Nanoencapsulación y rutas sintéticas para preparar medicamentos usados como tratamientos químicos contra cáncer colorrectal: una descripción general

Ilustraciones, gráficas

Autores:: Aguirre Giraldo , Santiago

Tipo de recurso:: Masters Thesis

Fecha de publicación:: 2021

Institución:: Universidad de Caldas

Repositorio:: Repositorio Institucional U. Caldas

Idioma:: spa

id	RUCALDAS2_94728d511a1770f8f642c9797bc47d9f
oai_identifier_str	oai:repositorio.ucaldas.edu.co:ucaldas/16840
network_acronym_str	RUCALDAS2
network_name_str	Repositorio Institucional U. Caldas
repository_id_str
dc.title.spa.fl_str_mv	Nanoencapsulación y rutas sintéticas para preparar medicamentos usados como tratamientos químicos contra cáncer colorrectal: una descripción general
title	Nanoencapsulación y rutas sintéticas para preparar medicamentos usados como tratamientos químicos contra cáncer colorrectal: una descripción general
spellingShingle	Nanoencapsulación y rutas sintéticas para preparar medicamentos usados como tratamientos químicos contra cáncer colorrectal: una descripción general Cáncer Epidemiología Medicamentos Cáncer colorrecta Nanomedicina Nanoencapsulado Quimioterapia Liberación controlada de fármacos
title_short	Nanoencapsulación y rutas sintéticas para preparar medicamentos usados como tratamientos químicos contra cáncer colorrectal: una descripción general
title_full	Nanoencapsulación y rutas sintéticas para preparar medicamentos usados como tratamientos químicos contra cáncer colorrectal: una descripción general
title_fullStr	Nanoencapsulación y rutas sintéticas para preparar medicamentos usados como tratamientos químicos contra cáncer colorrectal: una descripción general
title_full_unstemmed	Nanoencapsulación y rutas sintéticas para preparar medicamentos usados como tratamientos químicos contra cáncer colorrectal: una descripción general
title_sort	Nanoencapsulación y rutas sintéticas para preparar medicamentos usados como tratamientos químicos contra cáncer colorrectal: una descripción general
dc.creator.fl_str_mv	Aguirre Giraldo , Santiago
dc.contributor.advisor.none.fl_str_mv	Rios Vasquez, Luz Amalia
dc.contributor.author.none.fl_str_mv	Aguirre Giraldo , Santiago
dc.contributor.researchgroup.spa.fl_str_mv	Química teórica y bioinformática
dc.subject.lemb.none.fl_str_mv	Cáncer Epidemiología Medicamentos
topic	Cáncer Epidemiología Medicamentos Cáncer colorrecta Nanomedicina Nanoencapsulado Quimioterapia Liberación controlada de fármacos
dc.subject.proposal.spa.fl_str_mv	Cáncer colorrecta Nanomedicina Nanoencapsulado Quimioterapia Liberación controlada de fármacos
description	Ilustraciones, gráficas
publishDate	2021
dc.date.accessioned.none.fl_str_mv	2021-06-29T19:52:43Z
dc.date.available.none.fl_str_mv	2021-06-29T19:52:43Z
dc.date.issued.none.fl_str_mv	2021-10-01
dc.type.spa.fl_str_mv	Trabajo de grado - Maestría
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_bdcc
dc.type.content.spa.fl_str_mv	Text
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/masterThesis
format	http://purl.org/coar/resource_type/c_bdcc
dc.identifier.uri.none.fl_str_mv	https://repositorio.ucaldas.edu.co/handle/ucaldas/16840
dc.identifier.instname.spa.fl_str_mv	Universidad de Caldas
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad de Caldas
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.ucaldas.edu.co/
url	https://repositorio.ucaldas.edu.co/handle/ucaldas/16840 https://repositorio.ucaldas.edu.co/
identifier_str_mv	Universidad de Caldas Repositorio Institucional Universidad de Caldas
dc.language.iso.spa.fl_str_mv	spa
language	spa
dc.relation.references.spa.fl_str_mv	1. Lopart, N. MEDICINAL PLANTS AS A SOURCE OF ANTINEOPLASTIC COMPOUNDS. vol. 16 (2000) 2. Globocan. Cifras y estimaciones de cáncer en el mundo. Instituto Nacional de Cancerología, Colombia. 2018 vol. 380 https://gco.iarc.fr/today/data/factsheets/populations/170-colombia-fact-sheets.pdf (2018). 3. Incidencia, mortalidad y prevalencia de cáncer en Colombia 2007-2011. (2011). 4. Yamamoto, T., Uemura, K., Moriyama, K., Mitamura, K. & Taga, A. Inhibitory effect of maple syrup on the cell growth and invasion of human colorectal cancer cells. Oncol. Rep. 33, 1579–1584 (2015). 5. Di Lena, M., Travaglio, E. & Altomare, D. F. New strategies for colorectal cancer screening. World J. Gastroenterol. 19, 1855– 1860 (2013). 6. Doll, R. & Peto, R. The causes of cancer: Quantitative estimates of avoidable risks of cancer in the united states today. J. Natl. Cancer Inst. 66, 1192–1308 (1981). 7. Cisterna, B. A. et al. Targeted nanoparticles for colorectal cancer. Nanomedicine 11, 2443–2456 (2016). 8. GLOBOCAN. Estimated age-standardized incidence rates (World) in 2018, all cancers, both sexes, all ages. World Heal. Organ. 2018 (2018) 9. Organization, W. H. World health statistics 2018. Mathematics Education Journal vol. 1 http://dx.doi.org/10.1016/j.biotechadv.2010.07.003%0Ahttp://dx.doi.org/10.1016/j.scitotenv.2016.06.080%0Ahttp://dx.doi.org/ 10.1016/j.bbapap.2013.06.007%0Ahttps://www.frontiersin.org/article/10.3389/fmicb.2018.02309/full%0Ahttp://dx.doi.org/10. 1007/s13762- (2018). 10. Globocan Observatory, W. Cancer Today - World. Int. Agency Res. Cancer 876, 2018–2019 (2019) 11. Pardo, C., de Vries, E., Buitrago, L. & Gamboa, O. Atlas de mortalidad por cancer en Colombia. (2017). doi:http://dx.doi.org/10.1007/BF01411734. 12. Pardo, C. & Cendales, R. Cancer incidence estimates and mortality for the top five cancer in Colombia, 2007-2011. Colomb. Med. 49, 16–22 (2018). 13. Gustavsson, B. et al. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin. Colorectal Cancer 14, 1–10 (2015). 14. Henrikson, N. B. et al. Family history and the natural history of colorectal cancer: Systematic review. Genet. Med. 17, 702–712 (2015). 15. ASCO. Cancer Progress Timeline \| ASCO. American Society of Clinical Oncology https://www.asco.org/researchguidelines/cancer-progress-timeline/colorectal-cancer (2018). 16. Mei, H. et al. Fluorine-Containing Drugs Approved by the FDA in 2018. Chem. - A Eur. J. 25, 11797–11819 (2019). 17. Arias, B., García, N., Uribe, T. & Betancur, J. Colorectal Cancer: a clinical, genetic and molecular view. Med. Arch. 13–2, 14 (2013). 18. De Este Número, Í., Revistas, M., Reservados, D. & Number, N. History of rectal cancer and its surgical treatment. Rev. Mex. Coloproctología Mayo-Agosto 11, 60–63 (2005) 19. Lynch, P. M. HISTORY OF NON-POLYPOSIC HEREDITARY COLORECTAL CANCER. Rev. Médica Clínica Las Condes 28, 512–523 (2017) 20. Winawer, S. J. Natural history of colorectal cancer. Am. J. Med. 106, (1999). 21. Seifert, P., Baker, L., Reed, M. & Veitkevicius, K. Comparison of continuously infused 5-fluorouracil with bolus injection in treatment of patients with colorectal adenocarcinoma. Cancer Lett. 123–128 (1975). 22. Greegor, D. H. Diagnosis of Large-Bowel Cancer in the Asymptomatic Patient. JAMA J. Am. Med. Assoc. 201, 943–945 (1967). 23. ASCO. Colorectal Cancer: Types of Treatment \| Cancer.Net. American Society of Clinical Oncology https://www.cancer.net/cancer-types/colorectal-cancer/types-treatment?sectionTitle=Treatment (2019) 24. Hutterer, F. & Pichlmaier, H. Endoscopic Surgery in the Rectum. Endoscopy 31–35 (1985) doi:10.1055/s-2007-1018451. 25. Edwards, B. K. et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 116, 544–573 (2010). 26. Boland, R. et al. A National Cancer Institute Workshop on Microsatellite Instability for Cancer Detection and Familial Predisposition: Development of International Criteria for the Determination of microsatellite Instability in Colorectal Cancer. Cancer Res. 58, 5248–5257 (1998). 27. Saltz, L. et al. Irinotecan Plus Fluorouracil and Leucovorin for Metastatic Colorectal Cancer. Massachusetts Med. Soc. 343, 905–914 (2014). 28. Fernandez, F. G. et al. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann. Surg. 240, 438–450 (2004). 29. Chan, A. et al. Long-term Use of Aspirin and Nonsteroidal Anti-inflamatory Drugs and Risk of Colorectal Cancer. Am. Medican Assoc. 294, 914–923 (2005). 30. André, T. et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J. Clin. Oncol. 27, 3109–3116 (2009). 31. Twelves, C. et al. Capecitabine as adjuvant treatment for stage III colon cancer. N. Engl. J. Med. 352, 2696–2704 (2005). 32. Sauer, R. et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N. Engl. J. Med. 351, 1731–1740 (2004). 33. Nelson, H. et al. A Comparison of Laparoscopically Assisted and Open Colectomy for Colon Cancer. N. Engl. J. Med. 350, 2050–2059 (2004). 34. Hurwitz, H. et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. N. Engl. J. Med. 350, 2335–2342 (2004). 35. Suenaga, M. et al. Predictors of the efficacy of FOLFIRI plus bevacizumab as second-line treatment in metastatic colorectal cancer patients. Surg. Today 41, 1067–1074 (2011) 36. Morton, R. F. & Hammond, E. H. ASCO Provisional Clinical Opinion: KRAS , Cetuximab, and Panitumumab—Clinical Implications in Colorectal Cancer . J. Oncol. Pract. 5, 71–72 (2009). 37. Imperiale, T. F., Ransohoff, D. F., Itzkowitz, S. H., Turnbull, B. A. & Ross, M. E. Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average-risk population. N. Engl. J. Med. 351, 2704–2714 (2004). 38. Bressler, B. et al. Colonoscopic Miss Rates for Right-Sided Colon Cancer : 127, 452–456 (2004). 39. Barclay, R., Vicari, J., Doughty, A., Johanson, J. & Greenlaw, R. Colonoscopic withdrawal times and adenoma detection during screening colonoscopy: Commentary. N. Engl. J. Med. 355, 2533–2541 (2006). 40. Chang, G. J., Rodriguez-Bigas, M. A., Skibber, J. M. & Moyer, V. A. Lymph node evaluation and survival after curative resection of colon cancer: Systematic review. J. Natl. Cancer Inst. 99, 433–441 (2007). 41. Meyerhardt, J. et al. Association of Dietary Patterns With Cancer Recurrence and Survival in Patients With Stage III Colon Cancer. Am. Medican Assoc. 298, 754–764 (2007). 42. Watanabe, T. et al. Molecular Predictors of Survival After Adjuvant Chemotherapy for Colon Cancer. N. Engl. J. Med. 344, 1196–1206 (2001). 43. Soetikno, R. M. et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA - J. Am. Med. Assoc. 299, 1027–1035 (2008). 44. ASCO. The Genetics of Cancer \| Cancer.Net. American Society of Clinical Oncology https://www.cancer.net/navigatingcancer-care/cancer-basics/genetics/genetics-cancer (2018). 45. Poultsides, G. A. et al. Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment. J. Clin. Oncol. 27, 3379–3384 (2009). 46. Crispin, A., Birkner, B., Munte, A., Nusko, G. & Mansmann, U. Process quality and incidence of acute complications in a series of more than 230000 outpatient colonoscopies. Endoscopy 41, 1018–1025 (2009). 47. Van Cutsem, E. et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J. Clin. Oncol. 30, 1–9 (2012). 48. Tejpar, S. et al. Prognostic and predictive relevance of primary tumor location in patients with ras wild-type metastatic colorectal cancer retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 3, E1–E8 (2016) 49. Erlandsson, J. et al. Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. Lancet Oncol. 18, 1–11 (2017). 50. Grothey, A. et al. Duration of adjuvant chemotherapy for stage III colon cancer. N. Engl. J. Med. 378, 1177–1188 (2018). 51. Hagos, G. K. et al. Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo. Mol. Cancer Ther. 6, 2230–2239 (2007). 52. ESMO. Patient Guide with colorectal cancer (ESMO). (2016). 53. NCCN. Colon Cancer NCCN Guidelines for Patients. Natiinal Compr. Cancer Netw. 86 (2018). 54. NCCN Colon Cancer Panel. NCCN Clinical Practice Guidelines in Oncology: colon cancer. V2.2015. Natl. Compr. Cancer Netw. 1, 1–132 (2015). 55. Zhang, R., Song, X. Q., Liu, R. P., Ma, Z. Y. & Xu, J. Y. Fuplatin: An Efficient and Low-Toxic Dual-Prodrug. J. Med. Chem. 62, 4543–4554 (2019). 56. Inés Castro Núñez, Eduardo Echarri Arrieta, F. F. L. MEDICAMENTOS CITOSTÁTICOS Sociedad Española de Farmacéuticos de Hospitales. RAÍZ, TG., S.L. Gamonal, 19. 28031 (MADRID) vol. 4a Edición (2003). 57. Ota, Y., Nakamura, A., Elboray, E. E., Itoh, Y. & Suzuki, T. Design, synthesis, and biological evaluation of a conjugate of 5- fluorouracil and an LSD1 inhibitor. Chem. Pharm. Bull. 67, 192–195 (2019). 58. Ducreux, M. et al. Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma. Ann. Oncol. 13, 1192–1196 (2002). 59. Perkhofer, L. et al. Nal-IRI with 5-fluorouracil (5-FU) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - The NIFE trial (AIO-YMO HEP-0315) an open label, non-comparative, randomized, multicenter phase II study. BMC Cancer 19, 1–7 (2019). 60. Benson, A. B. et al. NCCN Guidelines ® Insights Colon Cancer, Version 2.2018 Featured Updates to the NCCN Guidelines. JNCCN J. Natl. Compr. Cancer Netw. 16, 359–369 (2018) 61. Glynne-Jones, R. et al. Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 25, 10–20 (2014). 62. Mohammadian, M., Zeynali, S., Azarbaijani, A. F., Khadem Ansari, M. H. & Kheradmand, F. Cytotoxic effects of the newlydeveloped chemotherapeutic agents 17-AAG in combination with oxaliplatin and capecitabine in colorectal cancer cell lines. Res. Pharm. Sci. 12, 517–525 (2017). 63. Di Desidero, T. et al. Pharmacokinetic analysis of metronomic capecitabine in refractory metastatic colorectal cancer patients. Invest. New Drugs 36, 709–714 (2018). 64. Müller, V. et al. Quality of life under capecitabine (Xeloda®) in patients with metastatic breast cancer: Data from a German non-interventional surveillance study. Oncol. Res. Treat. 37, 748–755 (2014). 65. Broto, M., McCabe, R., Galve, R. & Marco, M. P. A high throughput immunoassay for the therapeutic drug monitoring of tegafur. Analyst 142, 2404–2410 (2017). 66. Li, W. et al. Maintenance treatment of Uracil and Tegafur (UFT) in responders following first-line fluorouracil-based chemotherapy in metastatic gastric cancer: A randomized phase II study. Oncotarget 8, 37826–37834 (2017). 67. Peeters, M., Cervantes, A., Moreno Vera, S. & Taieb, J. Trifluridine/tipiracil: An emerging strategy for the management of gastrointestinal cancers. Futur. Oncol. 14, 1629–1645 (2018). 68. Side Effects of Lonsurf (Trifluridine and Tipiracil Tablets), Warnings, Uses. https://www.rxlist.com/lonsurf-side-effects-drugcenter.htm. 69. Orlandi, P. et al. Pharmacological effects of the simultaneous and sequential combinations of trifluridine/tipiracil (TAS-102) and 5-fluorouracil in fluoropyrimidine-sensitive colon cancer cells. Invest. New Drugs 38, 92–98 (2020). 70. Trifluridine / tipiracil (Lonsurf) for metastatic colorectal cancer: Overview. (2016). 71. Kitada, N. et al. Factors affecting sensitivity to antitumor platinum derivatives of human colorectal tumor cell lines. Cancer Chemother. Pharmacol. 62, 577–584 (2008). 72. Paraskar, A., Soni, S., Roy, B., Papa, A. & Sengupta, S. Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy. Nanotechnology 23, 1–17 (2012). 73. Grothey, A. & Goldberg, R. M. A review of oxaliplatin and its clinical use in colorectal cancer. Expert Opin. Pharmacother. 5, 2159–2170 (2004). 74. Rubiano, J. A., Garrido, A. & Castillo, J. S. Uso de bevacizumab en pacientes con cáncer de colon metastásico en el Instituto Nacional de Cancerología: una serie de casos. Rev. Colomb. Cancerol. 16, 227–233 (2012). 75. Conroy, T. et al. Quality-of-life findings from a randomised phase-III study of XELOX vs FOLFOX-6 in metastatic colorectal cancer. Br. J. Cancer 102, 59–67 (2010) 76. Jeremic, B., Acimovic, L. & Mijatovic, L. Carboplatin and etoposide in advanced colorectal carcinoma. A phase II study. Cancer 71, 2706–2708 (1993). 77. Harrington, S. E. & Smith, T. J. Role of Chemotherapy at the End of life. JAMA - J. Am. Med. Assoc. 299, 1–22 (2008) 78. Saber, M. M., Al-mahallawi, A. M., Nassar, N. N., Stork, B. & Shouman, S. A. Targeting colorectal cancer cell metabolism through development of cisplatin and metformin nano-cubosomes. BMC Cancer 18, 1–11 (2018). 79. De Jongh, F. E. et al. Weekly high-dose cisplatin is a feasible treatment option: Analysis on prognostic factors for toxicity in 400 patients. Br. J. Cancer 88, 1199–1206 (2003) 80. Kaku, Y., Tsuchiya, A., Kanno, T. & Nishizaki, T. Irinotecan induces cell cycle arrest, but not apoptosis or necrosis, in Caco-2 and CW2 colorectal cancer cell lines. Pharmacology 95, 154–159 (2015). 81. Irinotecan (Campto) \| Cancer information \| Cancer Research UK. https://www.cancerresearchuk.org/about-cancer/cancer-ingeneral/treatment/cancer-drugs/drugs/irinotecan 82. Ikehata, M. et al. Different effects of epigenetic modifiers on the cytotoxicity induced by 5-fluorouracil, irinotecan or oxaliplatin in colon cancer cells. Biol. Pharm. Bull. 37, 67–73 (2014). 83. Starling, N., Tilden, D., White, J. & Cunningham, D. Cost-effectiveness analysis of cetuximab/irinotecan vs active/best supportive care for the treatment of metastatic colorectal cancer patients who have failed previous chemotherapy treatment. Br. J. Cancer 96, 206–212 (2007). 84. Hare, J. I. et al. Treatment of Colorectal Cancer Using a Combination of Liposomal Irinotecan (Irinophore CTM) and 5- Fluorouracil. PLoS One 8, (2013). 85. Hegde, V. S. & Nagalli, S. Leucovorin. StatPearls (StatPearls Publishing, 2020) 86. Folinic Acid - Drug Information - Chemocare. http://chemocare.com/chemotherapy/drug-info/folinic-acid.aspx. 87. Tsukihara, H., Tsunekuni, K. & Takechi, T. Folic acid-metabolizing enzymes regulate the antitumor effect of 5-fluoro-2′- deoxyuridine in colorectal cancer cell lines. PLoS One 11, 1–10 (2016). 88. Zoetemelk, M., Ramzy, G. M. & Rausch, M. Folinic Acid and Oxaliplatin and Its Activity in. (2020). 89. Pectasides, D. et al. Oxaliplatin plus high-dose leucovorin and 5-fluorouracil in pretreated advanced breast cancer: A phase II study. Ann. Oncol. 14, 537–542 (2003). 90. Wei, N., Chu, E., Wu, S. yu, Wipf, P. & Schmitz, J. C. The cytotoxic effects of regorafenib in combination with protein kinase D inhibition in human colorectal cancer cells. Oncotarget 6, 4745–4756 (2015). 91. Regorafenib. Metastatic colorectal cancer in treatment failure: may prolong survival by a few weeks - PubMed. https://pubmed.ncbi.nlm.nih.gov/24516902/. 92. Dennert, G. & Horneber, M. Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients. Cochrane Database Syst. Rev. 2017, (2006). 93. Gandin, V., Khalkar, P., Braude, J. & Fernandes, A. P. Organic selenium compounds as potential chemotherapeutic agents for improved cancer treatment. Free Radic. Biol. Med. 127, 80–97 (2018). 94. Cao, S., Durrani, F. A., Rustum, Y. M. & Yu, Y. E. Ugt1a is required for the protective effect of selenium against irinotecaninduced toxicity. Cancer Chemother. Pharmacol. 69, 1107–1111 (2012). 95. Romano, B., Font, M., Encío, I., Palop, J. A. & Sanmartín, C. Synthesis and antiproliferative activity of novel methylselenocarbamates. Eur. J. Med. Chem. 83, 674–684 (2014). 96. Jardim, G. A. M. et al. Synthesis of selenium-quinone hybrid compounds with potential antitumor activity via Rh-Catalyzed CH bond activation and click reactions. Molecules 23, (2018). 97. He, J. et al. Inhibition of thioredoxin reductase by a novel series of bis-1,2-benzisoselenazol-3(2H)-ones: Organoselenium compounds for cancer therapy. Bioorganic Med. Chem. 20, 3816–3827 (2012). 98. Iqbal, M. A. et al. Green synthesis of mono- and di-selenium-N-heterocyclic carbene adducts: Characterizations, crystal structures and pro-apoptotic activities against human colorectal cancer. J. Organomet. Chem. 801, 130–138 (2016). 99. Haque, R. A. et al. Synthesis, structure, anticancer, and antioxidant activity of para-xylyl linked bis-benzimidazolium salts and respective dinuclear Ag(I) N-heterocyclic carbene complexes (Part-II). Med. Chem. Res. 22, 4663–4676 (2013). 100. Haque, R. A., Iqbal, M. A., Khadeer Ahamed, M. B., Majid, A. M. S. A. & Abdul Hameed, Z. A. Design, synthesis and structural studies of meta-xylyl linked bis-benzimidazolium salts: Potential anticancer agents against ‘human colon cancer’. Chem. Cent. J. 6, (2012). 101. Plano, D. et al. Design, Synthesis, and Biological Evaluation of Novel Selenium (Se-NSAID) Molecules as Anticancer Agents. J. Med. Chem. 59, 1946–1959 (2016). 102. Avendaño, C. & Menéndez, C. Medicinal Chemistry of Anticancer Drugs. (2008) 103. A new route to the synthesis of 5-Fluorouracil. J. Fluor. Chem. 58, 99–104 (1989). 104. Carda, M. Synthetic Methodology Applied to Drug Synthesis. (2016). 105. organic-chemistry. Biginelli Reaction. https://www.organic-chemistry.org/namedreactions/biginelli-reaction.shtm. 106. In, K. I. N., No, H. & Nagar, N. L. B. Wo 2010/065586 a2. 2, (2010). 107. Smart, K. F., Aggio, R. B. M., Van Houtte, J. R. & Villas-Bôas, S. G. Analytical platform for metabolome analysis of microbial cells using methyl chloroformate derivatization followed by gas chromatography-mass spectrometry. Nat. Protoc. 5, 1709– 1729 (2010). 108. Zasada, A., Mironiuk-Puchalska, E. & Koszytkowska-Stawińska, M. Synthesis of Tegafur by the Alkylation of 5-Fluorouracil under the Lewis Acid and Metal Salt-Free Conditions. Org. Process Res. Dev. 21, 885–889 (2017). 109. Zasada, A., Puchalska, E. & Stawinska, M. Synthesis of tegafur by alkylation of 5-fluorouracil under the Lewis acid-and metal salt-free conditions. http://www.forsanelhaq.com/showthread.php?t=151497. 110. Kobayashi, Y., Kumadaki, I. & Yamamoto, K. Simple synthesis of trifluoromethylated pyrimidine nucleosides. J. Chem. Chem. Commun. 536–537 (1977) doi:10.1039/C39770000536. 111. Patent - synthesis of trifluridine.pdf. (2012). 112. ELSEVIER. Organofluorine Pharmaceuticals. Organofluorine Compounds in Biology and Medicine (2015). doi:10.1016/b978-0-444-53748-5.00005-8 113. Suzuki, N., Ito, M. & Takechi, T. Discovery and Development of Trifluridine / Tipiracil. 3, 417–441 (2018) 114. Application, I., Under, P., Patent, T. H. E. & Treaty, C. Wo 2019/002407. vol. 1 (2019). 115. Allen, H. R., Maxson, R. N., Booth, H. S. & Herrmann, C. V. Sulfuryl Chloride. Org. Synth. 1, 114–117 (2007). 116. Habala, L. et al. Synthesis and structure-activity relationships of mono- and dialkyl-substituted oxaliplatin derivatives. Eur. J. Med. Chem. 40, 1149–1155 (2005). 117. Galanski, M. et al. Synthesis, crystal structure and cytotoxicity of new oxaliplatin analogues indicating that improvement of anticancer activity is still possible. Eur. J. Med. Chem. 39, 707–714 (2004). 118. Avendaño, C. & Menéndez, J. C. Medicinal Chemistry of Anticancer Drugs. Medicinal Chemistry of Anticancer Drugs (2008). doi:10.1016/B978-0-444-52824-7.X0001-7. 119. Wilson, J. J. & Lippard, S. J. Synthetic methods for the preparation of platinum anticancer complexes. Chem. Rev. 114, 4470– 4495 (2014). 120. Kawamura, K. et al. Synthesis, metabolite analysis, and in vivo evaluation of [11C]irinotecan as a novel positron emission tomography (PET) probe. Nucl. Med. Biol. 40, 651–657 (2013) 121. Martino, E. et al. The long story of camptothecin: From traditional medicine to drugs. Bioorganic Med. Chem. Lett. 27, 701– 707 (2017). 122. Felder, A. United States Patent [19]. (1998) 123. Zakrzewski, S. & Sansone, A. Preparation of Folinic Acid. J. Chem. Inf. Model. 53, 1689–1699 (2013). 124. Francese, G., Corana, F., Meneghetti, O. & Marazza, F. LC-MS characterization of trace impurities contained in calcium folinate. J. Pharm. Biomed. Anal. 39, 757–763 (2005). 125. Forsch, R. A., Rosowsky, A. & Wan, P. A new ine-step synthesis of Leucovorin from Folic Acid and of 5-formyl-5,6,7,8- tetrahydrohomofolic acid from Homofolic Acid using Dimethylamine-Norane in Formic Acid. 2582–2583 (1985) 126. Xiaochao, G. et al. Degradation of folic acid wastewater by electro-Fenton with three-dimensional electrode and its kinetic study. R. Soc. Open Sci. 5, 170926 (2018). 127. Wang, L. M. et al. An efficient and high-yielding protocol for the production of Regorafenib via a new synthetic strategy. Res. Chem. Intermed. 42, 3209–3218 (2016) 128. Du, F. et al. A new pathway via intermediate 4-amino-3-fluorophenol for the synthesis of regorafenib. Synth. Commun. 49, 576–586 (2019). 129. Czakó, B. & Kurti, L. Strategic Applications of Named Reactions in Organic Synthesis. Elsevier Academic Press vol. 1 (2005). 130. Koch, T. & Buchardt, O. Synthesis of L-(+)-Selenomethionine. Res. Cent. Med. Biotechnol. (1993). 131. Kogami, M. & Koketsu, M. An efficient method for the synthesis of selenium modified nucleosides: its application in the synthesis of Se-adenosyl-l-selenomethionine (SeAM). Org. Biomol. Chem. 13, 9405–9417 (2015). 132. Block, E. et al. Identification and synthesis of a novel selenium-sulfur amino acid found in selenized yeast: Rapid indirect detection NMR methods for characterizing low-level organoselenium compounds in complex matrices. J. Agric. Food Chem. 52, 3761–3771 (2004). 133. Plenevaux, A., Cantineau, R., Guillaume, M., Christiaens, L. & Tihange, G. Fast chemical synthesis of [Se]Lselenomethionine. Int. J. Radiat. Appl. Instrumentation. Part 38, 59–61 (1987). 134. Zhou, Z. S., Smith, A. E. & Matthews, R. G. L-selenohomocysteine: One-step synthesis from L-selenomethionine and kinetic analysis as substrate for methionine synthases. Bioorganic Med. Chem. Lett. 10, 2471–2475 (2000). 135. Iwaoka, M., Ooka, R., Nakazato, T., Yoshida, S. & Oishi, S. Synthesis of selenocysteine and selenomethionine derivatives from sulfur-containing amino acids. Chem. Biodivers. 5, 359–374 (2008). 136. Lim, D., Gründemann, D. & Seebeck, F. P. Total Synthesis and Functional Characterization of Selenoneine. Angew. Chemie 131, 15168–15172 (2019) 137. Shaaban, S. et al. Novel peptidomimetic compounds containing redox active chalcogens and quinones as potential anticancer agents. Eur. J. Med. Chem. 58, 192–205 (2012). 138. Cieza, L. Reacciones click: Síntesis de fármacos para el tratamiento del cáncer de mama. (2015) 139. Ibáñez, E. et al. Synthesis and antiproliferative activity of novel symmetrical alkylthio- and alkylseleno-imidocarbamates. Eur. J. Med. Chem. 46, 265–274 (2011). 140. Begini, F. et al. Continuous flow synthesis of 2,2′-diselenobis(benzoic acid) and derivatives. React. Chem. Eng. 5, 641–644 (2020). 141. Krasowska, D., Iraci, N., Santi, C., Drabowicz, J. & Cieslak, M. Diselenides and Benzisoselenazoles as Antiproliferative Agents and Glutathione-S-Transferase Inhibitors. Molecules 1–19 (2014). 142. Krasowska, D. et al. Ultrasound-assisted synthesis of alkali metals diselenides (M2Se2) and their application for the gram-scale preparation of 2,2’-diselenobis(benzoic acid). Arkivoc 2019, 24–37 (2019). 143. Liu, L. et al. Synthesis of NSAIDs–Se derivatives as potent anticancer agents. Med. Chem. Res. 27, 2071–2078 (2018) 144. Ravera, M. et al. Antiproliferative activity of Pt(IV) conjugates containing the non-steroidal anti-inflammatory drugs (NSAIDs) Ketoprofen and Naproxen. Int. J. Mol. Sci. 20, 1–18 (2019). 145. Hoshyar, N., Gray, S., Han, H. & Bao, G. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine 11, 673–692 (2016). 146. Hillaireau, H. & Couvreur, P. Nanocarriers’ entry into the cell: Relevance to drug delivery. Cell. Mol. Life Sci. 66, 2873–2896 (2009). 147. Tran, S., DeGiovanni, P.-J., Piel, B. & Rai, P. Cancer nanomedicine: a review of recent success in drug delivery. Clin Trans Med 6, 1–21 (2017). 148. Patra, J. K. et al. Nano based drug delivery systems: Recent developments and future prospects 10 Technology 1007 Nanotechnology 03 Chemical Sciences 0306 Physical Chemistry (incl. Structural) 03 Chemical Sciences 0303 Macromolecular and Materials Chemistry 11 Medical and He. J. Nanobiotechnology 16, 1–33 (2018). 149. Sahoo, S. K. & Labhasetwar, V. Nanotech approaches to drug delivery and imaging. Drug Discov. Today 8, 1112–1120 (2003) 150. Panchagnula, R. & Thomas, N. S. Biopharmaceutics and pharmacokinetics in drug research. Int. J. Pharm. 201, 131–150 (2000). 151. Jayaraman, M. et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chemie - Int. Ed. 51, 8529–8533 (2012). 152. Aljuffali, I., Huang, C.-H. & Fang, J.-Y. Nanomedical Strategies for Targeting Skin Microbiomes. Curr. Drug Metab. 16, 255– 271 (2015). 153. Tran, S., DeGiovanni, P.-J., Piel, B. & Rai, P. Cancer nanomedicine: a review of recent success in drug delivery. Clin. Transl. Med. 6, 0–21 (2017). 154. Witika, B. A. et al. Biocompatibility of Biomaterials for Nanoencapsulation: Current Approaches. Nanomaterials 10, 1649 (2020). 155. Naahidi, S. et al. Biocompatibility of engineered nanoparticles for drug delivery. J. Control. Release 166, 182–194 (2013). 156. Kohane, D. S. & Langer, R. Biocompatibility and drug delivery systems. Chem. Sci. 1, 441–446 (2010). 157. Oropesa, R. & Jáuregui, U. Las nanopartículas como portadores de fármacos: características y perspectivas Nanoparticles as drug carriers : characteristics and perspectives. CENIC Ciebcias Biológicas 43, (2012). 158. Williams, H. D. et al. Strategies to Address Low Drug Solubility in Discovery and Development. Pharmacol. Rev. 65, 315–499 (2013). 159. Zafar, N., Bashir, I., Alvi, N. & Sajid, M. I. Structural components of liposomes and characterization tools. Indo Am. J. Pharm. Res. 4, 3559–3567 (2014). 160. Balzola, A. NUEVOS VECTORES EN LA APLICACIÓN VÍA TÓPICA DE MEDICAMENTOS. LIPOSOMAS (I). (2018). 161. Paul, M. et al. Physicochemical characteristics of pentamidine-loaded polymethacrylate nanoparticles: Implication in the intracellular drug release in Leishmania major infected mice. J. Drug Target. 5, 481–490 (1998). 162. Margaroni, M. et al. PLGA nanoparticles modified with a TNFα mimicking peptide, soluble Leishmania antigens and MPLA induce T cell priming in vitro via dendritic cell functional differentiation. Eur. J. Pharm. Biopharm. 105, 18–31 (2016). 163. Fernandez, M. Desarrollo de una formulacion oral de Yoduro de N-yodometil-N,N-dimetil-N-(6,6-difenilhex-5-en-1-il) amonio para el tratamiento de la Leishmaniasis Cutánea. (Universidad de Antioquia, 2017). 164. Danhier, F. et al. PLGA-based nanoparticles: An overview of biomedical applications. J. Control. Release 161, 505–522 (2012). 165. Want, M. Y. et al. A new approach for the delivery of artemisinin: Formulation, characterization, and ex-vivo antileishmanial studies. J. Colloid Interface Sci. 432, 258–269 (2014). 166. Santos, I., Ponte, B., Boonme, P., Silva, A. & Souto, E. Nanoencapsulation of polyphenols for protective effect against colon– rectal cancer. Soc. Sci. China 33, 149–156 (2012). 167. Vasir, J. & Labhasetwar, V. Polymeric nanoparticles for gene delivery. Polym. Nanomater. Gene Ther. 3, 325–344 (2006). 168. JANI, P., HALBERT, G. W., LANGRIDGE, J. & FLORENCE, A. T. Nanoparticle Uptake by the Rat Gastrointestinal Mucosa: Quantitation and Particle Size Dependency. J. Pharm. Pharmacol. 42, 821–826 (1990). 169. Makadia, H. & Siegel, S. Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. Polym. 3, 1377–1397 (2011). 170. Schwarz, C. & Mehnert, W. Solid lipid nanoparticles (SLN) for controlled drug delivery. II. Drug incorporation and physicochemical characterization. J. Control. Release 16, 83–96 (1994). 171. Geszke-Moritz, M. & Moritz, M. Solid lipid nanoparticles as attractive drug vehicles: Composition, properties and therapeutic strategies. Mater. Sci. Eng. C 68, 982–994 (2016). 172. Qiu, Y. Understanding Drug Properties in Formulation and Process Design of Solid Oral Products. J. Valid. Technol. 74–84 (2010). 173. Liu, X., Testa, B. & Fahr, A. Lipophilicity and its relationship with passive drug permeation. Pharm. Res. 28, 962–977 (2011). 174. Gonçalves, L. M. D. et al. Development of solid lipid nanoparticles as carriers for improving oral bioavailability of glibenclamide. Eur. J. Pharm. Biopharm. 102, 41–50 (2016). 175. Li, X. et al. Nano carriers for drug transport across the blood–brain barrier. J. Drug Target. 25, 17–28 (2017). 176. Porter, C. J. H., Trevaskis, N. L. & Charman, W. N. Lipids and lipid-based formulations: Optimizing the oral delivery of lipophilic drugs. Nat. Rev. Drug Discov. 6, 231–248 (2007). 177. Fonseca-santos, B., Daflon, M. & Chorilli, M. Nanotechnology-based drug delivery systems for the treatment of Alzheimer ’ s disease. Int. J. Nanomedicine 10, 4981–5003 (2015). 178. Huang, J. R., Lee, M. H., Li, W. S. & Wu, H. C. Liposomal irinotecan for treatment of colorectal cancer in a preclinical model. Cancers (Basel). 11, 1–19 (2019). 179. Iqbal, S., Jubeen, F. & Sher, F. Future of 5-Fluorouracil in Cancer Therapeutics, Current Pharmacokinetics Issues and a Way Forward. J. Cancer Res. Pract. 6, 155–161 (2020) 180. Haggag, Y. A. et al. Polymeric nano-encapsulation of 5-fluorouracil enhances anti-cancer activity and ameliorates side effects in solid Ehrlich Carcinoma-bearing mice. Biomed. Pharmacother. 105, 215–224 (2018) 181. Kumar, G. V., Nair, L., Sankar, J. & Nair, S. A. Biological evaluation of 5-fluorouracil nanoparticles for cancer chemotherapy and its dependence on the carrier, PLGA. Int. J. Nanomedicine 1685 (2011) doi:10.2147/ijn.s20165. 182. Rajpoot, K. & Jain, S. K. Colorectal cancer-targeted delivery of oxaliplatin via folic acid-grafted solid lipid nanoparticles: preparation, optimization, and in vitro evaluation. Artif. Cells, Nanomedicine Biotechnol. 46, 1–12 (2017). 183. Zhang, W. et al. Nanostructured lipid carrier surface modified with Eudragit RS 100 and its potential ophthalmic functions. Int. J. Nanomedicine 9, 4305–4315 (2014). 184. Jain, A., Jain, S. K., Ganesh, N., Barve, J. & Beg, A. M. Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer. Nanomedicine Nanotechnology, Biol. Med. 6, 179–190 (2010). 185. Yassin, A. E. B. et al. Optimization of 5-fluorouracil solid-lipid nanoparticles: A preliminary study to treat colon cancer. Int. J. Med. Sci. 7, 398–408 (2010).
dc.rights.coar.fl_str_mv	http://purl.org/coar/access_right/c_14cb
dc.rights.accessrights.spa.fl_str_mv	info:eu-repo/semantics/closedAccess
eu_rights_str_mv	closedAccess
rights_invalid_str_mv	http://purl.org/coar/access_right/c_14cb
dc.format.mimetype.spa.fl_str_mv	application/pdf
dc.publisher.faculty.spa.fl_str_mv	Facultad de Ciencias Exactas y Naturales
dc.publisher.place.spa.fl_str_mv	Manizales, Caldas, Colombia
dc.publisher.program.spa.fl_str_mv	Maestría en Química
institution	Universidad de Caldas
bitstream.url.fl_str_mv	https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/1/Santiago%20_%20Aguirre%20Giraldo%20_2021.pdf https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/2/ACTA%20SUSTENTACI%c3%93N%20SANTIAGO%20AGUIRRE.docx%20%281%29.pdf https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/3/carta-autorizacion-publicacion-contenidos-repositorioinstitucional-Santiago%20Aguirre%20Giraldo.pdf https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/4/license.txt https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/5/Santiago%20_%20Aguirre%20Giraldo%20_2021.pdf.txt https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/7/ACTA%20SUSTENTACI%c3%93N%20SANTIAGO%20AGUIRRE.docx%20%281%29.pdf.txt https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/9/carta-autorizacion-publicacion-contenidos-repositorioinstitucional-Santiago%20Aguirre%20Giraldo.pdf.txt https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/6/Santiago%20_%20Aguirre%20Giraldo%20_2021.pdf.jpg https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/8/ACTA%20SUSTENTACI%c3%93N%20SANTIAGO%20AGUIRRE.docx%20%281%29.pdf.jpg https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/10/carta-autorizacion-publicacion-contenidos-repositorioinstitucional-Santiago%20Aguirre%20Giraldo.pdf.jpg
bitstream.checksum.fl_str_mv	5ae4de4018e09a762de02fbc7032dada 83fed40081ba0162898b94451e15002b 63f463f38adf8f36df6bb69fade9f1b3 2f9959eaf5b71fae44bbf9ec84150c7a 4f85351bf2eb63fd119bf532ba8031af e0159104faaefa588461339e416339ba d07e82e76661e102d5f400f5a13635b1 00917db91f860667b14ad65ad5e847cb 91fed43882af6009b9693772098de47b f06ee68d17d9590e9cb8569afd72f5f5
bitstream.checksumAlgorithm.fl_str_mv	MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5
repository.name.fl_str_mv	Repositorio Digital de la Universidad de Caldas
repository.mail.fl_str_mv	bdigital@metabiblioteca.com
_version_	1800535444374421504
spelling	Rios Vasquez, Luz Amalia3a5d1a8e172b3a023b10a5da7c455d95Aguirre Giraldo , Santiagoa3085fd4640bc97fbc4a9fc4da353d1cQuímica teórica y bioinformática2021-06-29T19:52:43Z2021-06-29T19:52:43Z2021-10-01https://repositorio.ucaldas.edu.co/handle/ucaldas/16840Universidad de CaldasRepositorio Institucional Universidad de Caldashttps://repositorio.ucaldas.edu.co/Ilustraciones, gráficasspa: El cáncer ha sido, según la Organización Mundial de la Salud (OMS), una de las causas más destacadas de morbilidad y mortalidad en todo el mundo, se estima que la tasa mundial de cáncer aumentó a 18,1 millones de nuevos casos y 9,6 millones de muertes en 2018. El cáncer colorrectal (CCR) según la “National Comprehensive Cancer Network –NCCN-” ocupa, con respecto al número de nuevos casos y la probabilidad en todo el mundo en ambos sexos, el cuarto grado en incidencia y el tercero en prevalencia respectivamente. El cáncer es la segunda causa de muerte a nivel mundial después de las enfermedades cardiovasculares y es responsable de una por cada 8 muertes en el mundo por encima, inclusive del SIDA, la tuberculosis y la malaria en su conjunto. En Colombia, según “New Global Cancer Data: GLOBOCAN 2018” el CCR ocupa el quinto lugar con una incidencia del 5,6% y una mortalidad del 7,4%. El cáncer es una enfermedad de un nivel de complejidad alto, debido a que puede promover la proliferación y la invasión de las distintas células del organismo a través del ciclo celular hiperactivo que da lugar a un incremento de la división celular. Para el tratamiento del cáncer en cualquier fase se incluyen la quimioterapia, la radioterapia, la inmunoterapia, la cirugía, y las terapias dirigidas a moléculas asociadas al cáncer. El cáncer colorrectal, comúnmente conocido como cáncer de colon o cáncer de intestino, es un cáncer de crecimiento celular descontrolado en el colon, el recto (partes del intestino grueso) o el apéndice. Los cánceres colorrectales se extienden más comúnmente a los ganglios linfáticos locales antes de viajar a órganos distantes. En este trabajo se exponen los siguientes medicamentos los cuales se encontró que son los más comúnmente usados como tratamientos químicos contra el cáncer colorrectal, así mismo la ruta sintética más eficiente, reportada en la literatura para su preparación: i) 5–fluorouracilo (5FU), ii) tegafur, iii) capecitabina, iv) trifluridina y tipiracilo, v) oxaliplatino, vi) carboplatino, vii) cisplatino, iv) irinotecan, v) leucovorina, vi) regorafenib y vii) compuestos derivados de selenio. De otra parte, la nanoencapsulación de medicamentos permite mejorar aspectos fisicoquímicos de los fármacos que han sido aprobados para el tratamiento de enfermedades como el cáncer, siendo estos aspectos los siguientes: baja solubilidad en agua, la elevada toxicidad, la poca biodisponibilidad, el perfil farmacocinético, la seguridad y la biocompatibilidad del medicamento; mejorando la focalización del medicamento a sitios específicos del cuerpo. Por esto, actualmente se han presentado grandes avances en esta rama de la medicina, siendo esta una solución factible a los aspectos mencionados. Debido a la importancia de la nanoencapsulación cada vez se reportan nuevos tipos de nanopartículas, y entre éstas las más relevantes son: nanopartículas poliméricas, nanopartículas de lípidos sólidos y liposomas. Es así, como en este trabajo se exponen los reportes sobre la nanoencapsulación polimérica (formulación PLGA–PEG) del 5–fluorouracilo (5-FU), el uso de nanopartículas de lípidos sólidos cargadas con oxaliplatino y el irinotecan en su forma liposomal. Finalmente, mediante este trabajo de revisión de la literatura sobre la temática expuesta anteriormente es necesario resaltar que fue posible concluir que la búsqueda de nuevos medicamentos terapéuticos innovadores que permitan combatir el cáncer colorrectal, es un importante reto en la actualidad, mediante su preparación a través de nuevas rutas sintéticas que sean más cortas, con mejores rendimientos globales y con el uso de reactivos disponibles comercialmente, de bajo costo y que no contaminen el medio ambiente. Además, la nanoencapsulación es una alternativa importante para focalizar el medicamento hacia el sitio activo y disminuir los efectos secundarios de los tratamientos disponibles contra el CCR.eng: Cancer has been, according to the World Health Organization (WHO), one of the most prominent causes of morbidity and mortality worldwide, it is estimated that the global rate of cancer increased to 18.1 million new cases and 9 , 6 million deaths in 2018. Colorectal cancer (CRC) according to the "National Comprehensive Cancer Network -NCCN-" occupies, with respect to the number of new cases and the probability worldwide in both sexes, the fourth degree in incidence and the third in prevalence respectively. Cancer is the second leading cause of death worldwide after cardiovascular diseases and is responsible for one in every 8 deaths in the world above, including AIDS, tuberculosis and malaria as a whole. In Colombia, according to “New Global Cancer Data: GLOBOCAN 2018”, the CRC ranks fifth with an incidence of 5.6% and a mortality of 7.4%. Cancer is a disease of a high level of complexity, because it can promote the proliferation and invasion of the different cells of the body through the overactive cell cycle that leads to an increase in cell division. Cancer treatment at any stage includes chemotherapy, radiation therapy, immunotherapy, surgery, and therapies targeting cancer-associated molecules. Colorectal cancer, commonly known as colon cancer or bowel cancer, is cancer of uncontrolled cell growth in the colon, rectum (parts of the large intestine), or appendix. Colorectal cancers most commonly spread to local lymph nodes before traveling to distant organs. In this work, the following drugs are exposed, which were found to be the most commonly used as chemical treatments against colorectal cancer, as well as the most efficient synthetic route, reported in the literature for their preparation: i) 5-fluorouracil (5FU) , ii) tegafur, iii) capecitabine, iv) trifluridine and tipiracil, v) oxaliplatin, vi) carboplatin, vii) cisplatin, iv) irinotecan, v) leucovorin, vi) regorafenib and vii) compounds derived from selenium. On the other hand, nanoencapsulation of drugs makes it possible to improve physicochemical aspects of drugs that have been approved for the treatment of diseases such as cancer, these aspects being the following: low solubility in water, high toxicity, low bioavailability, pharmacokinetic profile , the safety and biocompatibility of the drug; improving drug targeting to specific body sites For this reason, great advances have now been made in this branch of medicine, this being a feasible solution to the aforementioned aspects. Due to the importance of nanoencapsulation, new types of nanoparticles are increasingly being reported, and among these the most relevant are: polymeric nanoparticles, solid lipid nanoparticles and liposomes. Thus, as in this work reports on polymeric nanoencapsulation (PLGA-PEG formulation) of 5-fluorouracil (5-FU), the use of solid lipid nanoparticles loaded with oxaliplatin and irinotecan in its liposomal form are exposed. Finally, through this work to review the literature on the subject discussed above, it is necessary to highlight that it was possible to conclude that the search for new innovative therapeutic drugs that allow fighting colorectal cancer is an important challenge today, through its preparation through of new synthetic routes that are shorter, with better overall yields and with the use of commercially available, low-cost reagents that do not pollute the environment. Furthermore, nanoencapsulation is an important alternative for targeting the drug to the active site and reducing the side effects of available CRC treatments.Índice de figuras / Índice de esquemas/ Índice de tablas/ Abreviaturas/ 1. Resumen / 2. Objetivos/ 2.1 Objetivo general / 2.2 Objetivos específicos/ 3. Resultados / Capítulo I. Generalidades, historia y tratamientos químicos más utilizados contra en cáncer colorrectal/ 3.1 Generalidades del cáncer colorrectal/ 3.1.1 Descripción y causas del cáncer colorrectal/ 3.1.2 Estadios del cáncer colorrectal / 3.1.3 Epidemiología del cáncer colorrectal/.2 Historia del cáncer colorrectal / 3.3 Tratamientos químicos para el cáncer colorrectal/ 3.3.1 Quimioterapia del cáncer colorrectal/ 3.3.1.1 Derivados de pirimidinas (fluoropirimidinas con excepción del tipiracilo) / 3.3.1.2 Derivados de platino/ 3.3.1.3 Irinotecan: derivado de camptotecina/ 3.3.1.4 Leucovorina: un alcaloide de vinca / 3.3.1.5 Regorafenib: compuesto fluorado citotóxico usado en bioterapia / 3.3.2 Compuestos derivados de selenio: agentes quimioterapéuticos más actuales comúnmente usados para cáncer colorrectal / 3.3.3 Quimioterapias combinadas en el tratamiento del cáncer colorrectal / Capítulo II. Rutas sintéticas para la obtención de medicamentos utilizados como tratamientos químicos contra el cáncer colorrectal / 3.4 Rutas sintéticas de medicamentos usados para cáncer colorrectal / 3.4.1 Derivados de pirimidinas/ 3.4.1.1 Síntesis de 5–fluorouracilo/ 3.4.1.2 Síntesis de capecitabina/ 8 3.4.1.3 Síntesis de tegafur / 3.4.1.4 Síntesis de trifluridina / 3.4.1.5 Síntesis de tipiracilo / 3.4.2 Derivados de platino / 3.4.2.1 Síntesis de oxaliplatino / 3.4.2.2 Síntesis de carboplatino/ 3.4.2.3 Síntesis de cisplatino/ 3.4.3 Síntesis de irinotecan: derivado de camptotecina / 3.4.4 Síntesis de leucovorina: alcaloide de vinca/ 3.4.5 Síntesis de regorafenib: compuesto fluorado citotóxico usado en bioterapia / 3.4.6 Síntesis de agentes quimioterapéuticos más actuales comúnmente usados para cáncer colorrectal: compuestos derivados de selenio / 3.4.6.1 Síntesis de selenometionina (SeMet) / 3.4.6.2 Síntesis de seleniuros: compuestos a base de quinona mediante reacciones-click con cobre/ 3.4.6.3 Síntesis de seleniuros: metilimidoselenocarbamatos/ 3.4.6.4 Síntesis de etaselen / 3.4.6.5 Síntesis de selenediazoles: Se-NHC (Carbeno N-Heterocíclico de selenio) / 3.4.6.6 Síntesis de emedicamento antiinflamatorio no esteroideo de selenio (Se-NSAID) / Capítulo III. Nanoencapsulación de medicamentos utilizados como tratamientos químicos contra el cáncer colorrectal / 3.5 Nanomedicina: características generales sobre la nanoencapsulación de fármacos..61 3.6 Nanoformulaciones como vehículos de moléculas usadas en tratamientos químicos contra el cáncer colorrectal: aspectos generales y ejemplos/ 3.6.1 Aspectos generales de las nanoformulaciones / 3.6.1.1 Nanopartículas de liposomas / 3.6.1.2 Nanopartículas poliméricas de ácido poli láctico y ácido poli glicólico (PLGA) / 3.6.1.3 Nanopartículas de lípidos sólidos (SLN) / 3.6.2 Ejemplos de nanoformulaciones como vehículos para moléculas usadas contra el cáncer colorrectal / 3.6.2.1 Nanopartículas de liposomas encapsulando el irinotecan / 3.6.2.2 Nanopartículas poliméricas de 5-fluorouracilo/ 3.6.2.3 Nanopartículas de lípidos sólidos encapsulando el oxaliplatino / 9 3.7 El revestimiento de Eudragit: un polímero administrado por vía oral, usado como recubrimiento de las nanopartículas poliméricas o lipídicas en medicamentos para cáncer colorrectal / 4. Conclusiones/ 5. Bibliografía.MaestríaSe realizará publicación científica (artículo, ponencia, otro).Magister en QuímicaQuímica medicinalapplication/pdfspaNanoencapsulación y rutas sintéticas para preparar medicamentos usados como tratamientos químicos contra cáncer colorrectal: una descripción generalTrabajo de grado - Maestríahttp://purl.org/coar/resource_type/c_bdccTextinfo:eu-repo/semantics/masterThesishttp://purl.org/coar/version/c_970fb48d4fbd8a85Facultad de Ciencias Exactas y NaturalesManizales, Caldas, ColombiaMaestría en Química1. Lopart, N. MEDICINAL PLANTS AS A SOURCE OF ANTINEOPLASTIC COMPOUNDS. vol. 16 (2000)2. Globocan. Cifras y estimaciones de cáncer en el mundo. Instituto Nacional de Cancerología, Colombia. 2018 vol. 380 https://gco.iarc.fr/today/data/factsheets/populations/170-colombia-fact-sheets.pdf (2018).3. Incidencia, mortalidad y prevalencia de cáncer en Colombia 2007-2011. (2011).4. Yamamoto, T., Uemura, K., Moriyama, K., Mitamura, K. & Taga, A. Inhibitory effect of maple syrup on the cell growth and invasion of human colorectal cancer cells. Oncol. Rep. 33, 1579–1584 (2015).5. Di Lena, M., Travaglio, E. & Altomare, D. F. New strategies for colorectal cancer screening. World J. Gastroenterol. 19, 1855– 1860 (2013).6. Doll, R. & Peto, R. The causes of cancer: Quantitative estimates of avoidable risks of cancer in the united states today. J. Natl. Cancer Inst. 66, 1192–1308 (1981).7. Cisterna, B. A. et al. Targeted nanoparticles for colorectal cancer. Nanomedicine 11, 2443–2456 (2016).8. GLOBOCAN. Estimated age-standardized incidence rates (World) in 2018, all cancers, both sexes, all ages. World Heal. Organ. 2018 (2018)9. Organization, W. H. World health statistics 2018. Mathematics Education Journal vol. 1 http://dx.doi.org/10.1016/j.biotechadv.2010.07.003%0Ahttp://dx.doi.org/10.1016/j.scitotenv.2016.06.080%0Ahttp://dx.doi.org/ 10.1016/j.bbapap.2013.06.007%0Ahttps://www.frontiersin.org/article/10.3389/fmicb.2018.02309/full%0Ahttp://dx.doi.org/10. 1007/s13762- (2018).10. Globocan Observatory, W. Cancer Today - World. Int. Agency Res. Cancer 876, 2018–2019 (2019)11. Pardo, C., de Vries, E., Buitrago, L. & Gamboa, O. Atlas de mortalidad por cancer en Colombia. (2017). doi:http://dx.doi.org/10.1007/BF01411734.12. Pardo, C. & Cendales, R. Cancer incidence estimates and mortality for the top five cancer in Colombia, 2007-2011. Colomb. Med. 49, 16–22 (2018).13. Gustavsson, B. et al. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin. Colorectal Cancer 14, 1–10 (2015).14. Henrikson, N. B. et al. Family history and the natural history of colorectal cancer: Systematic review. Genet. Med. 17, 702–712 (2015).15. ASCO. Cancer Progress Timeline \| ASCO. American Society of Clinical Oncology https://www.asco.org/researchguidelines/cancer-progress-timeline/colorectal-cancer (2018).16. Mei, H. et al. Fluorine-Containing Drugs Approved by the FDA in 2018. Chem. - A Eur. J. 25, 11797–11819 (2019).17. Arias, B., García, N., Uribe, T. & Betancur, J. Colorectal Cancer: a clinical, genetic and molecular view. Med. Arch. 13–2, 14 (2013).18. De Este Número, Í., Revistas, M., Reservados, D. & Number, N. History of rectal cancer and its surgical treatment. Rev. Mex. Coloproctología Mayo-Agosto 11, 60–63 (2005)19. Lynch, P. M. HISTORY OF NON-POLYPOSIC HEREDITARY COLORECTAL CANCER. Rev. Médica Clínica Las Condes 28, 512–523 (2017)20. Winawer, S. J. Natural history of colorectal cancer. Am. J. Med. 106, (1999).21. Seifert, P., Baker, L., Reed, M. & Veitkevicius, K. Comparison of continuously infused 5-fluorouracil with bolus injection in treatment of patients with colorectal adenocarcinoma. Cancer Lett. 123–128 (1975).22. Greegor, D. H. Diagnosis of Large-Bowel Cancer in the Asymptomatic Patient. JAMA J. Am. Med. Assoc. 201, 943–945 (1967).23. ASCO. Colorectal Cancer: Types of Treatment \| Cancer.Net. American Society of Clinical Oncology https://www.cancer.net/cancer-types/colorectal-cancer/types-treatment?sectionTitle=Treatment (2019)24. Hutterer, F. & Pichlmaier, H. Endoscopic Surgery in the Rectum. Endoscopy 31–35 (1985) doi:10.1055/s-2007-1018451.25. Edwards, B. K. et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 116, 544–573 (2010).26. Boland, R. et al. A National Cancer Institute Workshop on Microsatellite Instability for Cancer Detection and Familial Predisposition: Development of International Criteria for the Determination of microsatellite Instability in Colorectal Cancer. Cancer Res. 58, 5248–5257 (1998).27. Saltz, L. et al. Irinotecan Plus Fluorouracil and Leucovorin for Metastatic Colorectal Cancer. Massachusetts Med. Soc. 343, 905–914 (2014).28. Fernandez, F. G. et al. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann. Surg. 240, 438–450 (2004).29. Chan, A. et al. Long-term Use of Aspirin and Nonsteroidal Anti-inflamatory Drugs and Risk of Colorectal Cancer. Am. Medican Assoc. 294, 914–923 (2005).30. André, T. et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J. Clin. Oncol. 27, 3109–3116 (2009).31. Twelves, C. et al. Capecitabine as adjuvant treatment for stage III colon cancer. N. Engl. J. Med. 352, 2696–2704 (2005).32. Sauer, R. et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N. Engl. J. Med. 351, 1731–1740 (2004).33. Nelson, H. et al. A Comparison of Laparoscopically Assisted and Open Colectomy for Colon Cancer. N. Engl. J. Med. 350, 2050–2059 (2004).34. Hurwitz, H. et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. N. Engl. J. Med. 350, 2335–2342 (2004).35. Suenaga, M. et al. Predictors of the efficacy of FOLFIRI plus bevacizumab as second-line treatment in metastatic colorectal cancer patients. Surg. Today 41, 1067–1074 (2011)36. Morton, R. F. & Hammond, E. H. ASCO Provisional Clinical Opinion: KRAS , Cetuximab, and Panitumumab—Clinical Implications in Colorectal Cancer . J. Oncol. Pract. 5, 71–72 (2009).37. Imperiale, T. F., Ransohoff, D. F., Itzkowitz, S. H., Turnbull, B. A. & Ross, M. E. Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average-risk population. N. Engl. J. Med. 351, 2704–2714 (2004).38. Bressler, B. et al. Colonoscopic Miss Rates for Right-Sided Colon Cancer : 127, 452–456 (2004).39. Barclay, R., Vicari, J., Doughty, A., Johanson, J. & Greenlaw, R. Colonoscopic withdrawal times and adenoma detection during screening colonoscopy: Commentary. N. Engl. J. Med. 355, 2533–2541 (2006).40. Chang, G. J., Rodriguez-Bigas, M. A., Skibber, J. M. & Moyer, V. A. Lymph node evaluation and survival after curative resection of colon cancer: Systematic review. J. Natl. Cancer Inst. 99, 433–441 (2007).41. Meyerhardt, J. et al. Association of Dietary Patterns With Cancer Recurrence and Survival in Patients With Stage III Colon Cancer. Am. Medican Assoc. 298, 754–764 (2007).42. Watanabe, T. et al. Molecular Predictors of Survival After Adjuvant Chemotherapy for Colon Cancer. N. Engl. J. Med. 344, 1196–1206 (2001).43. Soetikno, R. M. et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA - J. Am. Med. Assoc. 299, 1027–1035 (2008).44. ASCO. The Genetics of Cancer \| Cancer.Net. American Society of Clinical Oncology https://www.cancer.net/navigatingcancer-care/cancer-basics/genetics/genetics-cancer (2018).45. Poultsides, G. A. et al. Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment. J. Clin. Oncol. 27, 3379–3384 (2009).46. Crispin, A., Birkner, B., Munte, A., Nusko, G. & Mansmann, U. Process quality and incidence of acute complications in a series of more than 230000 outpatient colonoscopies. Endoscopy 41, 1018–1025 (2009).47. Van Cutsem, E. et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J. Clin. Oncol. 30, 1–9 (2012).48. Tejpar, S. et al. Prognostic and predictive relevance of primary tumor location in patients with ras wild-type metastatic colorectal cancer retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 3, E1–E8 (2016)49. Erlandsson, J. et al. Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. Lancet Oncol. 18, 1–11 (2017).50. Grothey, A. et al. Duration of adjuvant chemotherapy for stage III colon cancer. N. Engl. J. Med. 378, 1177–1188 (2018).51. Hagos, G. K. et al. Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo. Mol. Cancer Ther. 6, 2230–2239 (2007).52. ESMO. Patient Guide with colorectal cancer (ESMO). (2016).53. NCCN. Colon Cancer NCCN Guidelines for Patients. Natiinal Compr. Cancer Netw. 86 (2018).54. NCCN Colon Cancer Panel. NCCN Clinical Practice Guidelines in Oncology: colon cancer. V2.2015. Natl. Compr. Cancer Netw. 1, 1–132 (2015).55. Zhang, R., Song, X. Q., Liu, R. P., Ma, Z. Y. & Xu, J. Y. Fuplatin: An Efficient and Low-Toxic Dual-Prodrug. J. Med. Chem. 62, 4543–4554 (2019).56. Inés Castro Núñez, Eduardo Echarri Arrieta, F. F. L. MEDICAMENTOS CITOSTÁTICOS Sociedad Española de Farmacéuticos de Hospitales. RAÍZ, TG., S.L. Gamonal, 19. 28031 (MADRID) vol. 4a Edición (2003).57. Ota, Y., Nakamura, A., Elboray, E. E., Itoh, Y. & Suzuki, T. Design, synthesis, and biological evaluation of a conjugate of 5- fluorouracil and an LSD1 inhibitor. Chem. Pharm. Bull. 67, 192–195 (2019).58. Ducreux, M. et al. Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma. Ann. Oncol. 13, 1192–1196 (2002).59. Perkhofer, L. et al. Nal-IRI with 5-fluorouracil (5-FU) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - The NIFE trial (AIO-YMO HEP-0315) an open label, non-comparative, randomized, multicenter phase II study. BMC Cancer 19, 1–7 (2019).60. Benson, A. B. et al. NCCN Guidelines ® Insights Colon Cancer, Version 2.2018 Featured Updates to the NCCN Guidelines. JNCCN J. Natl. Compr. Cancer Netw. 16, 359–369 (2018)61. Glynne-Jones, R. et al. Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 25, 10–20 (2014).62. Mohammadian, M., Zeynali, S., Azarbaijani, A. F., Khadem Ansari, M. H. & Kheradmand, F. Cytotoxic effects of the newlydeveloped chemotherapeutic agents 17-AAG in combination with oxaliplatin and capecitabine in colorectal cancer cell lines. Res. Pharm. Sci. 12, 517–525 (2017).63. Di Desidero, T. et al. Pharmacokinetic analysis of metronomic capecitabine in refractory metastatic colorectal cancer patients. Invest. New Drugs 36, 709–714 (2018).64. Müller, V. et al. Quality of life under capecitabine (Xeloda®) in patients with metastatic breast cancer: Data from a German non-interventional surveillance study. Oncol. Res. Treat. 37, 748–755 (2014).65. Broto, M., McCabe, R., Galve, R. & Marco, M. P. A high throughput immunoassay for the therapeutic drug monitoring of tegafur. Analyst 142, 2404–2410 (2017).66. Li, W. et al. Maintenance treatment of Uracil and Tegafur (UFT) in responders following first-line fluorouracil-based chemotherapy in metastatic gastric cancer: A randomized phase II study. Oncotarget 8, 37826–37834 (2017).67. Peeters, M., Cervantes, A., Moreno Vera, S. & Taieb, J. Trifluridine/tipiracil: An emerging strategy for the management of gastrointestinal cancers. Futur. Oncol. 14, 1629–1645 (2018).68. Side Effects of Lonsurf (Trifluridine and Tipiracil Tablets), Warnings, Uses. https://www.rxlist.com/lonsurf-side-effects-drugcenter.htm.69. Orlandi, P. et al. Pharmacological effects of the simultaneous and sequential combinations of trifluridine/tipiracil (TAS-102) and 5-fluorouracil in fluoropyrimidine-sensitive colon cancer cells. Invest. New Drugs 38, 92–98 (2020).70. Trifluridine / tipiracil (Lonsurf) for metastatic colorectal cancer: Overview. (2016).71. Kitada, N. et al. Factors affecting sensitivity to antitumor platinum derivatives of human colorectal tumor cell lines. Cancer Chemother. Pharmacol. 62, 577–584 (2008).72. Paraskar, A., Soni, S., Roy, B., Papa, A. & Sengupta, S. Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy. Nanotechnology 23, 1–17 (2012).73. Grothey, A. & Goldberg, R. M. A review of oxaliplatin and its clinical use in colorectal cancer. Expert Opin. Pharmacother. 5, 2159–2170 (2004).74. Rubiano, J. A., Garrido, A. & Castillo, J. S. Uso de bevacizumab en pacientes con cáncer de colon metastásico en el Instituto Nacional de Cancerología: una serie de casos. Rev. Colomb. Cancerol. 16, 227–233 (2012).75. Conroy, T. et al. Quality-of-life findings from a randomised phase-III study of XELOX vs FOLFOX-6 in metastatic colorectal cancer. Br. J. Cancer 102, 59–67 (2010)76. Jeremic, B., Acimovic, L. & Mijatovic, L. Carboplatin and etoposide in advanced colorectal carcinoma. A phase II study. Cancer 71, 2706–2708 (1993).77. Harrington, S. E. & Smith, T. J. Role of Chemotherapy at the End of life. JAMA - J. Am. Med. Assoc. 299, 1–22 (2008)78. Saber, M. M., Al-mahallawi, A. M., Nassar, N. N., Stork, B. & Shouman, S. A. Targeting colorectal cancer cell metabolism through development of cisplatin and metformin nano-cubosomes. BMC Cancer 18, 1–11 (2018).79. De Jongh, F. E. et al. Weekly high-dose cisplatin is a feasible treatment option: Analysis on prognostic factors for toxicity in 400 patients. Br. J. Cancer 88, 1199–1206 (2003)80. Kaku, Y., Tsuchiya, A., Kanno, T. & Nishizaki, T. Irinotecan induces cell cycle arrest, but not apoptosis or necrosis, in Caco-2 and CW2 colorectal cancer cell lines. Pharmacology 95, 154–159 (2015).81. Irinotecan (Campto) \| Cancer information \| Cancer Research UK. https://www.cancerresearchuk.org/about-cancer/cancer-ingeneral/treatment/cancer-drugs/drugs/irinotecan82. Ikehata, M. et al. Different effects of epigenetic modifiers on the cytotoxicity induced by 5-fluorouracil, irinotecan or oxaliplatin in colon cancer cells. Biol. Pharm. Bull. 37, 67–73 (2014).83. Starling, N., Tilden, D., White, J. & Cunningham, D. Cost-effectiveness analysis of cetuximab/irinotecan vs active/best supportive care for the treatment of metastatic colorectal cancer patients who have failed previous chemotherapy treatment. Br. J. Cancer 96, 206–212 (2007).84. Hare, J. I. et al. Treatment of Colorectal Cancer Using a Combination of Liposomal Irinotecan (Irinophore CTM) and 5- Fluorouracil. PLoS One 8, (2013).85. Hegde, V. S. & Nagalli, S. Leucovorin. StatPearls (StatPearls Publishing, 2020)86. Folinic Acid - Drug Information - Chemocare. http://chemocare.com/chemotherapy/drug-info/folinic-acid.aspx.87. Tsukihara, H., Tsunekuni, K. & Takechi, T. Folic acid-metabolizing enzymes regulate the antitumor effect of 5-fluoro-2′- deoxyuridine in colorectal cancer cell lines. PLoS One 11, 1–10 (2016).88. Zoetemelk, M., Ramzy, G. M. & Rausch, M. Folinic Acid and Oxaliplatin and Its Activity in. (2020).89. Pectasides, D. et al. Oxaliplatin plus high-dose leucovorin and 5-fluorouracil in pretreated advanced breast cancer: A phase II study. Ann. Oncol. 14, 537–542 (2003).90. Wei, N., Chu, E., Wu, S. yu, Wipf, P. & Schmitz, J. C. The cytotoxic effects of regorafenib in combination with protein kinase D inhibition in human colorectal cancer cells. Oncotarget 6, 4745–4756 (2015).91. Regorafenib. Metastatic colorectal cancer in treatment failure: may prolong survival by a few weeks - PubMed. https://pubmed.ncbi.nlm.nih.gov/24516902/.92. Dennert, G. & Horneber, M. Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients. Cochrane Database Syst. Rev. 2017, (2006).93. Gandin, V., Khalkar, P., Braude, J. & Fernandes, A. P. Organic selenium compounds as potential chemotherapeutic agents for improved cancer treatment. Free Radic. Biol. Med. 127, 80–97 (2018).94. Cao, S., Durrani, F. A., Rustum, Y. M. & Yu, Y. E. Ugt1a is required for the protective effect of selenium against irinotecaninduced toxicity. Cancer Chemother. Pharmacol. 69, 1107–1111 (2012).95. Romano, B., Font, M., Encío, I., Palop, J. A. & Sanmartín, C. Synthesis and antiproliferative activity of novel methylselenocarbamates. Eur. J. Med. Chem. 83, 674–684 (2014).96. Jardim, G. A. M. et al. Synthesis of selenium-quinone hybrid compounds with potential antitumor activity via Rh-Catalyzed CH bond activation and click reactions. Molecules 23, (2018).97. He, J. et al. Inhibition of thioredoxin reductase by a novel series of bis-1,2-benzisoselenazol-3(2H)-ones: Organoselenium compounds for cancer therapy. Bioorganic Med. Chem. 20, 3816–3827 (2012).98. Iqbal, M. A. et al. Green synthesis of mono- and di-selenium-N-heterocyclic carbene adducts: Characterizations, crystal structures and pro-apoptotic activities against human colorectal cancer. J. Organomet. Chem. 801, 130–138 (2016).99. Haque, R. A. et al. Synthesis, structure, anticancer, and antioxidant activity of para-xylyl linked bis-benzimidazolium salts and respective dinuclear Ag(I) N-heterocyclic carbene complexes (Part-II). Med. Chem. Res. 22, 4663–4676 (2013).100. Haque, R. A., Iqbal, M. A., Khadeer Ahamed, M. B., Majid, A. M. S. A. & Abdul Hameed, Z. A. Design, synthesis and structural studies of meta-xylyl linked bis-benzimidazolium salts: Potential anticancer agents against ‘human colon cancer’. Chem. Cent. J. 6, (2012).101. Plano, D. et al. Design, Synthesis, and Biological Evaluation of Novel Selenium (Se-NSAID) Molecules as Anticancer Agents. J. Med. Chem. 59, 1946–1959 (2016).102. Avendaño, C. & Menéndez, C. Medicinal Chemistry of Anticancer Drugs. (2008)103. A new route to the synthesis of 5-Fluorouracil. J. Fluor. Chem. 58, 99–104 (1989).104. Carda, M. Synthetic Methodology Applied to Drug Synthesis. (2016).105. organic-chemistry. Biginelli Reaction. https://www.organic-chemistry.org/namedreactions/biginelli-reaction.shtm.106. In, K. I. N., No, H. & Nagar, N. L. B. Wo 2010/065586 a2. 2, (2010).107. Smart, K. F., Aggio, R. B. M., Van Houtte, J. R. & Villas-Bôas, S. G. Analytical platform for metabolome analysis of microbial cells using methyl chloroformate derivatization followed by gas chromatography-mass spectrometry. Nat. Protoc. 5, 1709– 1729 (2010).108. Zasada, A., Mironiuk-Puchalska, E. & Koszytkowska-Stawińska, M. Synthesis of Tegafur by the Alkylation of 5-Fluorouracil under the Lewis Acid and Metal Salt-Free Conditions. Org. Process Res. Dev. 21, 885–889 (2017).109. Zasada, A., Puchalska, E. & Stawinska, M. Synthesis of tegafur by alkylation of 5-fluorouracil under the Lewis acid-and metal salt-free conditions. http://www.forsanelhaq.com/showthread.php?t=151497.110. Kobayashi, Y., Kumadaki, I. & Yamamoto, K. Simple synthesis of trifluoromethylated pyrimidine nucleosides. J. Chem. Chem. Commun. 536–537 (1977) doi:10.1039/C39770000536.111. Patent - synthesis of trifluridine.pdf. (2012).112. ELSEVIER. Organofluorine Pharmaceuticals. Organofluorine Compounds in Biology and Medicine (2015). doi:10.1016/b978-0-444-53748-5.00005-8113. Suzuki, N., Ito, M. & Takechi, T. Discovery and Development of Trifluridine / Tipiracil. 3, 417–441 (2018)114. Application, I., Under, P., Patent, T. H. E. & Treaty, C. Wo 2019/002407. vol. 1 (2019).115. Allen, H. R., Maxson, R. N., Booth, H. S. & Herrmann, C. V. Sulfuryl Chloride. Org. Synth. 1, 114–117 (2007).116. Habala, L. et al. Synthesis and structure-activity relationships of mono- and dialkyl-substituted oxaliplatin derivatives. Eur. J. Med. Chem. 40, 1149–1155 (2005).117. Galanski, M. et al. Synthesis, crystal structure and cytotoxicity of new oxaliplatin analogues indicating that improvement of anticancer activity is still possible. Eur. J. Med. Chem. 39, 707–714 (2004).118. Avendaño, C. & Menéndez, J. C. Medicinal Chemistry of Anticancer Drugs. Medicinal Chemistry of Anticancer Drugs (2008). doi:10.1016/B978-0-444-52824-7.X0001-7.119. Wilson, J. J. & Lippard, S. J. Synthetic methods for the preparation of platinum anticancer complexes. Chem. Rev. 114, 4470– 4495 (2014).120. Kawamura, K. et al. Synthesis, metabolite analysis, and in vivo evaluation of [11C]irinotecan as a novel positron emission tomography (PET) probe. Nucl. Med. Biol. 40, 651–657 (2013)121. Martino, E. et al. The long story of camptothecin: From traditional medicine to drugs. Bioorganic Med. Chem. Lett. 27, 701– 707 (2017).122. Felder, A. United States Patent [19]. (1998)123. Zakrzewski, S. & Sansone, A. Preparation of Folinic Acid. J. Chem. Inf. Model. 53, 1689–1699 (2013).124. Francese, G., Corana, F., Meneghetti, O. & Marazza, F. LC-MS characterization of trace impurities contained in calcium folinate. J. Pharm. Biomed. Anal. 39, 757–763 (2005).125. Forsch, R. A., Rosowsky, A. & Wan, P. A new ine-step synthesis of Leucovorin from Folic Acid and of 5-formyl-5,6,7,8- tetrahydrohomofolic acid from Homofolic Acid using Dimethylamine-Norane in Formic Acid. 2582–2583 (1985)126. Xiaochao, G. et al. Degradation of folic acid wastewater by electro-Fenton with three-dimensional electrode and its kinetic study. R. Soc. Open Sci. 5, 170926 (2018).127. Wang, L. M. et al. An efficient and high-yielding protocol for the production of Regorafenib via a new synthetic strategy. Res. Chem. Intermed. 42, 3209–3218 (2016)128. Du, F. et al. A new pathway via intermediate 4-amino-3-fluorophenol for the synthesis of regorafenib. Synth. Commun. 49, 576–586 (2019).129. Czakó, B. & Kurti, L. Strategic Applications of Named Reactions in Organic Synthesis. Elsevier Academic Press vol. 1 (2005).130. Koch, T. & Buchardt, O. Synthesis of L-(+)-Selenomethionine. Res. Cent. Med. Biotechnol. (1993).131. Kogami, M. & Koketsu, M. An efficient method for the synthesis of selenium modified nucleosides: its application in the synthesis of Se-adenosyl-l-selenomethionine (SeAM). Org. Biomol. Chem. 13, 9405–9417 (2015).132. Block, E. et al. Identification and synthesis of a novel selenium-sulfur amino acid found in selenized yeast: Rapid indirect detection NMR methods for characterizing low-level organoselenium compounds in complex matrices. J. Agric. Food Chem. 52, 3761–3771 (2004).133. Plenevaux, A., Cantineau, R., Guillaume, M., Christiaens, L. & Tihange, G. Fast chemical synthesis of [Se]Lselenomethionine. Int. J. Radiat. Appl. Instrumentation. Part 38, 59–61 (1987).134. Zhou, Z. S., Smith, A. E. & Matthews, R. G. L-selenohomocysteine: One-step synthesis from L-selenomethionine and kinetic analysis as substrate for methionine synthases. Bioorganic Med. Chem. Lett. 10, 2471–2475 (2000).135. Iwaoka, M., Ooka, R., Nakazato, T., Yoshida, S. & Oishi, S. Synthesis of selenocysteine and selenomethionine derivatives from sulfur-containing amino acids. Chem. Biodivers. 5, 359–374 (2008).136. Lim, D., Gründemann, D. & Seebeck, F. P. Total Synthesis and Functional Characterization of Selenoneine. Angew. Chemie 131, 15168–15172 (2019)137. Shaaban, S. et al. Novel peptidomimetic compounds containing redox active chalcogens and quinones as potential anticancer agents. Eur. J. Med. Chem. 58, 192–205 (2012).138. Cieza, L. Reacciones click: Síntesis de fármacos para el tratamiento del cáncer de mama. (2015)139. Ibáñez, E. et al. Synthesis and antiproliferative activity of novel symmetrical alkylthio- and alkylseleno-imidocarbamates. Eur. J. Med. Chem. 46, 265–274 (2011).140. Begini, F. et al. Continuous flow synthesis of 2,2′-diselenobis(benzoic acid) and derivatives. React. Chem. Eng. 5, 641–644 (2020).141. Krasowska, D., Iraci, N., Santi, C., Drabowicz, J. & Cieslak, M. Diselenides and Benzisoselenazoles as Antiproliferative Agents and Glutathione-S-Transferase Inhibitors. Molecules 1–19 (2014).142. Krasowska, D. et al. Ultrasound-assisted synthesis of alkali metals diselenides (M2Se2) and their application for the gram-scale preparation of 2,2’-diselenobis(benzoic acid). Arkivoc 2019, 24–37 (2019).143. Liu, L. et al. Synthesis of NSAIDs–Se derivatives as potent anticancer agents. Med. Chem. Res. 27, 2071–2078 (2018)144. Ravera, M. et al. Antiproliferative activity of Pt(IV) conjugates containing the non-steroidal anti-inflammatory drugs (NSAIDs) Ketoprofen and Naproxen. Int. J. Mol. Sci. 20, 1–18 (2019).145. Hoshyar, N., Gray, S., Han, H. & Bao, G. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine 11, 673–692 (2016).146. Hillaireau, H. & Couvreur, P. Nanocarriers’ entry into the cell: Relevance to drug delivery. Cell. Mol. Life Sci. 66, 2873–2896 (2009).147. Tran, S., DeGiovanni, P.-J., Piel, B. & Rai, P. Cancer nanomedicine: a review of recent success in drug delivery. Clin Trans Med 6, 1–21 (2017).148. Patra, J. K. et al. Nano based drug delivery systems: Recent developments and future prospects 10 Technology 1007 Nanotechnology 03 Chemical Sciences 0306 Physical Chemistry (incl. Structural) 03 Chemical Sciences 0303 Macromolecular and Materials Chemistry 11 Medical and He. J. Nanobiotechnology 16, 1–33 (2018).149. Sahoo, S. K. & Labhasetwar, V. Nanotech approaches to drug delivery and imaging. Drug Discov. Today 8, 1112–1120 (2003)150. Panchagnula, R. & Thomas, N. S. Biopharmaceutics and pharmacokinetics in drug research. Int. J. Pharm. 201, 131–150 (2000).151. Jayaraman, M. et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chemie - Int. Ed. 51, 8529–8533 (2012).152. Aljuffali, I., Huang, C.-H. & Fang, J.-Y. Nanomedical Strategies for Targeting Skin Microbiomes. Curr. Drug Metab. 16, 255– 271 (2015).153. Tran, S., DeGiovanni, P.-J., Piel, B. & Rai, P. Cancer nanomedicine: a review of recent success in drug delivery. Clin. Transl. Med. 6, 0–21 (2017).154. Witika, B. A. et al. Biocompatibility of Biomaterials for Nanoencapsulation: Current Approaches. Nanomaterials 10, 1649 (2020).155. Naahidi, S. et al. Biocompatibility of engineered nanoparticles for drug delivery. J. Control. Release 166, 182–194 (2013).156. Kohane, D. S. & Langer, R. Biocompatibility and drug delivery systems. Chem. Sci. 1, 441–446 (2010).157. Oropesa, R. & Jáuregui, U. Las nanopartículas como portadores de fármacos: características y perspectivas Nanoparticles as drug carriers : characteristics and perspectives. CENIC Ciebcias Biológicas 43, (2012).158. Williams, H. D. et al. Strategies to Address Low Drug Solubility in Discovery and Development. Pharmacol. Rev. 65, 315–499 (2013).159. Zafar, N., Bashir, I., Alvi, N. & Sajid, M. I. Structural components of liposomes and characterization tools. Indo Am. J. Pharm. Res. 4, 3559–3567 (2014).160. Balzola, A. NUEVOS VECTORES EN LA APLICACIÓN VÍA TÓPICA DE MEDICAMENTOS. LIPOSOMAS (I). (2018).161. Paul, M. et al. Physicochemical characteristics of pentamidine-loaded polymethacrylate nanoparticles: Implication in the intracellular drug release in Leishmania major infected mice. J. Drug Target. 5, 481–490 (1998).162. Margaroni, M. et al. PLGA nanoparticles modified with a TNFα mimicking peptide, soluble Leishmania antigens and MPLA induce T cell priming in vitro via dendritic cell functional differentiation. Eur. J. Pharm. Biopharm. 105, 18–31 (2016).163. Fernandez, M. Desarrollo de una formulacion oral de Yoduro de N-yodometil-N,N-dimetil-N-(6,6-difenilhex-5-en-1-il) amonio para el tratamiento de la Leishmaniasis Cutánea. (Universidad de Antioquia, 2017).164. Danhier, F. et al. PLGA-based nanoparticles: An overview of biomedical applications. J. Control. Release 161, 505–522 (2012).165. Want, M. Y. et al. A new approach for the delivery of artemisinin: Formulation, characterization, and ex-vivo antileishmanial studies. J. Colloid Interface Sci. 432, 258–269 (2014).166. Santos, I., Ponte, B., Boonme, P., Silva, A. & Souto, E. Nanoencapsulation of polyphenols for protective effect against colon– rectal cancer. Soc. Sci. China 33, 149–156 (2012).167. Vasir, J. & Labhasetwar, V. Polymeric nanoparticles for gene delivery. Polym. Nanomater. Gene Ther. 3, 325–344 (2006).168. JANI, P., HALBERT, G. W., LANGRIDGE, J. & FLORENCE, A. T. Nanoparticle Uptake by the Rat Gastrointestinal Mucosa: Quantitation and Particle Size Dependency. J. Pharm. Pharmacol. 42, 821–826 (1990).169. Makadia, H. & Siegel, S. Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. Polym. 3, 1377–1397 (2011).170. Schwarz, C. & Mehnert, W. Solid lipid nanoparticles (SLN) for controlled drug delivery. II. Drug incorporation and physicochemical characterization. J. Control. Release 16, 83–96 (1994).171. Geszke-Moritz, M. & Moritz, M. Solid lipid nanoparticles as attractive drug vehicles: Composition, properties and therapeutic strategies. Mater. Sci. Eng. C 68, 982–994 (2016).172. Qiu, Y. Understanding Drug Properties in Formulation and Process Design of Solid Oral Products. J. Valid. Technol. 74–84 (2010).173. Liu, X., Testa, B. & Fahr, A. Lipophilicity and its relationship with passive drug permeation. Pharm. Res. 28, 962–977 (2011).174. Gonçalves, L. M. D. et al. Development of solid lipid nanoparticles as carriers for improving oral bioavailability of glibenclamide. Eur. J. Pharm. Biopharm. 102, 41–50 (2016).175. Li, X. et al. Nano carriers for drug transport across the blood–brain barrier. J. Drug Target. 25, 17–28 (2017).176. Porter, C. J. H., Trevaskis, N. L. & Charman, W. N. Lipids and lipid-based formulations: Optimizing the oral delivery of lipophilic drugs. Nat. Rev. Drug Discov. 6, 231–248 (2007).177. Fonseca-santos, B., Daflon, M. & Chorilli, M. Nanotechnology-based drug delivery systems for the treatment of Alzheimer ’ s disease. Int. J. Nanomedicine 10, 4981–5003 (2015).178. Huang, J. R., Lee, M. H., Li, W. S. & Wu, H. C. Liposomal irinotecan for treatment of colorectal cancer in a preclinical model. Cancers (Basel). 11, 1–19 (2019).179. Iqbal, S., Jubeen, F. & Sher, F. Future of 5-Fluorouracil in Cancer Therapeutics, Current Pharmacokinetics Issues and a Way Forward. J. Cancer Res. Pract. 6, 155–161 (2020)180. Haggag, Y. A. et al. Polymeric nano-encapsulation of 5-fluorouracil enhances anti-cancer activity and ameliorates side effects in solid Ehrlich Carcinoma-bearing mice. Biomed. Pharmacother. 105, 215–224 (2018)181. Kumar, G. V., Nair, L., Sankar, J. & Nair, S. A. Biological evaluation of 5-fluorouracil nanoparticles for cancer chemotherapy and its dependence on the carrier, PLGA. Int. J. Nanomedicine 1685 (2011) doi:10.2147/ijn.s20165.182. Rajpoot, K. & Jain, S. K. Colorectal cancer-targeted delivery of oxaliplatin via folic acid-grafted solid lipid nanoparticles: preparation, optimization, and in vitro evaluation. Artif. Cells, Nanomedicine Biotechnol. 46, 1–12 (2017).183. Zhang, W. et al. Nanostructured lipid carrier surface modified with Eudragit RS 100 and its potential ophthalmic functions. Int. J. Nanomedicine 9, 4305–4315 (2014).184. Jain, A., Jain, S. K., Ganesh, N., Barve, J. & Beg, A. M. Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer. Nanomedicine Nanotechnology, Biol. Med. 6, 179–190 (2010).185. Yassin, A. E. B. et al. Optimization of 5-fluorouracil solid-lipid nanoparticles: A preliminary study to treat colon cancer. Int. J. Med. Sci. 7, 398–408 (2010).info:eu-repo/semantics/closedAccesshttp://purl.org/coar/access_right/c_14cbCáncerEpidemiologíaMedicamentosCáncer colorrectaNanomedicinaNanoencapsuladoQuimioterapiaLiberación controlada de fármacosORIGINALSantiago _ Aguirre Giraldo _2021.pdfSantiago _ Aguirre Giraldo _2021.pdfDocumento de tesis de maestríaapplication/pdf3129087https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/1/Santiago%20_%20Aguirre%20Giraldo%20_2021.pdf5ae4de4018e09a762de02fbc7032dadaMD51ACTA SUSTENTACIÓN SANTIAGO AGUIRRE.docx (1).pdfACTA SUSTENTACIÓN SANTIAGO AGUIRRE.docx (1).pdfActa de sustentaciónapplication/pdf385195https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/2/ACTA%20SUSTENTACI%c3%93N%20SANTIAGO%20AGUIRRE.docx%20%281%29.pdf83fed40081ba0162898b94451e15002bMD52carta-autorizacion-publicacion-contenidos-repositorioinstitucional-Santiago Aguirre Giraldo.pdfcarta-autorizacion-publicacion-contenidos-repositorioinstitucional-Santiago Aguirre Giraldo.pdfcarta de autorización para publicación de contenidos en repositorio institucionalapplication/pdf315663https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/3/carta-autorizacion-publicacion-contenidos-repositorioinstitucional-Santiago%20Aguirre%20Giraldo.pdf63f463f38adf8f36df6bb69fade9f1b3MD53LICENSElicense.txtlicense.txttext/plain; charset=utf-814828https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/4/license.txt2f9959eaf5b71fae44bbf9ec84150c7aMD54TEXTSantiago _ Aguirre Giraldo _2021.pdf.txtSantiago _ Aguirre Giraldo _2021.pdf.txtExtracted texttext/plain159176https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/5/Santiago%20_%20Aguirre%20Giraldo%20_2021.pdf.txt4f85351bf2eb63fd119bf532ba8031afMD55ACTA SUSTENTACIÓN SANTIAGO AGUIRRE.docx (1).pdf.txtACTA SUSTENTACIÓN SANTIAGO AGUIRRE.docx (1).pdf.txtExtracted texttext/plain1757https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/7/ACTA%20SUSTENTACI%c3%93N%20SANTIAGO%20AGUIRRE.docx%20%281%29.pdf.txte0159104faaefa588461339e416339baMD57carta-autorizacion-publicacion-contenidos-repositorioinstitucional-Santiago Aguirre Giraldo.pdf.txtcarta-autorizacion-publicacion-contenidos-repositorioinstitucional-Santiago Aguirre Giraldo.pdf.txtExtracted texttext/plain5863https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/9/carta-autorizacion-publicacion-contenidos-repositorioinstitucional-Santiago%20Aguirre%20Giraldo.pdf.txtd07e82e76661e102d5f400f5a13635b1MD59THUMBNAILSantiago _ Aguirre Giraldo _2021.pdf.jpgSantiago _ Aguirre Giraldo _2021.pdf.jpgGenerated Thumbnailimage/jpeg5799https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/6/Santiago%20_%20Aguirre%20Giraldo%20_2021.pdf.jpg00917db91f860667b14ad65ad5e847cbMD56ACTA SUSTENTACIÓN SANTIAGO AGUIRRE.docx (1).pdf.jpgACTA SUSTENTACIÓN SANTIAGO AGUIRRE.docx (1).pdf.jpgGenerated Thumbnailimage/jpeg12320https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/8/ACTA%20SUSTENTACI%c3%93N%20SANTIAGO%20AGUIRRE.docx%20%281%29.pdf.jpg91fed43882af6009b9693772098de47bMD58carta-autorizacion-publicacion-contenidos-repositorioinstitucional-Santiago Aguirre Giraldo.pdf.jpgcarta-autorizacion-publicacion-contenidos-repositorioinstitucional-Santiago Aguirre Giraldo.pdf.jpgGenerated Thumbnailimage/jpeg10509https://repositorio.ucaldas.edu.co/bitstream/ucaldas/16840/10/carta-autorizacion-publicacion-contenidos-repositorioinstitucional-Santiago%20Aguirre%20Giraldo.pdf.jpgf06ee68d17d9590e9cb8569afd72f5f5MD510ucaldas/16840oai:repositorio.ucaldas.edu.co:ucaldas/168402021-10-11 15:57:38.113Repositorio Digital de la Universidad de Caldasbdigital@metabiblioteca.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

Nanoencapsulación y rutas sintéticas para preparar medicamentos usados como tratamientos químicos contra cáncer colorrectal: una descripción general

Publicaciones similares