Síntesis de copolímeros anfifílicos bioconjugados con colesterol y su aplicación en la encapsulación y liberación de anfotericina B

En el presente trabajo se estudió la síntesis de copolímeros en bloque anfifílicos basados en acrilato de colesterilo, acrilato de butilo y polietilenglicol mediante la técnica ARGET-ATRP, la polimerización fue confirmada empleando FT-IR, RMN1H, GPC y DSC. Adicionalmente, se estableció el efecto de...

Full description

Autores:
Rodríguez Molina, Yeimy Johana
Tipo de recurso:
Trabajo de grado de pregrado
Fecha de publicación:
2016
Institución:
Universidad de Ciencias Aplicadas y Ambientales U.D.C.A
Repositorio:
Repositorio Institucional UDCA
Idioma:
spa
OAI Identifier:
oai:repository.udca.edu.co:11158/565
Acceso en línea:
https://repository.udca.edu.co/handle/11158/565
Palabra clave:
Copolímeros Anfífilicos
Colesterol
Anfotericina B
Copolimeros de bloque
Anfotericina B
Química
Rights
closedAccess
License
Derechos Reservados - Universidad de Ciencias Aplicadas y Ambientales
id RepoUDCA2_97028bd6d0845085de0dd5c0378d5f07
oai_identifier_str oai:repository.udca.edu.co:11158/565
network_acronym_str RepoUDCA2
network_name_str Repositorio Institucional UDCA
repository_id_str
dc.title.spa.fl_str_mv Síntesis de copolímeros anfifílicos bioconjugados con colesterol y su aplicación en la encapsulación y liberación de anfotericina B
title Síntesis de copolímeros anfifílicos bioconjugados con colesterol y su aplicación en la encapsulación y liberación de anfotericina B
spellingShingle Síntesis de copolímeros anfifílicos bioconjugados con colesterol y su aplicación en la encapsulación y liberación de anfotericina B
Copolímeros Anfífilicos
Colesterol
Anfotericina B
Copolimeros de bloque
Anfotericina B
Química
title_short Síntesis de copolímeros anfifílicos bioconjugados con colesterol y su aplicación en la encapsulación y liberación de anfotericina B
title_full Síntesis de copolímeros anfifílicos bioconjugados con colesterol y su aplicación en la encapsulación y liberación de anfotericina B
title_fullStr Síntesis de copolímeros anfifílicos bioconjugados con colesterol y su aplicación en la encapsulación y liberación de anfotericina B
title_full_unstemmed Síntesis de copolímeros anfifílicos bioconjugados con colesterol y su aplicación en la encapsulación y liberación de anfotericina B
title_sort Síntesis de copolímeros anfifílicos bioconjugados con colesterol y su aplicación en la encapsulación y liberación de anfotericina B
dc.creator.fl_str_mv Rodríguez Molina, Yeimy Johana
dc.contributor.advisor.spa.fl_str_mv Pérez Pérez, León Darío, dir.
dc.contributor.author.spa.fl_str_mv Rodríguez Molina, Yeimy Johana
dc.contributor.corporatename.spa.fl_str_mv Universidad de Ciencias Aplicadas y Ambientales, UDCA
dc.subject.spa.fl_str_mv Copolímeros Anfífilicos
Colesterol
Anfotericina B
topic Copolímeros Anfífilicos
Colesterol
Anfotericina B
Copolimeros de bloque
Anfotericina B
Química
dc.subject.lemb.spa.fl_str_mv Copolimeros de bloque
Anfotericina B
Química
description En el presente trabajo se estudió la síntesis de copolímeros en bloque anfifílicos basados en acrilato de colesterilo, acrilato de butilo y polietilenglicol mediante la técnica ARGET-ATRP, la polimerización fue confirmada empleando FT-IR, RMN1H, GPC y DSC. Adicionalmente, se estableció el efecto de la estructura de los copolímeros en el autoensamblaje en medio acuoso para la formación de micelas y sus propiedades coloidales mediante análisis de DLS, TEM y potencial Z. Finalmente, se estudió la capacidad de las micelas poliméricas bioconjugadas con colesterol, para encapsular y liberar anfotericina B (anfB) empleando espectroscopia UV/VIS. De acuerdo a los resultados obtenidos, propiedades como el diámetro hidrodinámico y morfología de las micelas no se ven afectados por la composición de los copolímeros. Así mismo, al estudiar la encapsulación y liberación de anfB, se encontró que estas propiedades dependen en gran medida del carácter hidrofóbico del copolímero. Alcanzando mayor encapsulación del fármaco a medida que aumenta el contenido de colesterol, mientras que en los estudios de liberación se evidencio que a menor contenido de colesterol la liberación del fármaco es mayor.
publishDate 2016
dc.date.accessioned.spa.fl_str_mv 2016-09-09T15:52:40Z
dc.date.available.spa.fl_str_mv 2016-09-09T15:52:40Z
dc.date.issued.spa.fl_str_mv 2016
dc.type.spa.fl_str_mv Trabajo de grado - Pregrado
dc.type.coarversion.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.coar.spa.fl_str_mv http://purl.org/coar/resource_type/c_7a1f
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/bachelorThesis
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/TP
format http://purl.org/coar/resource_type/c_7a1f
status_str publishedVersion
dc.identifier.uri.spa.fl_str_mv https://repository.udca.edu.co/handle/11158/565
url https://repository.udca.edu.co/handle/11158/565
dc.language.iso.spa.fl_str_mv spa
language spa
dc.relation.references.spa.fl_str_mv Adams, M., & Kwon, G. S. (2004). Spectroscopic investigation of the aggregation state of amphotericin B during loading, freeze-drying, and reconstitution of polymeric micelles. Journal of Pharmacy and Pharmaceutical Sciences, 7(4), 1–6
Adams, M. L., & Kwon, G. S. (2003). Relative aggregation state and hemolytic activity of amphotericin B encapsulated by poly(ethylene oxide)-block-poly(Nhexyl-L-aspartamide)-acyl conjugate micelles: Effects of acyl chain length. Journal of Controlled Release, 87(1-3), 23–32.
Alex, R., & Bodmeier, R. (1990). Encapsulation of water-soluble drugs by a modified solvent evaporation method. I. Effect of process and formulation variables on drug entrapment. Journal of Microencapsulation, 7(3), 347–55.
Avella, E. (2006). Espectroscopia IR. In Análisis Orgánico (pp. 2–4). Universidad Nacional de Colombia.
Baginski, M. (2002). Comparative molecular dynamics simulations of amphotericin B–cholesterol/ergosterol membrane channels. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1567, 63–78.
Barwicz, J., Christian, S., & Gruda, I. (1992). Effects of the aggregation state of amphotericin B on its toxicity to mice. Antimicrobial Agents and Chemotherapy, 36(10), 2310–2315.
carrillo, N. A., Yáñez, D., Aguirre, P., Amar, Y., Vidal, S., & Egaña, R. (2013). Encapsulación de Biomoléculas Usando Polímeros Naturales : “ Un Nuevo Enfoque en la Entrega de Fármacos en Medicina .” Avances En Ciencias Veterinarias, 28(2), 31–40.
Choi, S. W., & Kim, J. H. (2007). Design of surface-modified poly(d,l-lactide-coglycolide) nanoparticles for targeted drug delivery to bone. Journal of Controlled Release, 122(1), 24–30.
Cleary, J. D., & Wasan, K. M. (2011). Amphotericin B : A New Look at Cellular Binding, 30–36.
Colombani, O., Ruppel, M., Schubert, F., Zettl, H., Pergushov, D. V., & M??ller, A. H. E. (2007). Synthesis of poly(n-butyl acrylate)-block-poly(acrylic acid) diblock copolymers by ATRP and their micellization in water. Macromolecules, 40(12), 4338–4350.
Davis, K. a, & Matyjaszewski, K. (2000). Atom Transfer Radical Polymerization of tert -Butyl Acrylate and Preparation of Block Copolymers, 4039–4047.
Diaz, I. L., Parra, C., Linarez, M., & Perez, L. D. (2015). Design of Micelle Nanocontainers Based on PDMAEMA-b-PCL-b-PDMAEMA Triblock Copolymers for the Encapsulation of Amphotericin B. AAPS PharmSciTech, 16(5), 1069–1078.
Diaz, I. L., & Perez, L. D. (2015). Synthesis and micellization properties of triblock copolymers PDMAEMA-b-PCL-b-PDMAEMA and their applications in the fabrication of amphotericin B-loaded nanocontainers. Colloid and Polymer Science, 293(3), 913–923.
Diezi, T. A., & Kwon, G. (2012). Amphotericin B/sterol co-loaded PEG-phospholipid micelles: effects of sterols on aggregation state and hemolytic activity of amphotericin B. Pharmaceutical Research, 29(7), 1737–1744.
Dong, H., & Matyjaszewski, K. (2008). ARGET ATRP of 2-(Dimethylamino)ethyl methacrylate as an intrinsic reducing agent. Macromolecules, 41(19), 6868– 6870.
Faucher, S., Okrutny, P., & Zhu, S. (2006). Facile and effective purification of polymers produced by atom transfer radical polymerization via simple catalyst precipitation and microfiltration. Macromolecules, 39(1), 3–5.
Filippin, F. B., & Souza, L. C. (2006). Eficiência terapêutica das formulações lipídicas de anfotericina B. Revista Brasileira de Ciências Farmacêuticas, 42(2), 167– 194.
Gaitzsch, J., Appelhans, D., Gräfe, D., Schwille, P., & Voit, B. (2011). Photocrosslinked and pH sensitive polymersomes for triggering the loading and release of cargo. Chemical Communications (Cambridge, England), 47(12), 3466–8.
Gaucher, G., Dufresne, M.-H., Sant, V. P., Kang, N., Maysinger, D., & Leroux, J.-C. (2005). Block copolymer micelles: preparation, characterization and application in drug delivery. Journal of Controlled Release, 109(1-3), 169–188.
Gómez, C. (2014). NANOPARTÍCULAS POLIMÉRICAS : TECNOLOGÍA Y APLICACIONES FARMACÉUTICAS ( Polymeric nanoparticles : technologie and pharmaceutical applications ). Revista Farmacologica de Chile, 7(2), 7–16.
Gregorí Valdés, B. S. (2005). Estructura y actividad de los antifúngicos. Revista Cubana de Farmacia, 39(2).
Hamill, R. J. (2013). Amphotericin B formulations: A comparative review of efficacy and toxicity. Drugs, 73(9), 919–934.
Horne, D. S. (1995). Steric stabilization and casein micelle stability. Journal of Colloid And Interface Science, 111(1), 250–260.
Jakubowski, W., Min, K., & Matyjaszewski, K. (2006). Activators regenerated by electron transfer for atom transfer radical polymerization of styrene. Macromolecules, 39(1), 39–45.
Jáuregui-haza, R. O. U. J. (2012). Las nanopartículas como portadores de fármacos : características y perspectivas Nanoparticles as drug carriers : characteristics and perspectives, 43(3).
Jeong, B., Han Bae, Y., & Wan Kim, S. (1999). Biodegradable thermosensitive micelles of PEG-PLGA-PEG triblock copolymers. Colloids and Surfaces B: Biointerfaces, 16(1-4), 185–193.
Jia, L., Albouy, P. A., Di Cicco, A., Cao, A., & Li, M. H. (2011). Self-assembly of amphiphilic liquid crystal block copolymers containing a cholesteryl mesogen: Effects of block ratio and solvent. Polymer, 52(12), 2565–2575.
Katime, I., Quintana, J., & Villacampa, M. (2003). Micelas. Revista Iberoamericana, 4(2), 123–151.
Konak, C., Ganchev, B., Teodorescu, M., Matyjaszewski, K., Kopeckova, P., & Kopecek, J. (2002). Poly[N-(2-hydroxypropyl)methacrylamide-block-n-butyl acrylate] micelles in water/DMF mixed solvents. Polymer, 43(13), 3735–3741.
Kwak, Y., & Matyjaszewski, K. (2009). ARGET ATRP of methyl methacrylate in the presence of nitrogen-based ligands as reducing agents. Polymer International, 58(3), 242–247
Laniado, R., & Cabrales, M. N. (2009). Amphotericin B: side effects and toxicity. Revista Iberoamericana de Micologia, 26(4), 223–227.
Laskar, P., Saha, B., Ghosh, S., & Dey, J. (2015). PEG based random copolymer micelles as drug carriers: Effect of hydrophobe content on drug solubilization and cytotoxicity. RSC Adv., 5
Laskar, P., Samanta, S., Ghosh, S. K., & Dey, J. (2014). In vitro evaluation of pHsensitive cholesterol-containing stable polymeric micelles for delivery of camptothecin. Journal of Colloid and Interface Science, 430, 305–314.
Lavasanifar, A., Samuel, J., & Kwon, G. S. (2002). The effect of fatty acid substitution on the in vitro release of amphotericin B from micelles composed of poly(ethylene oxide)-block-poly(N-hexyl stearate-L-aspartamide). Journal of Controlled Release, 79(1-3), 165–172.
Lavasanifar, A., Samuel, J., Sattari, S., & Kwon, G. S. (2002). Block Copolymer Micelles for the Amphotericin B. Pharmaceutical Research, 19(4), 418–422.
Lee, A. L. Z., Venkataraman, S., Sirat, S. B. M., Gao, S., Hedrick, J. L., & Yang, Y. Y. (2012). The use of cholesterol-containing biodegradable block copolymers to exploit hydrophobic interactions for the delivery of anticancer drugs. Biomaterials, 33(6), 1921–1928.
Leibler, L., Orland, H., & Wheeler, J. C. (2003). Theory of critical micelle concentration for solutions of block copolymers. Journal of Chemical Physics, 79(7), 3550–3557.
Luengo-Alonso, C., Torrado, J. J., Ballesteros, M. P., Malfanti, A., Bersani, S., Salmaso, S., & Caliceti, P. (2015). A novel performing PEG-cholane nanoformulation for Amphotericin B delivery. International Journal of Pharmaceutics, 495(1), 41–51.
Luisi, P. L. (2001). Are micelles and vesicles chemical equilibrium systems? Journal of Chemical Education, 78(3), 380–384.
Ma, Q., & Wooley, K. L. (2000). The preparation oft-butyl acrylate, methyl acrylate, and styrene block copolymers by atom transfer radical polymerization: Precursors to amphiphilic and hydrophilic block copolymers and conversion to complex nanostructured materials. Journal of Polymer Science Part A: Polymer Chemistry, 38(S1), 4805–4820.
Matyjaszewski, K. (1994). No Title. Retrieved from
Matyjaszewski, K. (2012). Atom Transfer Radical Polymerization (ATRP): Current Status and Future Perspectives. Macromolecules, 45(10), 4015–4039
Matyjaszewski, K., & Xia, J. (2001). Atom transfer radical polymerization. Chemical Reviews, 101(9), 2921–2990.
Myles, D. G., Biol, D., Jaffe, L. A., Brawley, S. H., Bernard, U. C., The, F., … Langerll, R. (1994). Biodegradable Long-Circulating Polymeric Nanospheres ILlauana Upon solvent evaporation , the. Science, 263(January), 1600–1603
Osouli, K. (2013). No Title. Retrieved from https://www.researchgate.net/post/How_do_I_synthesize_acryloyl_chloride
Pasquali, R. C., Chiappetta, D. A., & Bregni, C. (2005a). Los Copol í meros en Bloques Anfif í licos y sus Aplicaciones Farmac é uticas, 24(4).
Pasquali, R. C., Chiappetta, D. A., & Bregni, C. (2005b). No Title. Retrieved from
Picos, D., Gómez, M., Fernández, D., & Núñez, L. (2000). Microesferas biodegradables de liberación controlada para administración parenteral. Control, 34(1), 70–77.
Pinto Reis, C., Neufeld, R. J., Ribeiro, A. J., & Veiga, F. (2006). Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles. Nanomedicine: Nanotechnology, Biology, and Medicine, 2(1), 8–21.
Pittella, F., Cabral, H., Maeda, Y., Mi, P., Watanabe, S., Takemoto, H., … Kataoka, K. (2014). Systemic siRNA delivery to a spontaneous pancreatic tumor model in transgenic mice by PEGylated calcium phosphate hybrid micelles. Journal of Controlled Release, 178(1), 18–24.
Rodríguez-Hernandez, J., Chécot, F., Gnanou, Y., & Lecommandoux, S. (2005). Toward “smart” nano-objects by self-assembly of block copolymers in solution. Progress in Polymer Science (Oxford), 30(7), 691–724.
Rösler, A., Vandermeulen, G. W. M., & Klok, H. A. (2012). Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Advanced Drug Delivery Reviews, 64(SUPPL.), 270–279.
Saenz, Hernaez, Sanz, K. (2004). Liberación Controlada De Fármacos. Micropartículas. Revista Iberoamericana de Polimeros, 5(2)(2), 15.
Saha, S., Copic, D., Bhaskar, S., Clay, N., Donini, A., Hart, A. J., & Lahann, J. (2012). Chemically controlled bending of compositionally anisotropic microcylinders. Angewandte Chemie - International Edition, 51(3), 660–665.
Sánchez-Brunete, J. A., Dea, M. A., Rama, S., Bolás, F., Alunda, J. M., TorradoSantiago, S., & Torrado, J. J. (2004). Amphotericin B molecular organization as an essential factor to improve activity/toxicity ratio in the treatment of visceral leishmaniasis. Journal of Drug Targeting, 12(7), 453–60.
Serrano, E., Zubeldia, A., Eceiza, A., Remiro, P., & Mondragon, I. (2002). Análisis Microscópico Y Físico-Químico Del Auto-, (Kraton 4274), 777–782.
Sevimli, S., Sagnella, S., Kavallaris, M., Bulmus, V., & Davis, T. P. (2012). Synthesis, self-assembly and stimuli responsive properties of cholesterol conjugated polymers. Polymer Chemistry, 3(8), 2057.
Shameli, K., Ahmad, M. Bin, Jazayeri, S. D., Sedaghat, S., Shabanzadeh, P., Jahangirian, H., … Abdollahi, Y. (2012). Synthesis and characterization of polyethylene glycol mediated silver nanoparticles by the green method. International Journal of Molecular Sciences, 13(6), 6639–6650.
Shen, H., Hong, S., Prud’Homme, R. K., & Liu, Y. (2011). Self-assembling process of flash nanoprecipitation in a multi-inlet vortex mixer to produce drug-loaded polymeric nanoparticles. Journal of Nanoparticle Research, 13(9), 4109–4120.
Siegwart, D. J., Oh, J. K., & Matyjaszewski, K. (2012). ATRP in the design of functional materials for biomedical applications. Progress in Polymer Science (Oxford), 37(1), 18–37.
Soppimath, K. S., Aminabhavi, T. M., & Kulkarni, A. R. (2001). Biodegradable polymeric nanoparticles as drug delivery devices. Controlled Release, 70, 1– 20.
Spink, C. H. (2008). Differential Scanning Calorimetry. Methods in Cell Biology, 84(07), 115–141
Suriñach Cornet Santiago Bordas Alsina, N. Clavaguera, M. T. Clavaguera-Mora, M. D. B. (2002). La calorimetría diferencial de barrido y su aplicación a la Ciencia de Materiales. Boletín de La Sociedad Española de Cerámica Y Vidrio, 31, 11–17.
Torchilin, V. P. (2005). Block copolymer micelles as a solution for drug delivery problems. Expert Opinion on Therapeutic Patents, 15, 63–75.
Torrado, J. J., Espada, R., Ballesteros, M. P., & Torrado-Santiago, S. (2010). In vivo study of a polymeric glucose-sensitive insulin delivery system using a rat model. Journal of Pharmaceutical Sciences, 99(10), 4215–4227.
Vakil, R., & Kwon, G. S. (2008). Effect of cholesterol on the release of amphotericin B from PEG-phospholipid micelles. Molecular Pharmaceutics, 5(1), 98–104.
Vîjan, L. E. (2015). Comparative study of the interactions of amphotericin B with cholesteryl / stigmasteryl comparative study of the interactions of amphotericin b with, (November).
Vijan, L. E., & Topala, C. (2009). The characterizing of the interaction of amphotericin B with cholesteryl esters. Journal of Molecular Liquids, 147(1-2), 135–138.
Wang, J.-S., & Matyjaszewski, K. (1995). Controlled/“Living” Radical Polymerization. Halogen Atom Transfer Radical Polymerization Promoted by a Cu(I)/Cu(II) Redox Process. Macromolecules, 28(23), 7901–7910.
Wasan, E. K., Bartlett, K., Gershkovich, P., Sivak, O., Banno, B., Wong, Z., … Wasan, K. M. (2009). Development and characterization of oral lipid-based Amphotericin B formulations with enhanced drug solubility, stability and antifungal activity in rats infected with Aspergillus fumigatus or Candida albicans. International Journal of Pharmaceutics, 372(1-2), 76–84.
Xing, L., & Mattice, W. L. (1997). Strong solubilization of small molecules by triblockcopolymer micelles in selective solvents. Macromolecules, 30(6), 1711–1717.
Yan, Q., Yuan, J., Zhang, F., Sui, X., Xie, X., Yin, Y., … Wei, Y. (2009). Cellulosebased dual graft molecular brushes as potential drug nanocarriers: Stimulusresponsive micelles, self-assembled phase transition behavior, and tunable crystalline morphologies. Biomacromolecules, 10(8), 2033–2042.
Zhang, X., Zhu, X., Ke, F., Ye, L., Chen, E. qiang, Zhang, A. ying, & Feng, Z. guo. (2009). Preparation and self-assembly of amphiphilic triblock copolymers with polyrotaxane as a middle block and their application as carrier for the controlled release of Amphotericin B. Polymer, 50(18), 4343–4351.
dc.rights.spa.fl_str_mv Derechos Reservados - Universidad de Ciencias Aplicadas y Ambientales
dc.rights.coar.fl_str_mv http://purl.org/coar/access_right/c_14cb
dc.rights.uri.spa.fl_str_mv https://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rights.accessrights.spa.fl_str_mv info:eu-repo/semantics/closedAccess
dc.rights.creativecommons.spa.fl_str_mv Atribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0)
rights_invalid_str_mv Derechos Reservados - Universidad de Ciencias Aplicadas y Ambientales
https://creativecommons.org/licenses/by-nc-sa/4.0/
Atribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0)
http://purl.org/coar/access_right/c_14cb
eu_rights_str_mv closedAccess
dc.format.spa.fl_str_mv pdf
dc.publisher.faculty.spa.fl_str_mv Facultad de Ciencias
dc.publisher.program.spa.fl_str_mv Química
institution Universidad de Ciencias Aplicadas y Ambientales U.D.C.A
bitstream.url.fl_str_mv https://repository.udca.edu.co/bitstreams/c399f36d-ddc1-4b99-b71e-cfc7934bba8b/download
https://repository.udca.edu.co/bitstreams/d6351d38-e978-4b52-97ea-b56f27e6998f/download
https://repository.udca.edu.co/bitstreams/335749bf-b4d1-401b-9b60-f1794a7d6163/download
https://repository.udca.edu.co/bitstreams/9202d661-2fc1-4b9f-ac11-a0cd035f98b3/download
bitstream.checksum.fl_str_mv e2c69c7656b97c1aa7df31af26718c01
2f74f9efb1f35a4eba0119b6d20770ef
132b7d38a849ee0df2f55d169b9bdd3e
8a4605be74aa9ea9d79846c1fba20a33
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
repository.name.fl_str_mv Repositorio - Universidad de Ciencias Aplicadas y Ambientales UDCA.
repository.mail.fl_str_mv bdigital@metabiblioteca.com
_version_ 1818152469166817280
spelling Pérez Pérez, León Darío, dir.Rodríguez Molina, Yeimy JohanaUniversidad de Ciencias Aplicadas y Ambientales, UDCA2016-09-09T15:52:40Z2016-09-09T15:52:40Z2016https://repository.udca.edu.co/handle/11158/565En el presente trabajo se estudió la síntesis de copolímeros en bloque anfifílicos basados en acrilato de colesterilo, acrilato de butilo y polietilenglicol mediante la técnica ARGET-ATRP, la polimerización fue confirmada empleando FT-IR, RMN1H, GPC y DSC. Adicionalmente, se estableció el efecto de la estructura de los copolímeros en el autoensamblaje en medio acuoso para la formación de micelas y sus propiedades coloidales mediante análisis de DLS, TEM y potencial Z. Finalmente, se estudió la capacidad de las micelas poliméricas bioconjugadas con colesterol, para encapsular y liberar anfotericina B (anfB) empleando espectroscopia UV/VIS. De acuerdo a los resultados obtenidos, propiedades como el diámetro hidrodinámico y morfología de las micelas no se ven afectados por la composición de los copolímeros. Así mismo, al estudiar la encapsulación y liberación de anfB, se encontró que estas propiedades dependen en gran medida del carácter hidrofóbico del copolímero. Alcanzando mayor encapsulación del fármaco a medida que aumenta el contenido de colesterol, mientras que en los estudios de liberación se evidencio que a menor contenido de colesterol la liberación del fármaco es mayor.PregradoQuímico(a)pdfspaDerechos Reservados - Universidad de Ciencias Aplicadas y Ambientaleshttps://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/closedAccessAtribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0)http://purl.org/coar/access_right/c_14cbCopolímeros AnfífilicosColesterolAnfotericina BCopolimeros de bloqueAnfotericina BQuímicaSíntesis de copolímeros anfifílicos bioconjugados con colesterol y su aplicación en la encapsulación y liberación de anfotericina BTrabajo de grado - Pregradohttp://purl.org/coar/resource_type/c_7a1finfo:eu-repo/semantics/bachelorThesisinfo:eu-repo/semantics/publishedVersionhttp://purl.org/redcol/resource_type/TPhttp://purl.org/coar/version/c_970fb48d4fbd8a85Adams, M., & Kwon, G. S. (2004). Spectroscopic investigation of the aggregation state of amphotericin B during loading, freeze-drying, and reconstitution of polymeric micelles. Journal of Pharmacy and Pharmaceutical Sciences, 7(4), 1–6Adams, M. L., & Kwon, G. S. (2003). Relative aggregation state and hemolytic activity of amphotericin B encapsulated by poly(ethylene oxide)-block-poly(Nhexyl-L-aspartamide)-acyl conjugate micelles: Effects of acyl chain length. Journal of Controlled Release, 87(1-3), 23–32.Alex, R., & Bodmeier, R. (1990). Encapsulation of water-soluble drugs by a modified solvent evaporation method. I. Effect of process and formulation variables on drug entrapment. Journal of Microencapsulation, 7(3), 347–55.Avella, E. (2006). Espectroscopia IR. In Análisis Orgánico (pp. 2–4). Universidad Nacional de Colombia.Baginski, M. (2002). Comparative molecular dynamics simulations of amphotericin B–cholesterol/ergosterol membrane channels. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1567, 63–78.Barwicz, J., Christian, S., & Gruda, I. (1992). Effects of the aggregation state of amphotericin B on its toxicity to mice. Antimicrobial Agents and Chemotherapy, 36(10), 2310–2315.carrillo, N. A., Yáñez, D., Aguirre, P., Amar, Y., Vidal, S., & Egaña, R. (2013). Encapsulación de Biomoléculas Usando Polímeros Naturales : “ Un Nuevo Enfoque en la Entrega de Fármacos en Medicina .” Avances En Ciencias Veterinarias, 28(2), 31–40.Choi, S. W., & Kim, J. H. (2007). Design of surface-modified poly(d,l-lactide-coglycolide) nanoparticles for targeted drug delivery to bone. Journal of Controlled Release, 122(1), 24–30.Cleary, J. D., & Wasan, K. M. (2011). Amphotericin B : A New Look at Cellular Binding, 30–36.Colombani, O., Ruppel, M., Schubert, F., Zettl, H., Pergushov, D. V., & M??ller, A. H. E. (2007). Synthesis of poly(n-butyl acrylate)-block-poly(acrylic acid) diblock copolymers by ATRP and their micellization in water. Macromolecules, 40(12), 4338–4350.Davis, K. a, & Matyjaszewski, K. (2000). Atom Transfer Radical Polymerization of tert -Butyl Acrylate and Preparation of Block Copolymers, 4039–4047.Diaz, I. L., Parra, C., Linarez, M., & Perez, L. D. (2015). Design of Micelle Nanocontainers Based on PDMAEMA-b-PCL-b-PDMAEMA Triblock Copolymers for the Encapsulation of Amphotericin B. AAPS PharmSciTech, 16(5), 1069–1078.Diaz, I. L., & Perez, L. D. (2015). Synthesis and micellization properties of triblock copolymers PDMAEMA-b-PCL-b-PDMAEMA and their applications in the fabrication of amphotericin B-loaded nanocontainers. Colloid and Polymer Science, 293(3), 913–923.Diezi, T. A., & Kwon, G. (2012). Amphotericin B/sterol co-loaded PEG-phospholipid micelles: effects of sterols on aggregation state and hemolytic activity of amphotericin B. Pharmaceutical Research, 29(7), 1737–1744.Dong, H., & Matyjaszewski, K. (2008). ARGET ATRP of 2-(Dimethylamino)ethyl methacrylate as an intrinsic reducing agent. Macromolecules, 41(19), 6868– 6870.Faucher, S., Okrutny, P., & Zhu, S. (2006). Facile and effective purification of polymers produced by atom transfer radical polymerization via simple catalyst precipitation and microfiltration. Macromolecules, 39(1), 3–5.Filippin, F. B., & Souza, L. C. (2006). Eficiência terapêutica das formulações lipídicas de anfotericina B. Revista Brasileira de Ciências Farmacêuticas, 42(2), 167– 194.Gaitzsch, J., Appelhans, D., Gräfe, D., Schwille, P., & Voit, B. (2011). Photocrosslinked and pH sensitive polymersomes for triggering the loading and release of cargo. Chemical Communications (Cambridge, England), 47(12), 3466–8.Gaucher, G., Dufresne, M.-H., Sant, V. P., Kang, N., Maysinger, D., & Leroux, J.-C. (2005). Block copolymer micelles: preparation, characterization and application in drug delivery. Journal of Controlled Release, 109(1-3), 169–188.Gómez, C. (2014). NANOPARTÍCULAS POLIMÉRICAS : TECNOLOGÍA Y APLICACIONES FARMACÉUTICAS ( Polymeric nanoparticles : technologie and pharmaceutical applications ). Revista Farmacologica de Chile, 7(2), 7–16.Gregorí Valdés, B. S. (2005). Estructura y actividad de los antifúngicos. Revista Cubana de Farmacia, 39(2).Hamill, R. J. (2013). Amphotericin B formulations: A comparative review of efficacy and toxicity. Drugs, 73(9), 919–934.Horne, D. S. (1995). Steric stabilization and casein micelle stability. Journal of Colloid And Interface Science, 111(1), 250–260.Jakubowski, W., Min, K., & Matyjaszewski, K. (2006). Activators regenerated by electron transfer for atom transfer radical polymerization of styrene. Macromolecules, 39(1), 39–45.Jáuregui-haza, R. O. U. J. (2012). Las nanopartículas como portadores de fármacos : características y perspectivas Nanoparticles as drug carriers : characteristics and perspectives, 43(3).Jeong, B., Han Bae, Y., & Wan Kim, S. (1999). Biodegradable thermosensitive micelles of PEG-PLGA-PEG triblock copolymers. Colloids and Surfaces B: Biointerfaces, 16(1-4), 185–193.Jia, L., Albouy, P. A., Di Cicco, A., Cao, A., & Li, M. H. (2011). Self-assembly of amphiphilic liquid crystal block copolymers containing a cholesteryl mesogen: Effects of block ratio and solvent. Polymer, 52(12), 2565–2575.Katime, I., Quintana, J., & Villacampa, M. (2003). Micelas. Revista Iberoamericana, 4(2), 123–151.Konak, C., Ganchev, B., Teodorescu, M., Matyjaszewski, K., Kopeckova, P., & Kopecek, J. (2002). Poly[N-(2-hydroxypropyl)methacrylamide-block-n-butyl acrylate] micelles in water/DMF mixed solvents. Polymer, 43(13), 3735–3741.Kwak, Y., & Matyjaszewski, K. (2009). ARGET ATRP of methyl methacrylate in the presence of nitrogen-based ligands as reducing agents. Polymer International, 58(3), 242–247Laniado, R., & Cabrales, M. N. (2009). Amphotericin B: side effects and toxicity. Revista Iberoamericana de Micologia, 26(4), 223–227.Laskar, P., Saha, B., Ghosh, S., & Dey, J. (2015). PEG based random copolymer micelles as drug carriers: Effect of hydrophobe content on drug solubilization and cytotoxicity. RSC Adv., 5Laskar, P., Samanta, S., Ghosh, S. K., & Dey, J. (2014). In vitro evaluation of pHsensitive cholesterol-containing stable polymeric micelles for delivery of camptothecin. Journal of Colloid and Interface Science, 430, 305–314.Lavasanifar, A., Samuel, J., & Kwon, G. S. (2002). The effect of fatty acid substitution on the in vitro release of amphotericin B from micelles composed of poly(ethylene oxide)-block-poly(N-hexyl stearate-L-aspartamide). Journal of Controlled Release, 79(1-3), 165–172.Lavasanifar, A., Samuel, J., Sattari, S., & Kwon, G. S. (2002). Block Copolymer Micelles for the Amphotericin B. Pharmaceutical Research, 19(4), 418–422.Lee, A. L. Z., Venkataraman, S., Sirat, S. B. M., Gao, S., Hedrick, J. L., & Yang, Y. Y. (2012). The use of cholesterol-containing biodegradable block copolymers to exploit hydrophobic interactions for the delivery of anticancer drugs. Biomaterials, 33(6), 1921–1928.Leibler, L., Orland, H., & Wheeler, J. C. (2003). Theory of critical micelle concentration for solutions of block copolymers. Journal of Chemical Physics, 79(7), 3550–3557.Luengo-Alonso, C., Torrado, J. J., Ballesteros, M. P., Malfanti, A., Bersani, S., Salmaso, S., & Caliceti, P. (2015). A novel performing PEG-cholane nanoformulation for Amphotericin B delivery. International Journal of Pharmaceutics, 495(1), 41–51.Luisi, P. L. (2001). Are micelles and vesicles chemical equilibrium systems? Journal of Chemical Education, 78(3), 380–384.Ma, Q., & Wooley, K. L. (2000). The preparation oft-butyl acrylate, methyl acrylate, and styrene block copolymers by atom transfer radical polymerization: Precursors to amphiphilic and hydrophilic block copolymers and conversion to complex nanostructured materials. Journal of Polymer Science Part A: Polymer Chemistry, 38(S1), 4805–4820.Matyjaszewski, K. (1994). No Title. Retrieved fromMatyjaszewski, K. (2012). Atom Transfer Radical Polymerization (ATRP): Current Status and Future Perspectives. Macromolecules, 45(10), 4015–4039Matyjaszewski, K., & Xia, J. (2001). Atom transfer radical polymerization. Chemical Reviews, 101(9), 2921–2990.Myles, D. G., Biol, D., Jaffe, L. A., Brawley, S. H., Bernard, U. C., The, F., … Langerll, R. (1994). Biodegradable Long-Circulating Polymeric Nanospheres ILlauana Upon solvent evaporation , the. Science, 263(January), 1600–1603Osouli, K. (2013). No Title. Retrieved from https://www.researchgate.net/post/How_do_I_synthesize_acryloyl_chloridePasquali, R. C., Chiappetta, D. A., & Bregni, C. (2005a). Los Copol í meros en Bloques Anfif í licos y sus Aplicaciones Farmac é uticas, 24(4).Pasquali, R. C., Chiappetta, D. A., & Bregni, C. (2005b). No Title. Retrieved fromPicos, D., Gómez, M., Fernández, D., & Núñez, L. (2000). Microesferas biodegradables de liberación controlada para administración parenteral. Control, 34(1), 70–77.Pinto Reis, C., Neufeld, R. J., Ribeiro, A. J., & Veiga, F. (2006). Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles. Nanomedicine: Nanotechnology, Biology, and Medicine, 2(1), 8–21.Pittella, F., Cabral, H., Maeda, Y., Mi, P., Watanabe, S., Takemoto, H., … Kataoka, K. (2014). Systemic siRNA delivery to a spontaneous pancreatic tumor model in transgenic mice by PEGylated calcium phosphate hybrid micelles. Journal of Controlled Release, 178(1), 18–24.Rodríguez-Hernandez, J., Chécot, F., Gnanou, Y., & Lecommandoux, S. (2005). Toward “smart” nano-objects by self-assembly of block copolymers in solution. Progress in Polymer Science (Oxford), 30(7), 691–724.Rösler, A., Vandermeulen, G. W. M., & Klok, H. A. (2012). Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Advanced Drug Delivery Reviews, 64(SUPPL.), 270–279.Saenz, Hernaez, Sanz, K. (2004). Liberación Controlada De Fármacos. Micropartículas. Revista Iberoamericana de Polimeros, 5(2)(2), 15.Saha, S., Copic, D., Bhaskar, S., Clay, N., Donini, A., Hart, A. J., & Lahann, J. (2012). Chemically controlled bending of compositionally anisotropic microcylinders. Angewandte Chemie - International Edition, 51(3), 660–665.Sánchez-Brunete, J. A., Dea, M. A., Rama, S., Bolás, F., Alunda, J. M., TorradoSantiago, S., & Torrado, J. J. (2004). Amphotericin B molecular organization as an essential factor to improve activity/toxicity ratio in the treatment of visceral leishmaniasis. Journal of Drug Targeting, 12(7), 453–60.Serrano, E., Zubeldia, A., Eceiza, A., Remiro, P., & Mondragon, I. (2002). Análisis Microscópico Y Físico-Químico Del Auto-, (Kraton 4274), 777–782.Sevimli, S., Sagnella, S., Kavallaris, M., Bulmus, V., & Davis, T. P. (2012). Synthesis, self-assembly and stimuli responsive properties of cholesterol conjugated polymers. Polymer Chemistry, 3(8), 2057.Shameli, K., Ahmad, M. Bin, Jazayeri, S. D., Sedaghat, S., Shabanzadeh, P., Jahangirian, H., … Abdollahi, Y. (2012). Synthesis and characterization of polyethylene glycol mediated silver nanoparticles by the green method. International Journal of Molecular Sciences, 13(6), 6639–6650.Shen, H., Hong, S., Prud’Homme, R. K., & Liu, Y. (2011). Self-assembling process of flash nanoprecipitation in a multi-inlet vortex mixer to produce drug-loaded polymeric nanoparticles. Journal of Nanoparticle Research, 13(9), 4109–4120.Siegwart, D. J., Oh, J. K., & Matyjaszewski, K. (2012). ATRP in the design of functional materials for biomedical applications. Progress in Polymer Science (Oxford), 37(1), 18–37.Soppimath, K. S., Aminabhavi, T. M., & Kulkarni, A. R. (2001). Biodegradable polymeric nanoparticles as drug delivery devices. Controlled Release, 70, 1– 20.Spink, C. H. (2008). Differential Scanning Calorimetry. Methods in Cell Biology, 84(07), 115–141Suriñach Cornet Santiago Bordas Alsina, N. Clavaguera, M. T. Clavaguera-Mora, M. D. B. (2002). La calorimetría diferencial de barrido y su aplicación a la Ciencia de Materiales. Boletín de La Sociedad Española de Cerámica Y Vidrio, 31, 11–17.Torchilin, V. P. (2005). Block copolymer micelles as a solution for drug delivery problems. Expert Opinion on Therapeutic Patents, 15, 63–75.Torrado, J. J., Espada, R., Ballesteros, M. P., & Torrado-Santiago, S. (2010). In vivo study of a polymeric glucose-sensitive insulin delivery system using a rat model. Journal of Pharmaceutical Sciences, 99(10), 4215–4227.Vakil, R., & Kwon, G. S. (2008). Effect of cholesterol on the release of amphotericin B from PEG-phospholipid micelles. Molecular Pharmaceutics, 5(1), 98–104.Vîjan, L. E. (2015). Comparative study of the interactions of amphotericin B with cholesteryl / stigmasteryl comparative study of the interactions of amphotericin b with, (November).Vijan, L. E., & Topala, C. (2009). The characterizing of the interaction of amphotericin B with cholesteryl esters. Journal of Molecular Liquids, 147(1-2), 135–138.Wang, J.-S., & Matyjaszewski, K. (1995). Controlled/“Living” Radical Polymerization. Halogen Atom Transfer Radical Polymerization Promoted by a Cu(I)/Cu(II) Redox Process. Macromolecules, 28(23), 7901–7910.Wasan, E. K., Bartlett, K., Gershkovich, P., Sivak, O., Banno, B., Wong, Z., … Wasan, K. M. (2009). Development and characterization of oral lipid-based Amphotericin B formulations with enhanced drug solubility, stability and antifungal activity in rats infected with Aspergillus fumigatus or Candida albicans. International Journal of Pharmaceutics, 372(1-2), 76–84.Xing, L., & Mattice, W. L. (1997). Strong solubilization of small molecules by triblockcopolymer micelles in selective solvents. Macromolecules, 30(6), 1711–1717.Yan, Q., Yuan, J., Zhang, F., Sui, X., Xie, X., Yin, Y., … Wei, Y. (2009). Cellulosebased dual graft molecular brushes as potential drug nanocarriers: Stimulusresponsive micelles, self-assembled phase transition behavior, and tunable crystalline morphologies. Biomacromolecules, 10(8), 2033–2042.Zhang, X., Zhu, X., Ke, F., Ye, L., Chen, E. qiang, Zhang, A. ying, & Feng, Z. guo. (2009). Preparation and self-assembly of amphiphilic triblock copolymers with polyrotaxane as a middle block and their application as carrier for the controlled release of Amphotericin B. Polymer, 50(18), 4343–4351.Facultad de CienciasQuímicaPublicationTEXTTRABAJO DE GRADO FINAL_Yeimy Rodriguez.pdf.txtTRABAJO DE GRADO FINAL_Yeimy Rodriguez.pdf.txtExtracted texttext/plain97320https://repository.udca.edu.co/bitstreams/c399f36d-ddc1-4b99-b71e-cfc7934bba8b/downloade2c69c7656b97c1aa7df31af26718c01MD53THUMBNAILTRABAJO DE GRADO FINAL_Yeimy Rodriguez.pdf.jpgTRABAJO DE GRADO FINAL_Yeimy Rodriguez.pdf.jpgGenerated Thumbnailimage/jpeg3800https://repository.udca.edu.co/bitstreams/d6351d38-e978-4b52-97ea-b56f27e6998f/download2f74f9efb1f35a4eba0119b6d20770efMD54ORIGINALTRABAJO DE GRADO FINAL_Yeimy Rodriguez.pdfTRABAJO DE GRADO FINAL_Yeimy Rodriguez.pdfapplication/pdf2802964https://repository.udca.edu.co/bitstreams/335749bf-b4d1-401b-9b60-f1794a7d6163/download132b7d38a849ee0df2f55d169b9bdd3eMD51LICENSElicense.txtlicense.txttext/plain; charset=utf-81748https://repository.udca.edu.co/bitstreams/9202d661-2fc1-4b9f-ac11-a0cd035f98b3/download8a4605be74aa9ea9d79846c1fba20a33MD5211158/565oai:repository.udca.edu.co:11158/5652024-05-09 14:31:22.123https://creativecommons.org/licenses/by-nc-sa/4.0/Derechos Reservados - Universidad de Ciencias Aplicadas y Ambientalesopen.accesshttps://repository.udca.edu.coRepositorio - Universidad de Ciencias Aplicadas y Ambientales UDCA.bdigital@metabiblioteca.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