Rivera-Monroy, Z. J. Peptides Derived from (RRWQWRMKKLG)2-K-Ahx Induce Selective Cellular Death in Breast Cancer Cell Lines through Apoptotic Pathway. Int J Mol Sci 2020, 21 (12), 1–13. https://doi.org/10.3390/ijms21124550.
Barragán-Cárdenas, A. C.; Insuasty-Cepeda, D. S.; Cárdenas-Martínez, K. J.; López-Meza, J.; Ochoa-Zarzosa, A.; Umaña-Pérez, A.; Rivera-Monroy, Z. J.; García-Castañeda, J. E. LfcinB-Derived Peptides: Specific and Punctual Change of an Amino Acid in Monomeric and Dimeric Sequences Increase Selective Cytotoxicity in Colon Cancer Cell Lines. Arabian Journal of Chemistry 2022, 15 (8), 1–12. https://doi.org/10.1016/j.arabjc.2022.103998.
D’Addio, S. M.; Bothe, J. R.; Neri, C.; Walsh, P. L.; Zhang, J.; Pierson, E.; Mao, Y.; Gindy, M.; Leone, A.; Templeton, A. C. New and Evolving Techniques for the Characterization of Peptide Therapeutics. J Pharm Sci 2016, 105 (10), 2989–3006. https://doi.org/10.1016/j.xphs.2016.06.011.
European Medicines Agency. ICH Topic Q 6 A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances; 2000. http://www.emea.eu.int.
European Medicines Agency. ICH Guideline M4 (R4) on Common Technical Document (CTD) for the Registration of Pharmaceuticals for Human Use-Organisation of CTD; 2021. www.ema.europa.eu/contact.
Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER). Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls Information for Synthetic Peptide Substances; 1994.
Chiangjong, W.; Chutipongtanate, S.; Hongeng, S. Anticancer Peptide: Physicochemical Property, Functional Aspect and Trend in Clinical Application (Review). Int J Oncol 2020, 57 (3), 678–696. https://doi.org/10.3892/ijo.2020.5099.
Swietlow, A.; Lower, A. A Holistic Quality Control Strategy for Peptide Active Pharmaceutical Ingredients (APIs). In Peptide Therapeutics: Strategy and Tactics for Chemistry, Manufacturing and Controls; Srivastava, V., Ed.; Royal Society of Chemistry, 2019; pp 194–273. https://doi.org/10.1039/9781788016445-fp001.
Rodríguez, V.; Pineda, H.; Ardila, N.; Insuasty, D.; Cárdenas, K.; Román, J.; Urrea, M.; Ramírez, D.; Fierro, R.; Rivera, Z.; García, J. Efficient Fmoc Group Removal Using Diluted 4-Methylpiperidine: An Alternative for a Less-Polluting SPPS-Fmoc/TBu Protocol. Int J Pept Res Ther 2019, 26 (1), 585–587. https://doi.org/10.1007/s10989-019-09865-9.
León-Calvijo, M. A.; Leal-Castro, A. L.; Almanzar-Reina, G. A.; Rosas-Pérez, J. E.; García-Castañeda, J. E.; Rivera-Monroy, Z. J. Antibacterial Activity of Synthetic Peptides Derived from Lactoferricin against Escherichia Coli ATCC 25922 and Enterococcus Faecalis ATCC 29212. Biomed Res Int 2015, 2015, 1–9. https://doi.org/10.1155/2015/453826.
Insuasty Cepeda, D. S.; Pineda Castañeda, H. M.; Rodríguez Mayor, A. V.; García Castañeda, J. E.; Maldonado Villamil, M.; Fierro Medina, R.; Rivera Monroy, Z. J. Synthetic Peptide Purification via Solid-Phase Extraction with Gradient Elution: A Simple, Economical, Fast, and Efficient Methodology. Molecules 2019, 24 (7), 1–9. https://doi.org/10.3390/molecules24071215.
Porto, D. L.; da Silva, A. R. R.; Oliveira, A. de S.; Nogueira, F. H. A.; Pedrosa, M. de F. F.; Aragão, C. F. S. Development and Validation of a Stability Indicating HPLC-DAD Method for the Determination of the Peptide Stigmurin. Microchemical Journal 2020, 157, 1–9. https://doi.org/10.1016/j.microc.2020.104921.
González-López, N. M.; Insuasty-Cepeda, D. S.; Huertas-Ortiz, K. A.; Reyes-Calderón, J. E.; Martínez-Ramírez, J. A.; Fierro-Medina, R.; Jenny Rivera-Monroy, Z.; García-Castañeda, J. E. Gradient Retention Factor Concept Applied to Method Development for Peptide Analysis by Means of RP-HPLC. ACS Omega 2022, 7, 44817–44824. https://doi.org/10.1021/acsomega.2c04907.
Meyer, V. R. Practical High-Performance Liquid Chromatography, 5th ed.; John Wiley and Sons, 2010.
Snyder, L. R.; Kirkland, J. J. (Joseph J.; Dolan, J. W. Introduction to Modern Liquid Chromatography, 3rd ed.; John Wiley and Sons, 2010.
Sunde, H.; Ryder, K.; Bekhit, A. E. D. A.; Carne, A. Analysis of Peptides in a Sheep Beta Lactoglobulin Hydrolysate as a Model to Evaluate the Effect of Peptide Amino Acid Sequence on Bioactivity. Food Chem 2021, 365, 1–22. https://doi.org/10.1016/j.foodchem.2021.130346.
Field, J. K.; Euerby, M. R.; Lau, J.; Thøgersen, H.; Petersson, P. Investigation into Reversed Phase Chromatography Peptide Separation Systems Part I: Development of a Protocol for Column Characterisation. J Chromatogr A 2019, 1603 (11), 113–129.
Ehab Ibrahim, A.; Hashem, H.; Elhenawee, M.; Saleh, H. Monolithic and Core-Shell Particles Stationary Phase Morphologies in Protein Analysis; Peptide Mapping of Erythropoietin Hormone and Determination of Carbetocin. Ann Pharm Fr 2020, 78 (3), 206–216. https://doi.org/10.1016/j.pharma.2020.01.008.
Michalski, A.; Damoc, E.; Hauschild, J. P.; Lange, O.; Wieghaus, A.; Makarov, A.; Nagaraj, N.; Cox, J.; Mann, M.; Horning, S. Mass Spectrometry-Based Proteomics Using Q Exactive, a High-Performance Benchtop Quadrupole Orbitrap Mass Spectrometer. Molecular and Cellular Proteomics 2011, 10 (9), 1–13. https://doi.org/10.1074/mcp.M111.011015.
Gross, J. H. Mass Spectrometry: A Textbook, 3rd ed.; Springer, 2017.
Bruderer, R.; Bernhardt, O. M.; Gandhi, T.; Xuan, Y.; Sondermann, J.; Schmidt, M.; Gomez-Varela, D.; Reiter, L. Optimization of Experimental Parameters in Data-Independent Mass Spectrometry Significantly Increases Depth and Reproducibility of Results. Molecular and Cellular Proteomics 2017, 16 (12), 2296–2309. https://doi.org/10.1074/mcp.RA117.000314.
Geiger, T.; Cox, J.; Mann, M. Proteomics on an Orbitrap Benchtop Mass Spectrometer Using All-Ion Fragmentation. Molecular and Cellular Proteomics 2010, 9 (10), 2252–2261. https://doi.org/10.1074/mcp.M110.001537.
Roepstorff, P.; Fohlman, J. Proposal for a Common Nomenclature for Sequence Ions in Mass Spectra of Peptides. Biomed Mass Spectrom 1984, 11 (11), 601.
Wilson, D.; Daly, N. L. Nuclear Magnetic Resonance Seq (NMRseq): A New Approach to Peptide Sequence Tags. Toxins (Basel) 2018, 10 (11), 1–10. https://doi.org/10.3390/toxins10110437.
Mishra, N.; Coutinho, E. NMR in Structural Determination of Proteins and Peptides. J. Pharm. Sci. Technol. Manag 2020, 4 (1), 22–33.
Hinds, M. G.; Norton, R. S. NMR Spectroscopy of Peptides and Proteins. Mol Biotechnol 1997, 7, 315–331.
Bader, Z. PEPTIDE NMR; Zurich.
Choules, M. P.; Bisson, J.; Gao, W.; Lankin, D. C.; McAlpine, J. B.; Niemitz, M.; Jaki, B. U.; Franzblau, S. G.; Pauli, G. F. Quality Control of Therapeutic Peptides by 1H NMR HiFSA Sequencing. Journal of Organic Chemistry 2019, 84 (6), 3055–3073. https://doi.org/10.1021/acs.joc.8b02704.
Bustamante Rojas, C. Fases Del Desarrollo de Un Nuevo Fármaco. In Estrategias de investigación en medicina clínica ; Bogotá, 2001; pp 123–134.
Wu, L. C.; Chen, F.; Lee, S. L.; Raw, A.; Yu, L. X. Building Parity between Brand and Generic Peptide Products: Regulatory and Scientific Considerations for Quality of Synthetic Peptides. Int J Pharm 2017, 518 (1–2), 320–334. https://doi.org/10.1016/j.ijpharm.2016.12.051.
Xiong, G.; Wu, Z.; Yi, J.; Fu, L.; Yang, Z.; Hsieh, C.; Yin, M.; Zeng, X.; Wu, C.; Lu, A.; Chen, X.; Hou, T.; Cao, D. ADMETlab 2.0: An Integrated Online Platform for Accurate and Comprehensive Predictions of ADMET Properties. Nucleic Acids Res 2021, 49, W5–W14. https://doi.org/10.1093/nar/gkab255.
Barrero, J. A.; Cabrera, F.; Cruz, C. M. Gliptins vs. Milk-Derived Dipeptidyl-Peptidase Iv Inhibiting Biopeptides: Physicochemical Characterization and Pharmacokinetic Profiling. Vitae 2021, 28 (3), 1–14. https://doi.org/10.17533/UDEA.VITAE.V28N3A346531.
Hart, L. R.; Lebedenko, C. G.; Mitchell, S. M.; Daso, R. E.; Banerjee, I. A. In Silico Studies of Tumor Targeted Peptide‐Conjugated Natural Products for Targeting Over‐Expressed Receptors in Breast Cancer Cells Using Molecular Docking, Molecular Dynamics and MMGBSA Calculations. Applied Sciences 2022, 12 (1), 1–41. https://doi.org/10.3390/app12010515.
Iwaniak, A.; Minkiewicz, P.; Pliszka, M.; Mogut, D.; Darewicz, M. Characteristics of Biopeptides Released in Silico from Collagens Using Quantitative Parameters. Foods 2020, 9 (7), 1–29. https://doi.org/10.3390/foods9070965.
Minkiewicz, P.; Iwaniak, A.; Darewicz, M. Annotation of Peptide Structures Using SMILES and Other Chemical Codes-Practical Solutions. Molecules 2017, 22 (12), 1–17. https://doi.org/10.3390/molecules22122075.
Huertas Ortiz, K. A. Caracterización Fisicoquímica de Un Péptido Polivalente, Derivado de La Lactoferricina Bovina, Candidato a Fármaco Para El Tratamiento Del Cáncer de Mama, Universidad Nacional de Colombia, Bogotá, 2021.
Stoscheck, C. M. Quantitation of Protein. Methods Enzymol 1990, 182, 1–19.
Moffatt, F.; Senkans, P.; Ricketts, D. Approaches towards the Quantitative Analysis of Peptides and Proteins by Reversed-Phase High-Performance Liquid Chromatography in the Absence of a Pure Reference Sample. J Chromatogr A 2000, 891, 235–242.
Drochioiu, G.; Adochitei, A. Rapid Characterization of Peptide Secondary Structure by FT-IR Spectroscopy. Rev. Roum. Chim 2011, 56 (8), 783–791.
Roux, S.; Zékri, E.; Rousseau, B.; Cintrat, J. C.; Fay, N. Elimination and Exchange of Trifluoroacetate Counter-Ion from Cationic Peptides: A Critical Evaluation of Different Approaches. Journal of Peptide Science 2008, 14 (3), 354–359. https://doi.org/10.1002/psc.951.
Chapman, D.; I. Haris, P. The Conformational Analysis of Peptides Using Fourier Transform IR Spectroscopy. Biopolymers (Peptide Science) 1995, 37, 251–263.
Nugrahani, I.; Oktaviary, R.; Ibrahim, S.; Gusdinar, T.; Apsari, C. FTIR Method for Peptide Content Estimation and Degradation Kinetic Study of Canarium Nut Protein. Indonesian Journal of Pharmacy 2020, 31 (2), 78–83. https://doi.org/10.14499/indonesianjpharm31iss2pp78.
de Meutter, J.; Goormaghtigh, E. Evaluation of Protein Secondary Structure from FTIR Spectra Improved after Partial Deuteration. European Biophysics Journal 2021, 50 (3–4), 613–628. https://doi.org/10.1007/s00249-021-01502-y.
Cobb, J. S.; Zai-Rose, V.; Correia, J. J.; Janorkar, A. v. FT-IR Spectroscopic Analysis of the Secondary Structures Present during the Desiccation Induced Aggregation of Elastin-Like Polypeptide on Silica. ACS Omega 2020, 5 (14), 8403–8413. https://doi.org/10.1021/acsomega.0c00271.
Andrushchenko, V. v.; Vogel, H. J.; Prenner, E. J. Optimization of the Hydrochloric Acid Concentration Used for Trifluoroacetate Removal from Synthetic Peptides. Journal of Peptide Science 2007, 13 (1), 37–43. https://doi.org/10.1002/psc.793.
Sikora, K.; Neubauer, D.; Jaśkiewicz, M.; Kamysz, W. Citropin 1.1 Trifluoroacetate to Chloride Counter-Ion Exchange in HCl-Saturated Organic Solutions: An Alternative Approach. Int J Pept Res Ther 2018, 24 (2), 265–270. https://doi.org/10.1007/s10989-017-9611-7.
Bronsema, K. J.; Bischoff, R.; van de Merbel, N. C. Internal Standards in the Quantitative Determination of Protein Biopharmaceuticals Using Liquid Chromatography Coupled to Mass Spectrometry. Journal of Chromatography B 2012, 893–894, 1–14. https://doi.org/10.1016/j.jchromb.2012.02.021.
Tan, A.; Awaiye, K. USE OF INTERNAL STANDARDS IN LC-MS BIOANALYSIS. In Handbook of LC-MS Bioanalysis: Best Practices, Experimental Protocols, and Regulations; Wenkui, L., Jie, Z., Francis L.S., Tse., Eds.; John Wiley and Sons, 2013; pp 217–227.
Faria, M.; Halquist, M. S. Internal Standards for Absolute Quantification of Large Molecules (Proteins) from Biological Matrices by LC-MS/MS. In Calibration and Validation of Analytical Methods - A Sampling of Current Approaches; Stauffer, M., Ed.; InTech, 2018; pp 61–84. https://doi.org/10.5772/intechopen.75569.
Hoofnagle, A. N. Peptide Lost and Found: Internal Standards and the Mass Spectrometric Quantification of Peptides. Clin Chem 2010, 56 (10), 1515–1517. https://doi.org/10.1373/clinchem.2010.152181.
Jeanne Dit Fouque, D.; Maroto, A.; Memboeuf, A. Internal Standard Quantification Using Tandem Mass Spectrometry of a Tryptic Peptide in the Presence of an Isobaric Interference. Anal Chem 2018, 90 (24), 14126–14130. https://doi.org/10.1021/acs.analchem.8b05016.
Barroso, O.; Handelsman, D. J.; Strasburger, C.; Thevis, M. Analytical Challenges in the Detection of Peptide Hormones for Anti-Doping Purposes. Bioanalysis 2012, 4 (13), 1577–1590. https://doi.org/10.4155/bio.12.128.
van de Merbel, N. C. Protein Quantification by LC-MS: A Decade of Progress through the Pages of Bioanalysis. Bioanalysis 2019, 11 (7), 629–644. https://doi.org/10.4155/bio-2019-0032.
Medina, I. B. Estudio de La Degradación Proteolítica de Péptidos Derivados de LfcinB Funcionalizados Con El Motivo RGD, Universidad Nacional de Colombia, Bogotá, 2022.
Memdouh, S.; Gavrilović, I.; Ng, K.; Cowan, D.; Abbate, V. Advances in the Detection of Growth Hormone Releasing Hormone Synthetic Analogs. Drug Test Anal 2021, 13 (11–12), 1871–1887. https://doi.org/10.1002/dta.3183.
Masters, J. R. HeLa Cells 50 Years on: The Good, the Bad and the Ugly. Nat Rev Cancer 2002, 2 (4), 311–315. https://doi.org/10.1038/nrc774.
Lyapun, I. N.; Andryukov, B. G.; Bynina, M. P. HeLa Cell Culture: Immortal Heritage of Henrietta Lacks. Molecular Genetics, Microbiology and Virology 2019, 34 (4), 195–200. https://doi.org/10.3103/S0891416819040050.
Beskow, L. M. Lessons from HeLa Cells: The Ethics and Policy of Biospecimens. Annu Rev Genomics Hum Genet 2016, 17, 395–417. https://doi.org/10.1146/annurev-genom-083115-022536.
Ni, G.; Chen, S.; Chen, M.; Wu, J.; Yang, B.; Yuan, J.; Walton, S. F.; Li, H.; Wei, M. Q.; Wang, Y.; Chen, G.; Liu, X.; Wang, T. Host-Defense Peptides Caerin 1.1 and 1.9 Stimulate TNF-Alpha-Dependent Apoptotic Signals in Human Cervical Cancer HeLa Cells. Front Cell Dev Biol 2020, 8. https://doi.org/10.3389/fcell.2020.00676.
Shan, Y.; Huang, J.; Tan, J.; Gao, G.; Liu, S.; Wang, H.; Chen, Y. The Study of Single Anticancer Peptides Interacting with HeLa Cell Membranes by Single Molecule Force Spectroscopy. Nanoscale 2012, 4 (4), 1283–1286. https://doi.org/10.1039/c2nr11541g.
Xu, Z.; Ding, J.; Zhang, L.; Feng, X.; Zhou, J.; Shen, X.; Lu, H.; Qian, L.; Li, X. Peptidomics Analysis Revealed That a Novel Peptide VMP-19 Protects against Ang II-Induced Injury in Human Umbilical Vein Endothelial Cells. Mol Med Rep 2021, 23 (298), 1–11. https://doi.org/10.3892/MMR.2021.11937.
Zhu, G.; Sun, L.; Albanetti, T.; Linkous, T.; Larkin, C.; Schoner, R.; McGivney, J. B.; Dovichi, N. J. Quantitative Analysis of the Supernatant from Host and Transfected CHO Cells Using ITRAQ 8-Plex Technique. Biotechnol Bioeng 2016, 113 (10), 2140–2148. https://doi.org/10.1002/bit.25991.
dc.rights.coar.fl_str_mv http://purl.org/coar/access_right/c_abf2
dc.rights.license.spa.fl_str_mv Atribución-NoComercial-SinDerivadas 4.0 Internacional
dc.rights.uri.spa.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.accessrights.spa.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv Atribución-NoComercial-SinDerivadas 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.extent.spa.fl_str_mv xx, 101 páginas
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Universidad Nacional de Colombia
dc.publisher.program.spa.fl_str_mv Bogotá - Ciencias - Maestría en Ciencias Farmacéuticas
dc.publisher.faculty.spa.fl_str_mv Facultad de Ciencias
dc.publisher.place.spa.fl_str_mv Bogotá, Colombia
dc.publisher.branch.spa.fl_str_mv Universidad Nacional de Colombia - Sede Bogotá
institution Universidad Nacional de Colombia
bitstream.url.fl_str_mv https://repositorio.unal.edu.co/bitstream/unal/84397/1/license.txt
https://repositorio.unal.edu.co/bitstream/unal/84397/2/1032489937.2023.pdf
https://repositorio.unal.edu.co/bitstream/unal/84397/3/1032489937.2023.pdf.jpg
bitstream.checksum.fl_str_mv eb34b1cf90b7e1103fc9dfd26be24b4a
aa26c436d3891eb076e8af3c085b2389
11f52582dab8a749bbc3dcaaa2441553
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
repository.name.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
repository.mail.fl_str_mv repositorio_nal@unal.edu.co
_version_ 1814089746962448384
spelling Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2García Castañeda, Javier Eduardod233ac45968135ded4a8bcbe0460b111600Martínez Ramírez, Jorge Ariel17867d308b8a40fb2b3ed93fa4432138600González López, Nicolás Mateo19c7c509049e50223502fbeeccaae610600Síntesis y Aplicación de Moléculas PeptídicasNicolás Mateo González López [0000-0003-0009-1347]2023-08-01T17:34:10Z2023-08-01T17:34:10Z2023https://repositorio.unal.edu.co/handle/unal/84397Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, diagramasSegún la OMS el cáncer es una de las causas principales de muerte a nivel mundial, presentándose 10 millones de fallecimientos en el 2020. Las terapias para el manejo contra el cáncer son agresivas, poco selectivas y producen efectos adversos que afectan la calidad de vida del paciente. Esto ha generado la necesidad de desarrollar nuevos tratamientos contra el cáncer que sean seguros y eficaces. En la actualidad los péptidos han surgido como una alternativa terapéutica para el tratamiento de enfermedades, sin embargo, debido a que cada péptido posee propiedades fisicoquímicas únicas, hace que su caracterización analítica represente grandes retos, y esto hace que sea una etapa clave en el desarrollo de medicamentos. En este trabajo se desarrollaron e implementaron metodologías analíticas siguiendo las recomendaciones de las farmacopeas USP y europea para caracterizar péptidos utilizando como modelo experimental los péptidos anticancerígenos: RWQWRWQWR y (RRWQWRFKKLG)2-K-Ahx, los cuales se consideran promisorios para el desarrollo de un medicamento de amplio espectro contra el cáncer. Se realizó el escalamiento de la síntesis de los dos péptidos obteniendo tres lotes de aproximadamente 10, 50 y 100 mg de péptido puro (Capítulo 1) con el objetivo de determinar si el escalamiento del proceso sintético afectaba las propiedades fisicoquímicas del fármaco. Se desarrollaron e implementaron metodologías de análisis por RP-HPLC (Capítulo 2) y LC-MS (Capítulo 3) para confirmar su identidad. Los métodos de RP-HPLC desarrollados pueden ser utilizados para identificar y/o cuantificar péptidos con un amplio rango de hidrofobicidad/hidrofilicidad en mezclas complejas o provenientes de matrices biológicas. Se empleó espectroscopía RMN para caracterizar ambos péptidos (Capítulo 4), se modelaron sus propiedades fisicoquímicas utilizando herramientas bioinformáticas (Capítulo 5). Se desarrolló e implementó un método para determinar el contenido de péptido en cada lote empleando IS y evaluándolos a 280nm (Capítulo 6). Se identificó y cuantifico los péptidos en el medio de cultivo de la línea celular HeLa (Capítulo 9). Finalmente, se caracterizó cada péptido por FT-IR y se empleó esta técnica para implementar y monitorear el cambio del contraión trifluoroacetato a clorhidrato. (Capítulos 7 y 8). Las metodologías desarrolladas en este trabajo pueden ser aplicadas para la caracterización fisicoquímica de péptidos monoméricos o diméricos. Estas metodologías son versátiles y de amplia cobertura por lo que se pueden utilizar para caracterizar péptidos con diversas propiedades fisicoquímicas. (Texto tomado de la fuente)According to the WHO cancer is one of the leading causes of death worldwide, with 10 million deaths in 2020. The therapies for cancer management are aggressive, non-selective, and produce adverse effects that affect the quality of life of the patient. This has generated the need to develop new cancer treatments that are safe and effective. Currently, peptides have emerged as a therapeutic alternative for the treatment of diseases, however, since each peptide has unique physicochemical properties, its analytical characterization represents a great challenge and is a key stage in drug development. In this work, analytical methodologies recommended by the USP, and European pharmacopeias will be developed and implemented to characterize the anticancer peptides: RWQWRWQWR and (RRWQWRFKKLG)2-K-Ahx, which are considered promising for the development of a broad-spectrum cancer drug. The synthesis of the two peptides was scaled up, obtaining three batches of approximately 10, 50 and 100 mg of pure peptide (Chapter 1) with the objective of determining if the scaling up of the synthetic process affected the physicochemical properties of the drug. Analytical methodologies by RP-HPLC (Chapter 2) and LC-MS (Chapter 3) were developed to confirm their identity. The developed RP-HPLC methods can be used to identify and/or quantify peptides with a wide range of hydrophobicity/hydrophilicity in complex mixtures or from biological matrices. NMR was used to structurally characterize both peptides (Chapter 4). Their physicochemical properties were modeled using bioinformatics tools (Chapter 5). A method was developed and implemented to determine the peptide content in the batches using IS and evaluating them at 280nm (Chapter 6). Peptides were identified and quantified in the culture medium of the HeLa cell line (Chapter 9). Finally, each peptide was characterized by FT-IR and this technique was also used to monitor the change of the counterion trifluoroacetate to hydrochloride. (Chapters 7 and 8). The methodologies developed in this work can be applied for the physicochemical characterization of monomeric or dimeric peptides. These methodologies are versatile and have a wide coverage, so they can be used to characterize peptides with diverse physicochemical properties.MaestríaMagister en Ciencias FarmacéuticasAnálisis Farmacéuticoxx, 101 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Ciencias - Maestría en Ciencias FarmacéuticasFacultad de CienciasBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá540 - Química y ciencias afines::543 - Química analítica500 - Ciencias naturales y matemáticas::502 - Miscelánea610 - Medicina y salud::615 - Farmacología y terapéutica540 - Química y ciencias afines::542 - Técnicas, procedimientos, aparatos, equipos, materialesPéptidos sintéticosSynthetic peptidesCANCER-TRATAMIENTOCancer-treatmentPéptidos AnticancerígenosLactoferricina BovinaMetodologías AnalíticasFarmacopeaCaracterización AnalíticaPropiedades FisicoquímicasAnticancer PeptidesBovine LactoferricinAnalytical MethodologiesPharmacopoeiaAnalytical CharacterizationPhysicochemical PropertiesCaracterización fisicoquímica de péptidos sintéticos monoméricos y diméricos derivados de la Lactoferricina Bovina con actividad anticancerígena comprobadaPhysicochemical characterization of monomeric and dimeric synthetic peptides derived from Bovine Lactoferricin with proven anticancer activityTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMAmerican Cancer Society. Datos y Estadísticas Sobre El Cáncer Entre Los Hispanos/Latinos 2018-2020; Atlanta, 2018.Ministerio de Salud. Plan Nacional de Cuidados Integrales Del Cáncer (2020 - 2024); Lima, 2021.Tattersall, M. H. N.; Thomas, H. Recent Advances: Oncology. BMJ 1999, 318, 1–4.Xie, M.; Liu, D.; Yang, Y. Anti-Cancer Peptides: Classification, Mechanism of Action, Reconstruction and Modification. Open Biol 2020, 10 (7), 1–10. https://doi.org/10.1098/rsob.200004.Schirrmacher, V. From Chemotherapy to Biological Therapy: A Review of Novel Concepts to Reduce the Side Effects of Systemic Cancer Treatment (Review). Int J Oncol 2019, 54 (2), 407–419. https://doi.org/10.3892/ijo.2018.4661.Wefel, J. S.; Kayl, A. E.; Meyers, C. A. Neuropsychological Dysfunction Associated with Cancer and Cancer Therapies: A Conceptual Review of an Emerging Target. Br J Cancer 2004, 90 (9), 1691–1696. https://doi.org/10.1038/sj.bjc.6601772.Guerra, J. R.; Cárdenas, A. B.; Ochoa-Zarzosa, A.; Meza, J. L.; Umaña Pérez, A.; Fierro-Medina, R.; Rivera Monroy, Z. J.; García Castañeda, J. E. The Tetrameric Peptide LfcinB (20-25)4 Derived from Bovine Lactoferricin Induces Apoptosis in the MCF-7 Breast Cancer Cell Line. RSC Adv 2019, 9 (36), 20497–20504. https://doi.org/10.1039/c9ra04145a.Liscano, Y.; Oñate-Garzón, J.; Delgado, J. P. Peptides with Dual Antimicrobial–Anticancer Activity: Strategies to Overcome Peptide Limitations and Rational Design of Anticancer Peptides. Molecules 2020, 25 (18), 1–20. https://doi.org/10.3390/molecules25184245.Vergote, V.; Burvenich, C.; van de Wiele, C.; de Spiegeleer, B. Quality Specifications for Peptide Drugs: A Regulatory-Pharmaceutical Approach. Journal of Peptide Science 2009, 15 (11), 697–710. https://doi.org/10.1002/psc.1167.Hilchie, A. L.; Doucette, C. D.; Pinto, D. M.; Patrzykat, A.; Douglas, S.; Hoskin, D. W. Pleurocidin-Family Cationic Antimicrobial Peptides Are Cytolytic for Breast Carcinoma Cells and Prevent Growth of Tumor Xenografts. Breast Cancer Research 2011, 13 (5), 1–16. https://doi.org/10.1186/bcr3043.Felício, M. R.; Silva, O. N.; Gonçalves, S.; Santos, N. C.; Franco, O. L. Peptides with Dual Antimicrobial and Anticancer Activities. Front Chem 2017, 5 (5), 1–9. https://doi.org/10.3389/fchem.2017.00005.Hao, Y.; Yang, N.; Teng, D.; Wang, X.; Mao, R.; Wang, J. A Review of the Design and Modification of Lactoferricins and Their Derivatives. BioMetals 2018, 31 (3), 331–341. https://doi.org/10.1007/s10534-018-0086-6.Gibbons, J. A.; Kanwar, R. K.; Kanwar, J. R. Lactoferrin and Cancer in Different Cancer Models. Frontiers in Bioscience 2011, 3, 1080–1088.Mader, J. S.; Salsman, J.; Conrad, D. M.; Hoskin, D. W. Bovine Lactoferricin Selectively Induces Apoptosis in Human Leukemia and Carcinoma Cell Lines. Molecular Cancer Therapy 2005, 4 (4), 612–624.Boohaker, R. J.; Lee, M. W.; Vishnubhotla, P.; Perez, J. M.; Khaled, A. R. The Use of Therapeutic Peptides to Target and to Kill Cancer Cells. Curr Med Chem 2012, 19, 3794–3804.Huang, K. Y.; Tseng, Y. J.; Kao, H. J.; Chen, C. H.; Yang, H. H.; Weng, S. L. Identification of Subtypes of Anticancer Peptides Based on Sequential Features and Physicochemical Properties. Sci Rep 2021, 11 (1), 1–13. https://doi.org/10.1038/s41598-021-93124-9.D’Aloisio, V.; Dognini, P.; Hutcheon, G. A.; Coxon, C. R. PepTherDia: Database and Structural Composition Analysis of Approved Peptide Therapeutics and Diagnostics. Drug Discov Today 2021, 26 (6), 1409–1419. https://doi.org/10.1016/j.drudis.2021.02.019.Henninot, A.; Collins, J. C.; Nuss, J. M. The Current State of Peptide Drug Discovery: Back to the Future? J Med Chem 2018, 61 (4), 1382–1414. https://doi.org/10.1021/acs.jmedchem.7b00318.Wang, L.; Wang, N.; Zhang, W.; Cheng, X.; Yan, Z.; Shao, G.; Wang, X.; Wang, R.; Fu, C. Therapeutic Peptides: Current Applications and Future Directions. Signal Transduct Target Ther 2022, 7 (1), 1–27. https://doi.org/10.1038/s41392-022-00904-4.Lau, J. L.; Dunn, M. K. Therapeutic Peptides: Historical Perspectives, Current Development Trends, and Future Directions. Bioorg Med Chem 2018, 26 (10), 2700–2707. https://doi.org/10.1016/j.bmc.2017.06.052.Charoenkwan, P.; Chiangjong, W.; Lee, V. S.; Nantasenamat, C.; Hasan, M. M.; Shoombuatong, W. Improved Prediction and Characterization of Anticancer Activities of Peptides Using a Novel Flexible Scoring Card Method. Sci Rep 2021, 11 (1), 1–13. https://doi.org/10.1038/s41598-021-82513-9.Gaspar, D.; Salomé Veiga, A.; Castanho, M. A. R. B. From Antimicrobial to Anticancer Peptides. A Review. Front Microbiol 2013, 4, 1–16. https://doi.org/10.3389/fmicb.2013.00294.Paredes-Gamero, E. J.; Martins, M. N. C.; Cappabianco, F. A. M.; Ide, J. S.; Miranda, A. Characterization of Dual Effects Induced by Antimicrobial Peptides: Regulated Cell Death or Membrane Disruption. Biochim Biophys Acta 2012, 1820 (7), 1062–1072. https://doi.org/10.1016/j.bbagen.2012.02.015.Zhang, Y.; Lima, C. F.; Rodrigues, L. R. Anticancer Effects of Lactoferrin: Underlying Mechanisms and Future Trends in Cancer Therapy. Nutr Rev 2014, 72 (12), 763–773. https://doi.org/10.1111/nure.12155.Jiang, R.; Lonnerdal, B. Bovine Lactoferrin and Lactoferricin Exert Antitumor Activities on Human Colorectal Cancer Cells (HT-29) by Activating Various Signaling Pathways. Biochem Cell. Biol. 2017, 95 (1), 1–42.Pei, J.; Xiong, L.; Chu, M.; Guo, X.; Yan, P. Effect of Intramolecular Disulfide Bond of Bovine Lactoferricin on Its Molecular Structure and Antibacterial Activity against Trueperella Pyogenes Separated from Cow Milk with Mastitis. BMC Vet Res 2020, 16 (1), 1–10. https://doi.org/10.1186/s12917-020-02620-z.Yan, D.; Chen, D.; Shen, J.; Xiao, G.; van Wijnen, A. J.; Im, H. J. Bovine Lactoferricin, an Antimicrobial Peptide Is Anti-Inflammatory and Anti-Catabolic in Human Articular Cartilage and Synovium. J Cell Physiol 2013, 228 (2), 447–456. https://doi.org/10.1002/jcp.24151.Vorland, L. H.; Ulvatne, H.; Andersen, J.; Haukland, H. H.; Rekdal, Ø.; Svendsen, J. S.; Gutteberg, T. J.; Vorland, L. H. Lactoferricin of Bovine Origin Is More Active than Lactoferricins of Human, Murine and Caprine Origin. Scand J Infect Dis 1998, 30, 513–517.Fang, B.; Guo, H. Y.; Zhang, M.; Jiang, L.; Ren, F. Z. The Six Amino Acid Antimicrobial Peptide BLFcin6 Penetrates Cells and Delivers SiRNA. FEBS Journal 2013, 280 (4), 1007–1017. https://doi.org/10.1111/febs.12093.Huertas, N. de J.; Monroy, Z. J. R.; Medina, R. F.; Castañeda, J. E. G. Antimicrobial Activity of Truncated and Polyvalent Peptides Derived from the FKCRRQWQWRMKKGLA Sequence against Escherichia Coli ATCC 25922 and Staphylococcus Aureus ATCC 25923. Molecules 2017, 22 (6), 1–11. https://doi.org/10.3390/molecules22060987.Barragán-Cárdenas, A.; Insuasty-Cepeda, D. S.; Niño-Ramírez, V. A.; Umaña-Pérez, A.; Ochoa-Zarzosa, A.; López-Meza, J. E.; Rivera-Monroy, Z. J.; García-Castañeda, J. E. The Nonapeptide RWQWRWQWR: A Promising Molecule for Breast Cancer Therapy. ChemistrySelect 2020, 5 (31), 9691–9700. https://doi.org/10.1002/slct.202002101.Solarte, V. A.; Conget, P.; Vernot, J. P.; Rosas, J. E.; Rivera, Z. J.; García, J. E.; Arango-Rodríguez, M. L. A Tetrameric Peptide Derived from Bovine Lactoferricin as a Potential Therapeutic Tool for Oral Squamous Cell Carcinoma: A Preclinical Model. PLoS One 2017, 12 (3), 1–17. https://doi.org/10.1371/journal.pone.0174707.Insuasty-Cepeda, D. S.; Barragán-Cárdenas, A. C.; Ochoa-Zarzosa, A.; López-Meza, J. E.; Fierro-Medina, R.; García-Castañeda, J. E.; Rivera-Monroy, Z. J. Peptides Derived from (RRWQWRMKKLG)2-K-Ahx Induce Selective Cellular Death in Breast Cancer Cell Lines through Apoptotic Pathway. Int J Mol Sci 2020, 21 (12), 1–13. https://doi.org/10.3390/ijms21124550.Barragán-Cárdenas, A. C.; Insuasty-Cepeda, D. S.; Cárdenas-Martínez, K. J.; López-Meza, J.; Ochoa-Zarzosa, A.; Umaña-Pérez, A.; Rivera-Monroy, Z. J.; García-Castañeda, J. E. LfcinB-Derived Peptides: Specific and Punctual Change of an Amino Acid in Monomeric and Dimeric Sequences Increase Selective Cytotoxicity in Colon Cancer Cell Lines. Arabian Journal of Chemistry 2022, 15 (8), 1–12. https://doi.org/10.1016/j.arabjc.2022.103998.D’Addio, S. M.; Bothe, J. R.; Neri, C.; Walsh, P. L.; Zhang, J.; Pierson, E.; Mao, Y.; Gindy, M.; Leone, A.; Templeton, A. C. New and Evolving Techniques for the Characterization of Peptide Therapeutics. J Pharm Sci 2016, 105 (10), 2989–3006. https://doi.org/10.1016/j.xphs.2016.06.011.European Medicines Agency. ICH Topic Q 6 A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances; 2000. http://www.emea.eu.int.European Medicines Agency. ICH Guideline M4 (R4) on Common Technical Document (CTD) for the Registration of Pharmaceuticals for Human Use-Organisation of CTD; 2021. www.ema.europa.eu/contact.Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER). Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls Information for Synthetic Peptide Substances; 1994.Chiangjong, W.; Chutipongtanate, S.; Hongeng, S. Anticancer Peptide: Physicochemical Property, Functional Aspect and Trend in Clinical Application (Review). Int J Oncol 2020, 57 (3), 678–696. https://doi.org/10.3892/ijo.2020.5099.Swietlow, A.; Lower, A. A Holistic Quality Control Strategy for Peptide Active Pharmaceutical Ingredients (APIs). In Peptide Therapeutics: Strategy and Tactics for Chemistry, Manufacturing and Controls; Srivastava, V., Ed.; Royal Society of Chemistry, 2019; pp 194–273. https://doi.org/10.1039/9781788016445-fp001.Rodríguez, V.; Pineda, H.; Ardila, N.; Insuasty, D.; Cárdenas, K.; Román, J.; Urrea, M.; Ramírez, D.; Fierro, R.; Rivera, Z.; García, J. Efficient Fmoc Group Removal Using Diluted 4-Methylpiperidine: An Alternative for a Less-Polluting SPPS-Fmoc/TBu Protocol. Int J Pept Res Ther 2019, 26 (1), 585–587. https://doi.org/10.1007/s10989-019-09865-9.León-Calvijo, M. A.; Leal-Castro, A. L.; Almanzar-Reina, G. A.; Rosas-Pérez, J. E.; García-Castañeda, J. E.; Rivera-Monroy, Z. J. Antibacterial Activity of Synthetic Peptides Derived from Lactoferricin against Escherichia Coli ATCC 25922 and Enterococcus Faecalis ATCC 29212. Biomed Res Int 2015, 2015, 1–9. https://doi.org/10.1155/2015/453826.Insuasty Cepeda, D. S.; Pineda Castañeda, H. M.; Rodríguez Mayor, A. V.; García Castañeda, J. E.; Maldonado Villamil, M.; Fierro Medina, R.; Rivera Monroy, Z. J. Synthetic Peptide Purification via Solid-Phase Extraction with Gradient Elution: A Simple, Economical, Fast, and Efficient Methodology. Molecules 2019, 24 (7), 1–9. https://doi.org/10.3390/molecules24071215.Porto, D. L.; da Silva, A. R. R.; Oliveira, A. de S.; Nogueira, F. H. A.; Pedrosa, M. de F. F.; Aragão, C. F. S. Development and Validation of a Stability Indicating HPLC-DAD Method for the Determination of the Peptide Stigmurin. Microchemical Journal 2020, 157, 1–9. https://doi.org/10.1016/j.microc.2020.104921.González-López, N. M.; Insuasty-Cepeda, D. S.; Huertas-Ortiz, K. A.; Reyes-Calderón, J. E.; Martínez-Ramírez, J. A.; Fierro-Medina, R.; Jenny Rivera-Monroy, Z.; García-Castañeda, J. E. Gradient Retention Factor Concept Applied to Method Development for Peptide Analysis by Means of RP-HPLC. ACS Omega 2022, 7, 44817–44824. https://doi.org/10.1021/acsomega.2c04907.Meyer, V. R. Practical High-Performance Liquid Chromatography, 5th ed.; John Wiley and Sons, 2010.Snyder, L. R.; Kirkland, J. J. (Joseph J.; Dolan, J. W. Introduction to Modern Liquid Chromatography, 3rd ed.; John Wiley and Sons, 2010.Sunde, H.; Ryder, K.; Bekhit, A. E. D. A.; Carne, A. Analysis of Peptides in a Sheep Beta Lactoglobulin Hydrolysate as a Model to Evaluate the Effect of Peptide Amino Acid Sequence on Bioactivity. Food Chem 2021, 365, 1–22. https://doi.org/10.1016/j.foodchem.2021.130346.Field, J. K.; Euerby, M. R.; Lau, J.; Thøgersen, H.; Petersson, P. Investigation into Reversed Phase Chromatography Peptide Separation Systems Part I: Development of a Protocol for Column Characterisation. J Chromatogr A 2019, 1603 (11), 113–129.Ehab Ibrahim, A.; Hashem, H.; Elhenawee, M.; Saleh, H. Monolithic and Core-Shell Particles Stationary Phase Morphologies in Protein Analysis; Peptide Mapping of Erythropoietin Hormone and Determination of Carbetocin. Ann Pharm Fr 2020, 78 (3), 206–216. https://doi.org/10.1016/j.pharma.2020.01.008.Michalski, A.; Damoc, E.; Hauschild, J. P.; Lange, O.; Wieghaus, A.; Makarov, A.; Nagaraj, N.; Cox, J.; Mann, M.; Horning, S. Mass Spectrometry-Based Proteomics Using Q Exactive, a High-Performance Benchtop Quadrupole Orbitrap Mass Spectrometer. Molecular and Cellular Proteomics 2011, 10 (9), 1–13. https://doi.org/10.1074/mcp.M111.011015.Gross, J. H. Mass Spectrometry: A Textbook, 3rd ed.; Springer, 2017.Bruderer, R.; Bernhardt, O. M.; Gandhi, T.; Xuan, Y.; Sondermann, J.; Schmidt, M.; Gomez-Varela, D.; Reiter, L. Optimization of Experimental Parameters in Data-Independent Mass Spectrometry Significantly Increases Depth and Reproducibility of Results. Molecular and Cellular Proteomics 2017, 16 (12), 2296–2309. https://doi.org/10.1074/mcp.RA117.000314.Geiger, T.; Cox, J.; Mann, M. Proteomics on an Orbitrap Benchtop Mass Spectrometer Using All-Ion Fragmentation. Molecular and Cellular Proteomics 2010, 9 (10), 2252–2261. https://doi.org/10.1074/mcp.M110.001537.Roepstorff, P.; Fohlman, J. Proposal for a Common Nomenclature for Sequence Ions in Mass Spectra of Peptides. Biomed Mass Spectrom 1984, 11 (11), 601.Wilson, D.; Daly, N. L. Nuclear Magnetic Resonance Seq (NMRseq): A New Approach to Peptide Sequence Tags. Toxins (Basel) 2018, 10 (11), 1–10. https://doi.org/10.3390/toxins10110437.Mishra, N.; Coutinho, E. NMR in Structural Determination of Proteins and Peptides. J. Pharm. Sci. Technol. Manag 2020, 4 (1), 22–33.Hinds, M. G.; Norton, R. S. NMR Spectroscopy of Peptides and Proteins. Mol Biotechnol 1997, 7, 315–331.Bader, Z. PEPTIDE NMR; Zurich.Choules, M. P.; Bisson, J.; Gao, W.; Lankin, D. C.; McAlpine, J. B.; Niemitz, M.; Jaki, B. U.; Franzblau, S. G.; Pauli, G. F. Quality Control of Therapeutic Peptides by 1H NMR HiFSA Sequencing. Journal of Organic Chemistry 2019, 84 (6), 3055–3073. https://doi.org/10.1021/acs.joc.8b02704.Bustamante Rojas, C. Fases Del Desarrollo de Un Nuevo Fármaco. In Estrategias de investigación en medicina clínica ; Bogotá, 2001; pp 123–134.Wu, L. C.; Chen, F.; Lee, S. L.; Raw, A.; Yu, L. X. Building Parity between Brand and Generic Peptide Products: Regulatory and Scientific Considerations for Quality of Synthetic Peptides. Int J Pharm 2017, 518 (1–2), 320–334. https://doi.org/10.1016/j.ijpharm.2016.12.051.Xiong, G.; Wu, Z.; Yi, J.; Fu, L.; Yang, Z.; Hsieh, C.; Yin, M.; Zeng, X.; Wu, C.; Lu, A.; Chen, X.; Hou, T.; Cao, D. ADMETlab 2.0: An Integrated Online Platform for Accurate and Comprehensive Predictions of ADMET Properties. Nucleic Acids Res 2021, 49, W5–W14. https://doi.org/10.1093/nar/gkab255.Barrero, J. A.; Cabrera, F.; Cruz, C. M. Gliptins vs. Milk-Derived Dipeptidyl-Peptidase Iv Inhibiting Biopeptides: Physicochemical Characterization and Pharmacokinetic Profiling. Vitae 2021, 28 (3), 1–14. https://doi.org/10.17533/UDEA.VITAE.V28N3A346531.Hart, L. R.; Lebedenko, C. G.; Mitchell, S. M.; Daso, R. E.; Banerjee, I. A. In Silico Studies of Tumor Targeted Peptide‐Conjugated Natural Products for Targeting Over‐Expressed Receptors in Breast Cancer Cells Using Molecular Docking, Molecular Dynamics and MMGBSA Calculations. Applied Sciences 2022, 12 (1), 1–41. https://doi.org/10.3390/app12010515.Iwaniak, A.; Minkiewicz, P.; Pliszka, M.; Mogut, D.; Darewicz, M. Characteristics of Biopeptides Released in Silico from Collagens Using Quantitative Parameters. Foods 2020, 9 (7), 1–29. https://doi.org/10.3390/foods9070965.Minkiewicz, P.; Iwaniak, A.; Darewicz, M. Annotation of Peptide Structures Using SMILES and Other Chemical Codes-Practical Solutions. Molecules 2017, 22 (12), 1–17. https://doi.org/10.3390/molecules22122075.Huertas Ortiz, K. A. Caracterización Fisicoquímica de Un Péptido Polivalente, Derivado de La Lactoferricina Bovina, Candidato a Fármaco Para El Tratamiento Del Cáncer de Mama, Universidad Nacional de Colombia, Bogotá, 2021.Stoscheck, C. M. Quantitation of Protein. Methods Enzymol 1990, 182, 1–19.Moffatt, F.; Senkans, P.; Ricketts, D. Approaches towards the Quantitative Analysis of Peptides and Proteins by Reversed-Phase High-Performance Liquid Chromatography in the Absence of a Pure Reference Sample. J Chromatogr A 2000, 891, 235–242.Drochioiu, G.; Adochitei, A. Rapid Characterization of Peptide Secondary Structure by FT-IR Spectroscopy. Rev. Roum. Chim 2011, 56 (8), 783–791.Roux, S.; Zékri, E.; Rousseau, B.; Cintrat, J. C.; Fay, N. Elimination and Exchange of Trifluoroacetate Counter-Ion from Cationic Peptides: A Critical Evaluation of Different Approaches. Journal of Peptide Science 2008, 14 (3), 354–359. https://doi.org/10.1002/psc.951.Chapman, D.; I. Haris, P. The Conformational Analysis of Peptides Using Fourier Transform IR Spectroscopy. Biopolymers (Peptide Science) 1995, 37, 251–263.Nugrahani, I.; Oktaviary, R.; Ibrahim, S.; Gusdinar, T.; Apsari, C. FTIR Method for Peptide Content Estimation and Degradation Kinetic Study of Canarium Nut Protein. Indonesian Journal of Pharmacy 2020, 31 (2), 78–83. https://doi.org/10.14499/indonesianjpharm31iss2pp78.de Meutter, J.; Goormaghtigh, E. Evaluation of Protein Secondary Structure from FTIR Spectra Improved after Partial Deuteration. European Biophysics Journal 2021, 50 (3–4), 613–628. https://doi.org/10.1007/s00249-021-01502-y.Cobb, J. S.; Zai-Rose, V.; Correia, J. J.; Janorkar, A. v. FT-IR Spectroscopic Analysis of the Secondary Structures Present during the Desiccation Induced Aggregation of Elastin-Like Polypeptide on Silica. ACS Omega 2020, 5 (14), 8403–8413. https://doi.org/10.1021/acsomega.0c00271.Andrushchenko, V. v.; Vogel, H. J.; Prenner, E. J. Optimization of the Hydrochloric Acid Concentration Used for Trifluoroacetate Removal from Synthetic Peptides. Journal of Peptide Science 2007, 13 (1), 37–43. https://doi.org/10.1002/psc.793.Sikora, K.; Neubauer, D.; Jaśkiewicz, M.; Kamysz, W. Citropin 1.1 Trifluoroacetate to Chloride Counter-Ion Exchange in HCl-Saturated Organic Solutions: An Alternative Approach. Int J Pept Res Ther 2018, 24 (2), 265–270. https://doi.org/10.1007/s10989-017-9611-7.Bronsema, K. J.; Bischoff, R.; van de Merbel, N. C. Internal Standards in the Quantitative Determination of Protein Biopharmaceuticals Using Liquid Chromatography Coupled to Mass Spectrometry. Journal of Chromatography B 2012, 893–894, 1–14. https://doi.org/10.1016/j.jchromb.2012.02.021.Tan, A.; Awaiye, K. USE OF INTERNAL STANDARDS IN LC-MS BIOANALYSIS. In Handbook of LC-MS Bioanalysis: Best Practices, Experimental Protocols, and Regulations; Wenkui, L., Jie, Z., Francis L.S., Tse., Eds.; John Wiley and Sons, 2013; pp 217–227.Faria, M.; Halquist, M. S. Internal Standards for Absolute Quantification of Large Molecules (Proteins) from Biological Matrices by LC-MS/MS. In Calibration and Validation of Analytical Methods - A Sampling of Current Approaches; Stauffer, M., Ed.; InTech, 2018; pp 61–84. https://doi.org/10.5772/intechopen.75569.Hoofnagle, A. N. Peptide Lost and Found: Internal Standards and the Mass Spectrometric Quantification of Peptides. Clin Chem 2010, 56 (10), 1515–1517. https://doi.org/10.1373/clinchem.2010.152181.Jeanne Dit Fouque, D.; Maroto, A.; Memboeuf, A. Internal Standard Quantification Using Tandem Mass Spectrometry of a Tryptic Peptide in the Presence of an Isobaric Interference. Anal Chem 2018, 90 (24), 14126–14130. https://doi.org/10.1021/acs.analchem.8b05016.Barroso, O.; Handelsman, D. J.; Strasburger, C.; Thevis, M. Analytical Challenges in the Detection of Peptide Hormones for Anti-Doping Purposes. Bioanalysis 2012, 4 (13), 1577–1590. https://doi.org/10.4155/bio.12.128.van de Merbel, N. C. Protein Quantification by LC-MS: A Decade of Progress through the Pages of Bioanalysis. Bioanalysis 2019, 11 (7), 629–644. https://doi.org/10.4155/bio-2019-0032.Medina, I. B. Estudio de La Degradación Proteolítica de Péptidos Derivados de LfcinB Funcionalizados Con El Motivo RGD, Universidad Nacional de Colombia, Bogotá, 2022.Memdouh, S.; Gavrilović, I.; Ng, K.; Cowan, D.; Abbate, V. Advances in the Detection of Growth Hormone Releasing Hormone Synthetic Analogs. Drug Test Anal 2021, 13 (11–12), 1871–1887. https://doi.org/10.1002/dta.3183.Masters, J. R. HeLa Cells 50 Years on: The Good, the Bad and the Ugly. Nat Rev Cancer 2002, 2 (4), 311–315. https://doi.org/10.1038/nrc774.Lyapun, I. N.; Andryukov, B. G.; Bynina, M. P. HeLa Cell Culture: Immortal Heritage of Henrietta Lacks. Molecular Genetics, Microbiology and Virology 2019, 34 (4), 195–200. https://doi.org/10.3103/S0891416819040050.Beskow, L. M. Lessons from HeLa Cells: The Ethics and Policy of Biospecimens. Annu Rev Genomics Hum Genet 2016, 17, 395–417. https://doi.org/10.1146/annurev-genom-083115-022536.Ni, G.; Chen, S.; Chen, M.; Wu, J.; Yang, B.; Yuan, J.; Walton, S. F.; Li, H.; Wei, M. Q.; Wang, Y.; Chen, G.; Liu, X.; Wang, T. Host-Defense Peptides Caerin 1.1 and 1.9 Stimulate TNF-Alpha-Dependent Apoptotic Signals in Human Cervical Cancer HeLa Cells. Front Cell Dev Biol 2020, 8. https://doi.org/10.3389/fcell.2020.00676.Shan, Y.; Huang, J.; Tan, J.; Gao, G.; Liu, S.; Wang, H.; Chen, Y. The Study of Single Anticancer Peptides Interacting with HeLa Cell Membranes by Single Molecule Force Spectroscopy. Nanoscale 2012, 4 (4), 1283–1286. https://doi.org/10.1039/c2nr11541g.Xu, Z.; Ding, J.; Zhang, L.; Feng, X.; Zhou, J.; Shen, X.; Lu, H.; Qian, L.; Li, X. Peptidomics Analysis Revealed That a Novel Peptide VMP-19 Protects against Ang II-Induced Injury in Human Umbilical Vein Endothelial Cells. Mol Med Rep 2021, 23 (298), 1–11. https://doi.org/10.3892/MMR.2021.11937.Zhu, G.; Sun, L.; Albanetti, T.; Linkous, T.; Larkin, C.; Schoner, R.; McGivney, J. B.; Dovichi, N. J. Quantitative Analysis of the Supernatant from Host and Transfected CHO Cells Using ITRAQ 8-Plex Technique. Biotechnol Bioeng 2016, 113 (10), 2140–2148. https://doi.org/10.1002/bit.25991.EstudiantesInvestigadoresMaestrosPúblico generalLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/84397/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1032489937.2023.pdf1032489937.2023.pdfTesis de Maestría en Ciencias Farmacéuticasapplication/pdf3694464https://repositorio.unal.edu.co/bitstream/unal/84397/2/1032489937.2023.pdfaa26c436d3891eb076e8af3c085b2389MD52THUMBNAIL1032489937.2023.pdf.jpg1032489937.2023.pdf.jpgGenerated Thumbnailimage/jpeg5024https://repositorio.unal.edu.co/bitstream/unal/84397/3/1032489937.2023.pdf.jpg11f52582dab8a749bbc3dcaaa2441553MD53unal/84397oai:repositorio.unal.edu.co:unal/843972023-08-15 23:04:14.92Repositorio Institucional Universidad Nacional de Colombiarepositorio_nal@unal.edu.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

Publicaciones similares