JOURNAL OF JOURNAL OF
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Mexico / 2020 May / August Volume 4, No.2
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JOURNAL OF BIOENGINEERING AND BIOMEDICINE RESEARCH
JBBR JBBR
SECTION EDITORS
FOOD SCIENCE
Cristian Jiménez Martínez, PhD.
FOOD TECHNOLOGY
Humberto Hernández Sánchez, PhD.
BIOMEDICINE AND HEALTH Eva Ramón Gallegos, PhD.
Miguel Ángel Antonio Ibáñez Hernández, PhD.
ENVIRONMENT AND SUSTAINABILITY María Soledad Vásquez Murrieta, PhD.
Carlos Alberto Sandoval Carrasco, PhD MICROBIOLOGY
Guadalupe Aguilera Arreola, PhD.
Araceli Contreras Rodríguez, PhD.
Gerardo Aparicio Ozores, PhD.
MOLECULAR BIOTECHNOLOGY Juan Arturo Castelán Vega, PhD.
Alicia Jiménez Alberto, PhD.
PHARMACEUTICAL RESEARCH AND DEVELOPMENT
Mayra Pérez Tapia, PhD.
BIOINFORMATICS
Alfonso Méndez Tenorio, PhD.
Violeta Larios Serrato, PhD.
BIOENERGIES
Angélica María Salmerón Alcocer, PhD.
BIOACTIVE NATURAL PRODUCTS María del Socorro López Cortes, PhD.
NANOTECHNOLOGY AND NANOSCIENCES Liliana Alamilla Beltrán, PhD.
BIOENGINEERING
Fortunata Santoyo Tepole, PhD.
Oswaldo Arturo Ramos Monroy, PhD
EDITORS IN CHIEF
EDITORIAL BOARD
Deilia Ahuatzi-Chacón, PhD.
Rosa María Ribas-Aparicio, PhD.
María de Lourdes Meza Jiménez, PhD.
Universidad Popular Autónoma del Estado de Puebla, Puebla, Puebla.
Sandra Victoria Ávila Reyes, PhD.
Depto. Biotecnología, CeProBi, IPN, Yautepec, Morelos.
María Ximena Quintanilla Carvajal, PhD.
Facultad de Ingeniería, Universidad de la Sabana, Chía, Colombia.
Eduardo Castañeda Pérez, PhD.
Universidad Autónoma de Yucatán.
Patricia Rosales Martínez, PhD.
Instituto Politécnico Nacional, México.
Fernando Uriel Rojas Rojas, PhD.
Universidad Nacional Autónoma de México.
Luisa Ma Rodrigues Gouveia Da Silva, PhD.
Laboratorio Nacional de Energía e Geología, Lisboa, Portugal.
Brenda Román Ponce, PhD.
Claudia Leonor Ibarra Sánchez, PhD.
Institituo Politécnico Nacional, México.
Raúl Sánchez-Sánchez, PhD.
Pohang University of Science and Technology, South Korea.
Yanelly Trujillo Cabrera, PhD.
NANOLAB, México.
Fernanda Sarahi Fajardo Espinoza, PhD.
Universidad Anahuac, México.
José Octavio Rodiles López, PhD.
Universidad Michoacana de San Nicolás de Hidalgo.
Evangelina García Armenta, PhD.
Universidad Autónoma de Sinaloa, Culiacán, Sinaloa.
Liliana León López, PhD.
Universidad Autónoma de Sinaloa, Culiacán, Sinaloa.
Laurette Shona Learita Prince, PhD.
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Volume 4, No.2 Mexico / 2020 May / August
JOURNAL OF JOURNAL OF
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BIOENGINEERING AND BIOMEDICINE
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FOOD TECHNOLOGY
Encapsulación de una bebida de almendra adicionada con Lactobacillus brevis Lb9H PTA 075
Juárez Chairez Milagros Faridy, Gallardo Navarro Yoja Teresa, Rivera Espinoza Yadira, Meza Márquez Ofelia Gabriela
1-5
BIOMEDICINE AND HEALTH
Use of biopolymers as carriers for cancer treatment
López Mendoza Carlos Miguel, Terán Figueroa Y, Alcántara Quintana LE
6-22
MICROBIOLOGY
Outer membrane vesicles from Gram negative bacteria: A review
Eric Daniel Avila Calderón, María del Socorro Ruiz Palma, Francisco Miguel AntonioHernández, Itzel Joana Garduño Rojas, Ma.
Guadalupe Aguilera Arreola, Enrico Alejandro Ruiz, Zulema Gómez Lunar, and Araceli Contreras Rodríguez
23-30
BIOACTIVE NATURAL PRODUCTS
Pharmacological Potential of Tradescantia zebrina Leaf Extracts
Olivo Vidal Zendy Evelyn, Ruíz Ruíz Jorge, Vega Salazar Mayday, Ochoa Díaz López Héctor, Irecta Nájera César, Sánchez Chino Xariss M
31-37
BIOACTIVE NATURAL PRODUCTS
Comparison of vermicomposts and wormbed leachate produced with different organic substrates
Serrano Ramirez Rocio, Ruiz Valdiviezo Victor M, Ruiz Lau Nancy, Villalobos Maldonado Juan J and MontesMolina Joaquin A
38-46
Encapsulación de una bebida de almendra adicionada con Lactobacillus brevis Lb9H-PTA-120751
Juárez-Chairez Milagros Faridy, Gallardo-Navarro Yoja Teresa, Rivera-Espinoza Yadira, Meza-Márquez Ofelia Gabriela*
Instituto Politécnico Nacional. Escuela Nacional de Ciencias Biológicas-Zacatenco. Departamento de Ingeniería Bioquímica. Av. Wilfrido Massieu S/N, Esq. Cda. Miguel Stampa. Col. Unidad Profesional Adolfo López Mateos, Zacatenco. Alcaldía Gustavo A. Madero. C.P. 07738. Ciudad de México, México.
*Corresponding author: [email protected]
Abstract. Currently there are new technologies applied to food preservation whose objective is to avoid the loss or modification of the sensory and nutritional attributes of food. In the present study, the encapsulation technology was evaluated in order to maintain the viability of Lactobacillus brevis Lb9H-PTA-120751.
The almond drink was prepared by adding L. brevis Lb9H-PTA-120751 (2 x 108 CFU / mL) and was subsequently encapsulated using the ionic gelation method. On the other hand, the encapsulates were dried (50 ° C/3 h) and rehydrated to determine the viability of the lactobacillus by this process. Encapsulation by ionic gelation kept L. brevis Lb9H-PTA-120751 viable (2.0 x 107 CFU / mL) for 21 days, while the drying and rehydration process decreased the viability of lactobacillus (5 x 106 CFU / mL). The encapsulation process by ionic gelation can be used as a preservation method in almond drink added with L. brevis Lb9H- PTA-120751.
Keywords. Ionic gelation, colloidal stability, functional drink.
Resumen. Actualmente existen nuevas tecnologías aplicadas a la conservación de alimentos cuyo objetivo es evitar la pérdida o modificación de los atributos sensoriales y nutricionales de los alimentos. En el presente estudio se evalúo la tecnología de encapsulación con el fin de mantener la viabilidad de Lactobacillus brevis Lb9H-PTA-120751. La bebida de almendra se preparó adicionando L. brevis Lb9H-PTA-120751 (2 x 108 UFC/mL) y posteriormente se encapsuló utilizando el método de gelificación iónica. Por otro lado, los encapsulados se secaron (50 °C/3 h) y rehidrataron para determinar la viabilidad del lactobacilo mediante este proceso. La encapsulación mediante gelificación iónica mantuvo viable a L. brevis Lb9H-PTA-120751 (2.0 x 107 UFC/mL) durante 21 días, mientras que el proceso de secado y rehidratación disminuyó la viabilidad del lactobacilo (5 x 106 UFC/mL). El proceso de encapsulación mediante gelificación iónica puede utilizarse como método de conservación en bebida de almendra adicionada con L. brevis Lb9H- PTA-120751.
Palabras clave. Gelificación iónica, estabilidad coloidal, bebida funcional.
Recibido: 24 de abril de 2020 / Aceptado: 5 de mayo de 2020 / Publicado en línea: 31 de mayo de 2020
INTRODUCCIÓN
Las bebidas elaboradas a base de cereales o frutos secos como las bebidas de soya, arroz, coco y almendra cada vez tienen mayor aceptabilidad por parte del consumidor: Dentro de éstas, la bebida a base de almendra destaca en su valor nutricional por su aporte de proteínas, ácidos grasos insaturados, fibra, antioxidantes (tocoferoles) y minerales (calcio).1 Juárez-Chairez y Gallardo-Navarro2 elaboraron una bebida de almendras adicionada con Lactobacillus brevis Lb9H-PTA-120751 y está presentó un contenido de proteína mayor al reportado en otras bebidas vegetales. Sin embargo, la bebida presentó baja estabilidad coloidal debido a que las proteínas presentes en la almendra no presentaron una adecuada propiedad para emulsificar los glóbulos de grasa. Lo anterior pudo deberse a que las proteínas no se desnaturalizaron.2 Varios estudios han demostrado que, para mejorar la estabilidad coloidal en las bebidas elaboradas a base de nueces se deben aplicar ciertas tecnologías.
Una de estas tecnologías es la encapsulación que es un proceso en el que se introduce una sustancia a la cual se le llama núcleo, dentro de otra sustancia a la que se le llama material de pared, cápsula o recubrimiento.3-4 Para realizar el proceso de encapsulación se utilizan varias técnicas como el secado por aspersión, gelificación iónica, coacervación, atrapamiento de liposomas, liofilización, entre otras.5 El método de gelificación iónica se caracteriza por proteger el núcleo de condiciones adversas del medio como pH, temperatura y contaminación. Dicha técnica forma la cubierta de las cápsulas mediante una reacción de gelificación iónica entre el polisacárido y el ion de carga opuesta. Este proceso se realiza de manera muy rápida, económica y con equipos sencillos.6 El objetivo del presente estudio fue determinar la viabilidad de L. brevis Lb9H-PTA-120751 en una bebida de almendra encapsulada
mediante gelificación iónica como método de conservación con el fin de obtener una bebida de almendra con mayor estabilidad física durante el almacenamiento, ya que esto es uno de los principales factores de los que depende la aceptación de la bebida. L. brevis Lb9H- PTA-12075 (aislado a partir del agua miel) se seleccionó ya que ha demostrado que tiene efectos benéficos en la salud debido a que sobrevive a las condiciones simuladas del tracto gastrointestinal, tiene la capacidad de desconjugar las sales biliares (actividad sal biliar hidrolasa) que puede relacionarse con el efecto hipocolesterolémico.2 MÉTODOS, RESULTADOS Y DISCUSIÓN La bebida de almendra adicionada con L.
brevis Lb9H-PTA-12075 se preparó siguiendo la metodología propuesta por Juárez-Chairez y Gallardo-Navarro.2 Brevemente, la almendra se escaldó en agua hirviendo por 3 min, en seguida se realizó un secado durante 24 h a temperatura ambiente. Posteriormente, la almendra se molió con un procesador de alimentos (Nutribullet®), durante 1 min a 25000 rpm. La harina obtenida se mezcló con agua (almendra-agua 1:5) y con lecitina de soya (0.3 %). A continuación, la mezcla se filtró (tela de algodón de poro abierto), se pasteurizó (67 °C/33 min) y se inoculó con Lactobacillus brevis Lb9H- PTA-120751 (2 x 108 UFC/mL) el cual se encontraba suspendido en caldo MRS y glicerol al 70 % en una proporción de 50:50, finalmente, la bebida se mantuvo en refrigeración a 4 °C.
La encapsulación de la bebida de almendra adicionada con L. brevis Lb9H-PTA-120751 se llevó a cabo mediante la técnica de gelificación iónica.6 El alginato de sodio (grado alimenticio E-401, baja viscosidad, 50 mPa.s, marca Deiman) se disolvió en la bebida de almendra adicionada con L. brevis Lb9H-PTA-120751 (1 % p/v), posteriormente la mezcla se goteó sobre una solución de cloruro de calcio al 1 %. Los encapsulados reposaron durante
2 min en la solución, enseguida los encapsulados se separaron mediante un colador, se envasaron en viales que contenía bebida de almendra sin inocular y se mantuvieron a 4 °C.
Los encapsulados se caracterizaron físicamente tomando una muestra de 90 cápsulas y se midió el diámetro, peso y volumen.6 Para realizar la cuenta de células viables de L. brevis Lb9H- PTA-120751 se realizaron diluciones seriadas (1 x 10-10) y se tomaron alícuotas de 100 μL de cada dilución. Posteriormente, se sembró en cajas Petri previamente preparadas con agar MRS y se incubó a 37 °C durante 24 h. Finalmente, la cuenta se llevó a cabo por medio de la estimación de Unidad Formadora de Colonias (UFC). La cuenta se llevó a cabo los días 0, 7, 14, y 21.2
Con fines comparativos, los encapsulados se secaron en una estufa a 50 °C durante 3 h, posteriormente, los encapsulados se envasaron en viales y se mantuvieron a temperatura ambiente durante 7 días.
A continuación, los encapsulados se rehidrataron en agua destilada durante 24 h y finalmente, las células viables presentes en las cápsulas se contaron.6 El proceso de secado y rehidratado de las cápsulas se realizó con la finalidad de analizar la viabilidad del lactobacilo bajo este proceso de conservación ya que es un método sencillo y económico.
Todos los análisis se realizaron por triplicado. Los resultados se sometieron a un análisis estadístico descriptivo (media y desviación estándar), análisis de varianza (ANDEVA) de una vía y prueba de comparación de medias (Tukey) a un nivel de significancia de α = 0.05. El análisis estadístico se realizó con el software Minitab versión 16.1.0 (State College, PA, USA).
Los encapsulados presentaron una forma esférica y superficie regular (Figura 1), estas características coinciden con otros estudios que han encapsulado a L. plantarum.7
Fig.1. Encapsulados de bebida de almendra adicionada con L. brevis Lb9H-PTA-120751.
Los encapsulados presentaron un diámetro inicial de 4.54 ± 0.21 mm (Tabla 1), similar a lo obtenido en el estudio de Lupo.8 Los resultados de diámetro (mm), peso (g) y volumen (mm3) de las cápsulas de bebida de almendra adicionada con L. brevis Lb9H-PTA-120751 presentaron diferencia significativa (p ≤ 0.05) a partir del día 14, esto pudo deberse a que muchas sustancias sólidas ya sea de origen proteico (gelatina, albúmina) o polisacárido (pectina, alginato, almidones solubles), al ponerse en contacto con agua comienzan a absorberla aumentando de volumen, a esto se le conoce como imbibición.
Tabla 1. Diámetro, peso y volumen de las cápsulas elaboradas a partir de la bebida de almendra adicionada con L. brevis Lb9H-PTA-120751.
Los valores representan las medias ± desviación estándar. Letras diferentes por columna son significativamente diferente (p ≤ 0.05).
También se ha reportado que la tasa de imbibición disminuye con el tiempo de contacto entre el gel y el agua,9-10 por lo tanto, debido a el fenómeno de imbibición, el diámetro, peso y volumen de las cápsulas elaboradas aumentaron en el día 14, sin embargo, como resultado de la disminución en la
Día Diámetro (mm) Peso (g) Volumen (mm3) 0 4.54 ± 0.21 c 0.05 ± 0.006 b 49.36 ± 7.21 c 7 4.51 ± 0.14 c 0.04 ± 0.006 b 48.14 ± 4.53 c 14 4.96 ± 0.20 a 0.05 ± 0.003 a 64.26 ± 8.21 a 21 4.64 ± 0.19 b 0.04 ± 0.004 c 52.71 ± 6.44 b
tasa de imbibición, en el día 21, el diámetro, peso y volumen disminuyó significativamente (p ≤ 0.05).
Estos resultados coinciden con otros estudios.6 La viabilidad de L. brevis Lb9H-PTA-120751 en las cápsulas que se sometieron a gelificación iónica se mantuvo en una concentración de 2 x 107 UFC/
mL durante un periodo de 21 días, estos resultados son similares a los reportados por Alemán7 para encapsulados de L. plantarum. Cabe resaltar que en el medio en el que se almacenaron las cápsulas (bebida de almendra sin inocular) no se encontró la presencia de L. brevis Lb9H-PTA-120751, lo cual puede deberse a que el tamaño del poro de la cápsula es menor a el tamaño del lactobacilo, como lo reportaron Klein et al. 11.
Por otro lado, la viabilidad de L. brevis Lb9H- PTA-120751 en las cápsulas que se sometieron a el proceso de secado y rehidratación disminuyó (5 x 106 UFC/mL) (p ≤ 0.05) en comparación con el método de gelificación iónica (2 x 107 UFC/mL). La viabilidad pudo verse afectada por la disponibilidad de nutrientes, la presencia de oxígeno, las condiciones de secado (estrés producido por la temperatura) o por el agente encapsulante.12 Por tanto, para estudios posteriores se sugiere añadir una concentración mayor de L. brevis Lb9H-PTA-120751.
CONCLUSIONES
Lactobacillus brevis Lb9H-PTA-120751 adicionado en la bebida de almendra y posteriormente encapsulada mediante gelificación iónica se mantuvo viable en una concentración de 2.0 x 107 UFC/mL durante 21 días, mientras que el proceso de secado y rehidratación disminuyó la viabilidad del lactobacilo (5 x 106 UFC/mL). Los hallazgos del presente trabajo podrían ser de utilidad en la industria alimentaria con el fin de modificar las propiedades texturales en algunos alimentos y desarrollar nuevas bebidas funcionales.
AGRADECIMIENTOS
Los autores desean agradecer al Instituto Politécnico Nacional y a el Consejo Nacional de Ciencia y Tecnología (CONACyT).
REFERENCIAS
1) Kamil A, Chen CYO. 2012. Health benefits of almonds beyond cholesterol reduction.
J Agric Food Chem. 60(27):6694-6702.
doi:10.1021/jf2044795
2) Juárez-Chairez MF, Gallardo-Navarro YT.
2018. Desarrollo de una bebida de almendra adicionada con Lactobacillus brevis Lb9H- PTA-120751. Investigación y Desarrollo en Ciencia y Tecnología de Alimentos. 3:572- 578. http://www.fcb.uanl.mx/IDCyTA/files/
volume3/4/9/95.pdf
3) Nedovica V, Kalusevica A, Manojlovicb V, Levica S, Branko B. 2011. An overview of encapsulation technologies for food applications. Proc Food Sci. 1:1806-1815.
doi:10.1016/j.profoo.2011.09.265
4) Kurozawa LE, Hubinger MD. 2016.
Hydrophilic food compounds encapsulation by ionic gelation. Curr Opinion Food Sci.
15(26):50-55.
5) Fang Z, Bhandari B. 2010. Encapsulation of polyphenols a review. Trends Food Sci Technol. 21(10):510-523.
6) Cuatzo LMI. 2010. Efecto de las condiciones de proceso en la conservación de alimentos encapsulados por el método de gelificación iónica. Tesis de maestría. Instituto Politécnico Nacional. México. http://tesis.
ipn.mx/handle/123456789/9472
7) Alemán AM. 2015. Encapsulación de L.
plantarum por esferificación en grenetina- pectina y adición a un producto de humedad intermedia. Tesis de maestría. Universidad Veracruzana. México. https://cdigital.uv.mx/
handle/123456789/42596
8) Lupo PB. 2012. Estudio de la gelificación de alginatos para encapsulación:
caracterización, preparación y aplicaciones en alimentos funcionales. Tesis de doctorado.
Universitat de Barcelona. España. http://hdl.
handle.net/2445/64943
9) Avendaño-Romero GC, López-Malo A, Palou E. 2013. Propiedades del alginate y aplicaciones en alimentos. Temas selectos de ingeniería en alimentos. 7-1:87-96. http://
sgpwe.izt.uam.mx/files/users/uami/acym/
ALGINATOS_I.pdf
10) Badui DS. 2013. Química de los alimentos.
5ed. México: Pearson, ISBN: 970-26-0670- 5.
11) Klein J, Stock J, Vorlop KD. 1983. Pore size and properties of spherical Ca- alginate biocatalysts. Eur J Appl Microbiol Biotechnol. 18(1):86-91. doi:10.1007/
BF00500829
12) González SA. 2009. Estudio de la encapsulación de Bifidobacterium animalis subsp. lactis y su uso como probiótico.
Tesis de doctorado. Instituto Politécnico Nacional. México. http://tesis.ipn.mx/
handle/123456789/5979
Use of biopolymers as carriers for cancer treatment
López-Mendoza Carlos Miguel1, Terán-Figueroa Y2, Alcántara-Quintana LE3*
1Posgrado en Ciencias Biomédicas Básicas, Universidad Autónoma de San Luis Potosí
2Facultad de Enfermería y Nutrición, Universidad Autónoma de San Luis Potosí
3Cátedra CONACYT, adscrita a Facultad de Enfermería y Nutrición, Universidad Autónoma de San Luis Potosí
* Corresponding author: [email protected]
Abstract. In 2018, the number of people with cancer increased to 18 million new cases around the world, considering men and women of all ages. In Mexico, there were 190 thousand new cases reported, highlighting that half of those who suffer from it die from this disease. In our country, the most abundant types of cancer are breast, prostate, cervical and colorectal cancer. Work is currently under way on the development of new drug delivery technologies with biomaterials in order to optimize cancer therapy and reduce its side effects.
This review aims to show the advantages of biomaterials over common materials, such as their low cost, their biocompatibility with the human body and their biodegradation.
Keywords. Nanoparticles, Biopolymers, Cancer, Mortality
Resumen. En el 2018 el número de personas con cáncer aumentó a 18 millones de nuevos casos alrededor del mundo, tomando en cuenta hombres y mujeres de todas las edades. En México, fueron 190 mil nuevos casos reportados, resaltando que la mitad de los que lo padecen mueren por esta enfermedad. En nuestro país, los tipos de cáncer más abundantes son el cáncer de mama, de próstata, cervicouterino y el colorrectal.
Actualmente se está trabajando en el desarrollo de nuevas tecnologías de entrega de fármacos utilizando biomateriales con el fin de optimizar la terapia contra el cáncer y reducir sus efectos secundarios. Esta revisión pretende mostrar las ventajas de los biomateriales, sobre los materiales comunes, tales como su bajo costo, su biocompatibilidad con el cuerpo humano y su biodegradación.
Palabras clave. Nanopartículas, Biopolímeros, Cáncer, Mortalidad.
1. INTRODUCTION
Cancer is a disease derived from the process of uncontrolled cell division from a deregulated cell1. The normal cell division and growth process is controlled by signals, but in cancer cells these signals are lost, minimized or exacerbated, therefore, cells divide without control and a tumor
growth is formed.2 In 2018 alone, the number of people with cancer increased to 18 million new cases around the world, considering men and women of all ages. In Mexico, there were 190 thousand new cases reported, highlighting that half of those who suffer from it die from this disease. In our country, the most abundant types of cancer are breast, prostate, cervical and colorectal.3,4 Developing countries are the most Received: April 2, 2020 / Accepted: May 12, 2020 / Published Online: May 31, 2020
affected since, despite the efforts of the World Health Organization (WHO) and its plan to reduce cancer cases, it is necessary to have an organized and outstanding health system. Cancer is not only a disease that affects health, it also affects the social, psychological and economic status of people.
Therefore, this becomes a complicated health problem, so proposals have been made that go hand in hand with economic factors, where options are proposed that take on account population growth in the world, and with this a rise in disease. Some of the proposals are to improve the ways of diagnosis and the effectiveness of targeted therapies.5,6
The National Cancer Institute of the United States classifies therapies to combat it into surgery, chemotherapy, radiotherapy, immunotherapy, targeted therapy, hormonal, stem cell and precision medicine. These treatments can be indicated individually or jointly; pre-surgical and post-surgical; This will depend on the type of cancer and its stage.7 Chemotherapy is one of the most used methods; as a presurgical treatment, adjuvant or as a therapy. This is the case despite causing certain toxic effects such as nausea and vomiting, damage to the gastrointestinal mucosa, oral ulcerations, constipation or diarrhea, neurotoxicity, peripheral neuropathies and anemia.8,9 Regardless of the likelihood of a good prognosis, there are still challenges for effective treatment, such as tumor heterogeneity, resistance to chemotherapeutic agents and the relapse rate.
Therefore, it is worth considering an increase in individual therapy and the investigation of new markers that could lead to an increase in treatment specificity.10 This increase in specificity and release has been investigated further in recent years, with the development of new drug delivery technologies with materials in order to optimize cancer therapy and reduce its side effects.11,12
2. MATERIALS AND BIOMATERIALS
Systems have been created to deliver selected drugs and have proven to be more effective and safer than the free drug. They are called Drug Delivery Systems (DDS); these are composed, in a very simple way from a polymer, lipid, inorganic carriers or polymeric hydrogels with the addition of a drug (Figure 1).13
Fig. 1. Different types of nanocarriers used as controlled delivery vehicles for cancer treatment
Over the years, conventional therapies have been displaced by the local delivery of the therapeutic agent, which increases the effectiveness and lowers the doses needed for treatments, thereby increasing therapeutic adherence.
Chemotherapeutic agent therapies can be combined with hyperthermic, photodynamic or gene therapies.14,15 Recently the use of biomaterials has been preferred since they are biodegradable, this means that they are broken down by biological processes to their most basic components, so they do not form toxic metabolites for humans or the environment.16,17 The advantages of these biomaterials over common materials are their low cost, their biocompatibility with the human body and their biodegradation.18 The high costs, side effects and the ineffectiveness of some treatments
require the creation of novel ways of delivering drugs, so that they have minimal or no side effects in addition to increasing the specificity.
This can be achieved by conjugation with monoclonal antibodies, polypeptides, aptamers or small molecules by chemical, enzymatic or photo-conjugation reations.19
3. NANOPARTICLES AND CANCER
One of the applications of these biomaterials in medicine has been in the development of nanoparticles of biopolymers conjugated with drugs for their intracellular degradation and, consequently, the release of the drug.20 These have good qualities such as particle size and shape, their ease of cell permeability, their conjugation with other molecules, etc. Making them like intelligent polymers, that is, that they can respond to a stimulus and that they can be tissue-specific.21,22
3.1. NON-SPECIFIC NANOPARTICLES
Nonspecific nanoparticles consist of a drug core with a biopolymer shell, in its most basic form.
A polymer widely used in biomedicine is chitosan (CS), which is a linear cationic biopolymer, composed of glucosamines. This compound has proven to be stable and to have a low toxicity. It can be made with simple preparation methods, can encapsulate hydrophilic compounds and can be easily functionalized.23,24
A chemotherapeutic agent that has been tested in combination with chitosan, is Paclitaxel (PTX), a lipophilic drug, used to treat breast, ovarian, neck and non-small cell lung cancer. It has a mechanism of action which, unlike colchicine, stabilizes and protects the microtubules so that they are not depolymerized, arresting the cell cycle and therefore inducing apoptosis.
Although it has adverse effects such as
myelosuppression, bradycardia, hypotension, peripheral neuropathy, myalgias, arthralgias, nausea, diarrhea, alopecia and mucositis.25,26,27 An example of the union of PTX with CS is in the study conducted by Gupta U. and collaborators.28 They made CS nanoparticles, using the water- in-oil (W/O) nanoemulsion technique, with the aim of carrying out a DDS that delivers the PTX using CS nanoparticles and glutaraldehyde. They evaluated cytotoxicity with a triple negative breast cancer cell line (MDA-MB-231). The particle sizes increased when loading the PTX into the nanoparticles, from 137 nm to 226 nm.
At 120 hours, the nanoparticles reached their maximum release of PTX. They were stable in size for 90 days, varying its Z potential, indicating agglomeration.
To demonstrate its specificity against non-cancer cells, the authors performed a hemolysis analysis, which resulted in being low (~ 10%) compared to free PTX (40%). The free PTX had an IC50 of 15 µM, while the nanoparticles (PTX-CS-NP-10) had an IC50 of approximately 10 µM. Using the IC50, they demonstrated that, in 6 hours, the cells treated with the nanoparticles were in apoptosis and necrotic (54%), while with free PTX, only a small percentage of these cells were in apoptosis or necrotic (25%). The limitations of the study lead to the lack of a PTX release behavior, and of in vivo tests, which are needed to determine if these nanoparticles do not affect other organs, and therefore highlight their specificity.
Despite these results, some treatments for cancer and nanoparticles are similar in terms of the non-specificity that leads to their high toxicity.
Therefore, they have been used as a core to add other molecules that could direct or bind the particle with a cell to the receptor-molecule form, in which the nanoparticle will be directed in order to increase the release of the drug in the tissue,
improving its safety for healthy cells or other organs, and thereby reducing adverse effects.29,30 There are conditions to increase the effectiveness of these chemotherapeutic agents based on drug delivery systems; These usually are to identify target mechanisms or attack pathways to cancer cells, as well as the selectivity for drug delivery.
Usually cell membranes are targets, that is, based on their charge, protein expression and receptors that could differentiate them from normal cells.
3.2. DIRECTED NANOPARTICLES
One way to direct these nanoparticles is by adding folic acid (FA). Cancer cells have an overexpression of these receptors in their membrane, unlike healthy cells. This increases their uptake by receptor- mediated phagocytosis, in addition to their stability at different pH values.31,32 Another drug used in chemotherapy is Doxorubicin (DOX). It is a class I anthracycline, which is indicated for cervical, endometrial, pancreatic, prostate and neck cancer, among others. It exerts its effect within the cell in two ways: The first is through its intercalation in DNA, causing therefore the disruption of DNA repair mediated by topoisomerase II; and the second is the generation of free radicals, thus damaging DNA, proteins and cell membranes.33,34 In the study previously conducted by Csikós Z, and collaborators,35 they created nanoparticles coupled with DOX for targeted treatment. They used Poly-g- glutamic acid (PGA) and chitosan to form their nanoparticles (CS-PGA-FA-DOX).
They performed cytotoxicity tests with ovarian cancer cells (SK-OV-3) and nasopharyngeal epithelium (KB). In the latter, the expression of folate receptors was greater. In addition, they analyzed a xenograph murine cancer model in vivo of SK-OV-3. The nanoparticles had a size between 113-115 nm, being stable up to 6 months after their synthesis. When using them in vitro, and when these nanoparticles have FA molecules, their uptake
increases and therefore cell survival decreases at lower concentrations than with the pure drug, this for both cell lines. In the in vivo model, the tumor volume decreases unlike when it is only treated with DOX. The weight of the mouse decreased as the days went by at day 55 it was reduced by 15%; But when treated with the pure drug, it decreased up to 20%, confirming that it can be directed towards the tumor and very little to other vital organs. Which is precisely the point of developing these platforms and using them ensures less toxicity is generated.
Another chemotherapeutic agent used is Cisplatin (CDDP). It is one of the most potent agents used in humans and veterinary medicine. Despite its success in the treatment of diverse cancer types (lung, ovarian, head and neck carcinoma, breast, brain, etc.), it is associated with different side effects that include nephrotoxicity, vomiting, dizziness, myelosuppression, ototoxicity and neurotoxicity.
The mechanism of action of Cisplatin involves its conversion to a powerful electrophile when entering the cell, which causes it to bind with different molecules such as proteins or amino acids that have thiol groups and with nucleic acids. With the latter, it forms adducts in the DNA, thus preventing the cell from dividing and, therefore, apoptosis or cell necrosis is induced.36,37,38
Proteins that interact with the Epidermal Growth Factor Receptor (EGFR) have been used, since it has been observed that these signals contribute to metastasis.39 EGFR is overexpressed in cancer cells, in addition to the fact that in recent works the use of anti-EGFR drugs has decreased the frequency of resistance in cancer cells. This is in addition to the processes that are related, such as endocytosis and autophagy, as targets of the inhibition of these.40 Poly Lactic-co-Glycolic Acid (PLGA) is another biodegradable polymer approved by the FDA, it has been used as a carrier for drugs, proteins and other molecules such as DNA, RNA and peptides,
since it is biocompatible with the human body and very malleable; Therefore its utility in different types of DDS.41,42 Maleimides (Mal) are proteins that help bioconjugation because they have chains with cysteines, because of this they are able to conjugate antibodies, cytokines and enzymes.43 Geng X, et al. in 201244 worked with PLGA and functionalized it with maleimide. The latter was conjugated with TP13 due to its high affinity and specificity to EGFR. The DDS (TP13-Mal-PGA- Asp-Pt) was made as follows: the functionalized maleimide biopolymer (Mal - PLGA - Asp) that functions as a carrier (TP13 added to the terminal amino group of GE11), increases the specificity to the target and Cisplatin is in the carboxyl site within the biopolymer, so that besides from being directed, it functions as an antineoplastic. The cytotoxicity assay was used in a human hepatoma cell line (SMMC-7721). The concentration of Cisplatin in the particle was 570
± 77 µg/ml. The nanoparticles measured 87 ± 28 nm. Between 40 and 60 hours the release curve reached its peak. Although the release was less than a platform without MAL and TP13, it was observed that this is a compound that directed the nanoparticles that did contain it and achieved their cellular internalization. Therefore, a greater toxicity was achieved than those methods that are not targeted; Although no more than the use of pure Cisplatin, so we could conclude that it decreases its potency and with it, its side effects.
In 2019, Domínguez R, and collaborators45 made PLGA nanoparticles with chitosan using the nanoprecipitation method and loaded them with Cisplatin. An antibody, anti-HER2 Trastuzumab (TZ) was also conjugated by carbodiimide chemical conjugation. These were evaluated in a SKOV-3 cell culture. The size of the CDDP- PLGA nanoparticles was 126 ± 7.6 nm. When TZ was added, they increased in size to 192.89
± 16.7 nm. When assessing cytotoxicity, 16.1
µM free Cisplatin decreased viability by 50%
after 48 h. Unlike nanoparticles which at 48 h decreased the percentage of cell viability at a 4.7 µM concentration. When comparing the viability with the free TZ in the cell lines, a decrease in the viability of 50% was observed for the nanoparticles (CDDP-CS-PLGA-TZ), and for the free TZ the viability only decreased by 5%. This indicates that TZ gave specificity to the nanoparticle and that Cisplatin performed its effect inside the cell.
4. POLYMER FIBERS AND CANCER
Not only have nanoparticles gained importance in the field of biomedicine to treat cancer, we can also find fibers which can be used for in situ therapies. One method of creating biopolymer- based drug-carrying fibers is electrospinning, a process in which a polymer solution is injected and is attracted by a magnetic field to a collector plate, where the solvent will be evaporated and fibers of different sizes arranged randomly or in an organized manner, will remain.46 This facilitates the process of making drug-conjugated fibers.47 Polycaprolactone (PCL) is a biodegradable polymer that consists of an aliphatic linear polyester. It is hydrophobic, semi-crystalline and biocompatible. It has been used in medical applications such as sutures, tissue engineering, nerve regeneration, etc.48,49
In 2017, Urvashi A, et al.50 conducted a study where they manufactured fibers with biopolymers such as polycaprolactone and chitosan, adding Cisplatin so that it was released into the cervix. The fibers were made by electrospinning. To simulate the vaginal environment a Franz’s diffusion cell was used.
In addition, they conducted in vitro and in vivo studies. The first with Ehrlich ascites carcinoma (EAC) cells and the second with swiss albino
mice in a cervical cancer model induced by EAC cells. The release of the drug reached its peak after 30 days. As for the cell viability observed, it differed by a small percentage in relation to pure Cisplatin. This is extrapolated in the in vivo model, where not only cell viability decreased, but also the size of the implanted tumor.
Another innovative way to treat some types of cancer is through gene therapy, which involves small interfering RNA molecules (siRNA). They are small anti-sense RNAs (20-25 bp), that are involved in gene silencing after transcription.
siRNAs may decrease the regulation of the BCR-ABL region of chronic myeloid leukemia (CML). Although the half-life of these is close to 24 hours, in addition to having a negative charge and a rigid structure.51,52
Many nutraceuticals, such as resveratrol, have been investigated for their chemopreventive action and their safety is proven.53 Resveratrol is a poly-phenolic compound known to inhibit different targets including sphingosine kinase 1 (SphK1), decreasing cell proliferation and tissue inflammation. These nutraceuticals are not specific, and their bioavailability in vivo is low. 54 In 2019, Al-Attar T, et al.55 performed a fiber- based system with siRNAs. The delivery of the target siRNA induced BCR-ABL expression using holo-transferrin conjugated liposomes in conjunction with resveratrol, using electrospinned fibers. They used a myelogenous leukemia cell line (K562) and non-cancerous human umbilical venous endothelial cells (HUVEC), and their co-cultures. The fibers were made with polycaprolactone (PCL) and gelatin (GT). The liposomes used had holo-transferrin conjugated to polyethylene glycol (PEG) liposomes, encapsulating the siRNA. The effect of the use of liposomes with siRNAs showed greater silencing in the expression of the BCR-
ABL gene than the control or the use of siRNA alone. It also influences cell viability, although free siRNA showed similar levels of apoptosis and cell necrosis. While it is observed that by ligating the encapsulated siRNA to liposomes and adding PEG, there is a greater number of cells in apoptosis. In addition, they turned out to have a higher uptake of siRNA when they traveled in liposomes than when they were free.
When co-cultivating HUVEC + K562 cells, a greater capacity for resveratrol degradation was demonstrated than HUVEC cells alone.
This nutraceutical causes a 20% inhibition in cell viability after 72 h. At 90 h, the resveratrol release from the fibers reached its maximum. By administering the fibers loaded with resveratrol together with the liposomes encapsulating the siRNA, they decreased cell viability by 80%.
Another biopolymer used is Pluronic F127 (PF127), a synthetic polymer consisting of units of ethylene oxide (PEO) and polypropylene oxide (PPO). It has favorable properties such as biodegradability, low or no toxicity, biocompatibility and thermo sensitivity.56,57 Camptothecin (CPT) is a pentacyclic alkaloid extracted from Camptotheca acuminata, a tree native to China. The way of acting of this molecule and its analogues is by inhibiting the activity of topoisomerase I (TopI).58
In 2017, Ma P, et al.,59 used PLGA combined with PF127, loaded with Camptothecin in fibrous meshes of PF127, produced by electrospinning.
These meshes had a fiber diameter in the range between 1.31 µm and 1.44 µm. They prepared 4 formulations: PLGA-CPT corresponds to only PLGA fibers with CPT; PPC-I is a 5:1 PLGA/
PF127 fiber ratio with CPT, PPC-II is a 4:1 PLGA/PF127 ratio with CPT; and PPC-III is a 3:1 PLGA/PF127 ratio with CPT. Despite
these diameters, in PCC-III rosaries were formed, indicating instability of the solution or that electrospinning conditions needed to be modified. The release of CPT at 50 days was 65% for PPC-II, for PPC-III was 40%, for PPC-I and PLA/CPT it was less than 30%; indicating that when adding PF127 to the PLGA, it gives the fibers an accelerated degradation. For the cell viability test, with mouse colon carcinoma cells (CT-26), they reported, at 24 h, a decrease of this up to 65% with PPC-II and PPC-III. There was a significant difference with the PLGA-CPT meshes, this can be attributed to PF127 since it was the variable element in the formulations.
Another of these biopolymers is polybutyrate adipate terephthalate (PBAT). It is a synthetic, biodegradable and flexible polymer. It has been used for hygiene products, wrapping materials and in the biomedical field.60 Ecoflex is an aliphatic- aromatic copolyester based on 1,4-butanediol monomers, adipic acid and terephthalic acid. It is biodegradable, non-mutagenic and non-toxic.61 Another chemotherapeutic agent used is 5-fluoracil (5-FU). It is a fluoropyrimidine, which is incorporated into DNA and RNA, and inhibits the enzyme that synthesizes nucleotides:
thymidyl synthetase. This drug has been used primarily for the treatment of colorectal and breast cancer, also for neck and head cancer.
Having as adverse effects diarrhea, nausea, decreased appetite, photophobia, decrease in platelets and erythrocytes, among others.62,63 Curcumin is a metabolite extracted from the Curcuma longa plant, which has anti-tumorigenic, antioxidant and anti-inflammatory properties.
This molecule inhibits the proliferation and invasion of tumors by the suppression of signaling pathways and its effectiveness against breast, lung, neck and head, and prostate cancer has been demonstrated. Even with these activities, it
has limitations such as low bioavailability, water solubility and chemical stability, which is why it is found in DDS.64,65
Varshosaz J, and collaborators,66 carried out in 2018 the production of nano fibers with Ecoflex loaded with 5-FU and curcumin, using electrospinning to be coated with the meshes indicated for colorectal cancer occlusions. The diameters of the non-drug fibers ranged from 442 nm to 822 nm, and the average size of the fibers with drugs were between 498 nm and 591 nm.
Curcumin fibers with 5 FU (4 µM) decreased cell viability by 95%, while the 5 FU solution (4 mM) decreased it to 60% of HT29 cells (colorectal cancer cells). This makes these fibers a perfect coating for therapeutic meshes.
Poly lactic acid (PLA) is a polymer derived from lactic acid. It is a biodegradable material, malleable and easy to use. It has been used for drug delivery systems, orthopedic equipment, tissue engineering and implants.67,68
Zong, S, and collaborators69 made nanofibers based on PLA and PEO loaded with Cisplatin, prepared by electrospinning. They used a murine cancer model, with mouse cervical cancer cells (U14) in female KM mice. The fiber diameter obtained was between 0.2 and 0.5 µm. In the in vitro assay they compared the percentage of release in medium and in vaginal tissue, being 60% and 30% of the total, respectively.
Subsequently, they evaluated an in vivo model, where after 72 h of treatment, intravenous Cisplatin had been distributed and preserved in organs such as the heart, lung, liver, spleen, kidney and blood. This was in greater concentrations than with treatment with the Cisplatin fibers;
but the Cisplatin from the fibers had its higher concentration in the vaginal tissue and in the tumor site. Therefore, there was tumor inhibition after 9 days of administration. Regarding the
health of the mouse, it was observed that the Cisplatin fibers increased the safety of the drug, since the weight of the mouse did not decrease significantly (Table 1).
Table 1. Summary of the biopolymer carriers
5. COMPLEX BIOMATERIAL AND CANCER SYSTEMS
Despite these two simple systems (nanoparticles and fibers), there are complexes, made up of two or more DDS in order to control and direct the chemotherapeutic agents, and therefore increase specificity and couple other therapies.
An example of these platforms was carried out by Zhong G, et al.70 They used a formulation of 3 blocks of biopolymers: Polyethylene glycol (PEG), guanidine-functionalized polycarbonate (PGC) and poly lactates (PDLA) using the OROP technique, which consists in the polymerization and consensation of a growing chain in an ending site.71 Making micelles, due to the charges of the resulting chain, of the 3 different molecule blocks (Figure 2).
Fig. 2. Schematic representation of systemic drug delivery for treatment of malignant tumors including various types of biopolymeric systems using the OROP technique.
They used both a normal hepatocyte cell line (HL7702) and cancer cell lines, such as: HPV- related adenocarcinoma cells (BCAP37); human hepatoma (HEPG2); human lung carcinoma (A549) and human squamous cell carcinoma (A431). In addition, they evaluated these platforms against multi-drug resistant cancer cell lines such as: resistant human breast cancer (Bats72 and Bads200). Also, they conducted the experiment with an in vivo breast cancer model:
mice injected with metastatic cells (HT1). When comparing the effect of these platforms against PTX and DOX alone, it was observed that they need the PGC block to increase their specificity towards the target cells, in addition to having shown greater efficiency in the toxicity models used. Such platforms inhibit metastasis, although
Type of
carrier Polymer Drug Molecule
added Cell line tested
NP* CS PTX - MDA-
MB-231
NP* PLGA/CS CDDP TZ SK-OV-3
Fibers * PCL/CS CDDP EAC/in vivo
Fibers* PLGA/PF17 CPT CT-26
Fibers* Ecoflex® 5 – FU
CUR HT-29
Fibers* PLA/PEO CDDP U14/ in vivo
Fibers* PCL/GT RVT siRNA K562 /
HUVEC/
Co-Culture
Fibers* PCL/PANAM DOX HDFa/A431/
HeLa/MCF7
Complex PGA/ CS/ PEG DOX FA SK-OV-3
KB
Complex PLGA CDDP TP13 SMMC-7721
Complex PEG/PGC/PDL
HL7702/
BCAP37/
HEPG2/
A549/A431/
Bats72/
Bads200/ in vivo
Complex CS DOX CoFe2O4/TiO2 B16F10
Complex PSS/PAH/CS/PEC CDDP CaCO3 HeLa/MCF-7
Complex HPMC CAR RB Caco-2/HDF
Complex PEG/PEI DOX AuNP DLD-1/HCT-
116/ in vivo
* - Involves a simple carrier; Complex – involves two or more carriers; NP – Nanoparticles; CS – Chitosan; PTX - Paclitaxel; PLGA – Poli-lactic-co- glicolic-acid; CDDP – Cisplatin; TZ – Trastuzumab; PCL – Polycaprolactone;
CPT – Camptothecin;PF17 – Pluronic F17; 5-FU – 5- Fluorouracil; CUR – Curcumin; PLA – Poly lactic acid; PEO – Poly (ethylene oxide); GT – Gelatin;
RVT – Resveratrol; siRNA – Small interfering RNA; PANAM – Poly (amido- amine); PEG – Polyethylene glicol; DOX - Doxorubicin; FA – Folic acid;
PGC -Guanidinium-functionalized polycarbonate; PDL - Polylactides; PSS – Anionic polystyrene sulfonate sodium salt; PAH – Cationic poly(allylmine) hidrochloride; PEC - Pectin; PEI – Polyethylenimine
it is observed that when subjected to cells for prolonged periods, they can generate resistance.
A hyperthermia treatment consists in increasing cell temperature, more than normal. This can be directed and kills cancer cells by destroying proteins and cell structure. This treatment can decrease tumor volume and can act in conjunction with radiotherapy and chemotherapy.72
Radmansouri M, and collaborators73 could observe that a disadvantage of magnetic nanoparticles is that they are easily carried away from their target by blood flow and dispersed to other organs during treatment. To reduce this effect, they can be coupled to a polymer matrix. Nanofibers prepared by electrospinning, due to their porosity, can be loaded with these magnetic nanomaterials.
The nanoparticles prepared by the authors were made with cobalt ferrite and titanium oxide, loaded into chitosan nanofibers for hyperthermic treatment. Doxorubicin (DOX) was incorporated into chitosan fibers to investigate the simultaneous effect of hyperthermia and chemotherapy towards melanoma (B16F10). The chitosan fibers were prepared by electrospinning.
The nanoparticles had an average diameter of 20 nm; while the diameter of the chitosan fibers with the cobalt ferrite, titanium oxide and doxorubicin nanoparticles were 90 nm on average. Fibers of pure chitosan ranged from 80 to 150 nm.
The fibers had a DOX encapsulation efficiency of 95%. They applied cycles of hyperthermia in the fibers with DOX. This platform had a greater release efficiency towards the tumor than those that were not given the treatment with hyperthermia. The strong interaction between DOX and chitosan resulted in a slow release.
According to the results, magnetic nanofibers loaded with DOX exhibited an improvement in the efficacy of anti-tumor activity. On the third day, cell death was 78%, in addition to inhibiting
cell growth without applying the magnetic field.
Another complex system is the layer-by-layer (LbL) assembly, which is a method for coating substrates with polymers, colloids, biomolecules and cells through the adsorption characteristic of opposite charges. This gives superior control compared to other carrier techniques, at an industrial or research level.74
Vergaro V, et al.75 used the LbL method to make capsules or microparticles using 4 polysaccharides in 2 in 2 combinations: anionic polystyrene sulfonate with poly allylamine hydrochloride (PSS/PAH) and chitosan with polyanion pectin (CHI/PEC), with microparticles of CaCO3 as support. They used them as a delivery system for Cisplatin. They used human cervical cancer cells (HeLa) and a human breast cancer line (MCF- 7). The microparticles had a biconcave shape and measured about 2 µm. Cell lines captured 90%
of the microparticles within 3 hours of being administered. Although at this time, the cell viability did not decrease, but remained at 80%
when treated with the drug-free microparticles, unlike the controls where the latter decreased over time. But when these particles were loaded with 10 µM and 100 µM Cisplatin, there was a lower cell viability, about 50% and 30% respectively.
Showing differences with the controls and the treatment with free Cisplatin. Demonstrating that natural polymers have greater cellular uptake than synthetic polymers and therefore greater efficiency in the delivery of the drug, that is translated as a decrease in cell viability.
The authors also observed a greater amount of platinum in the DNA of the cell lines with the biopolymers forming adducts.
Another complex system was that of Bala P, and collaborators,76 who made a DDS consisting of electrospun poly e-caprolactone fibers (PCL), containing a polymer synthesized from poly amido-amine (PANAM) in the core and PCL
branches. It was synthesized via ring opening polymerization and DOX was added to the solution before electrospinning. It was tested in order to demonstrate biocompatibility with adult human dermal fibroblasts (HDFa). In addition, to assess toxicity they used cell lines of epidermal carcinoma (A431), cervical cancer (HeLa) and breast cancer (MCF-7). The fibers measured in diameter from 0.7 to 0.9 µm. The biomaterial turned out to have biocompatibility with human fibroblasts, although unlike PCL fibers with DOX, PCL-DOX-PANAM fibers were found to have a prolonged release, so cell viability was not aggressively decreased. But it took 9 days to decrease it to 50%. This is helpful, since the cells do not develop resistance to the drug.
Photodynamic therapy is based on the exposure of cells or tissue to a photosensitizing drug followed by radiation with visible light at an appropriate wavelength, which can induce cell death, necrosis or autophagy. It consists of three components: the photosensitizer (such as light and oxygen), the formation of the oxygen singlet (1O2), and a significant toxicity which results in apoptosis or cellular necrosis.77 Rose Bengal Acetate (RB) is one of these photosensitizers which has been recognized in recent years for its induction of cell death and autophagy.78
Carmofur (CAR) is another antineoplastic compound that contains a reactive electrophilic carbonyl that targets the catalytic cysteines in the human acid ceramidase enzyme. Inhibiting it can treat diseases such as prostate cancer, glioblastoma and melanoma.79
A dual platform was made by Li H, and collaborators,80 using Carmofur, (CAR) and Rose Bengal (RB), by coaxial electrospinning.
Hydroxypropyl methylcellulose (HPMC) was used as the polymer core because it is a known mucoadhesive. Human colorectal
adenocarcinoma cells (Caco-2) and dermal human fibroblasts (HDF) were used for in vitro assays. The diameter obtained for the fibers with the free drug was 226 ± 73 nm, like those loaded with RB: 238 ± 72 nm. However, the fibers loaded with CAR and both active ingredients showed reduced diameters of 200 ± 72 nm and 196 nm ± 57 nm, respectively. The species made were: the starting point is that all the fibers carried HPMC; S1: HPMC fibers only; S2: the core solution was CAR and the HPMC fibers with CAR also; S3: RB in the core and HPMC fibers also with RB; S4: CAR and RB core and fibers made with HPMC, CAR and RB. The S3 and S4 fibers reached their maximum RB release concentration (90%) at 10 hours. Although approximately 80% of the CAR from S4 was released at 10 hours. For the HDF cell line, viability with the pure antineoplastic decreased by 60%, but the S4 fibers with and without sensitization were the closest to obtaining this percentage. For the Caco-2 line without sensitizing, the S2 and S4 fibers were close to the viability denoted by the treatment with the pure drug, but when sensitized, these viabilities decreased up to 20% only for S4.
Proving that these fibers can be an optional method for the treatment of cancer in a mucosa such as the mouth.
In another study, Hung W, and collaborators,81 investigated two complex nanoparticles formed by a nucleus of 5 nm gold nanoparticles, Polyethylene glycol (PEG), polyethyleneimine (PEI), a pyrene functional group (this was present at 2 different concentrations - A and B) and a chemotherapeutic agent, Doxorubicin (DOX). The manufacture was as follows: a PEG arm was added to the gold nanoparticle, from which PEI and DOX were joined, forming a platform with two formulations: DOX-AuPPPyA and DOX-AuPPPyB. The particle size for both was 0.2 µm. Cytotoxicity was measured in
Dukes human colorectal cancer lines (DLD- 1) and in another human colorectal cancer cell line (HCT-116). In addition, a 6-week-old naked mouse was studied in a xenograph model, DLD-1 cells were applied, subcutaneously injected into the right leg, and the mouse weight and tumor size were measured. The treatments were administered 3 a week, by intraperitoneal injection. The cell viability of the DLD-1 line decreased 40% with both particle formulations, unlike the free drug at a concentration of 10 µM, where cell viability decreased 40%. For the HCT-116 line, cell viability with the pure drug, at a 10 µM concentration, decreased to 50%. This was similar to DOX-AuPPPyA, while DOX-AuPPPyB decreased viability by 40%, similar to a 5 µM DOX concentration, in 24 hours of treatment.
The efficiency of particle uptake and DOX release within these cells falls in the range of 5 to 10 µM of free DOX. After 29 days, they stopped measuring the tumor. Without treatment it measured 600 mm3, with DOX treatment it measured 400 mm3, the DOX- AuPPPyA samples measured 300 mm3, and for DOX-AuPPPyB they measured about 150 mm3. Regarding the toxicity of these nanoparticles, the mice weights were evaluated, and these were constant in all treatments.
A few DDS are in a clinical trial, but NK105 and NC-6004 had success on them. The first, was on a phase III clinical trial, comparing the non- inferiority with the PTX alone in breast cancer patients. NK105 is a DDS that involves a micellar nanoparticle made by PEG and PTX which in the past year had a better safety and efficacy than the PTX alone.82 For NC-6004, a carrier made with PEG and CDDP had a significative advance in clinical trials, because it proved to make less toxicity than CDDP alone in the treatment of solid tumours, in patients (Figure 3).83
Fig. 3. Synthesis and self-assembly of polymers.
Anticancer strategy using copolymers as macromolecular chemotherapeutics.
CONCLUSIONS
Drug delivery systems propose novel alternatives to reduce the side effects caused by cancer treatment, with the likelihood of increasing their specificity in later years as new biomarkers exclusive to cancerous cell types are discovered.
In addition, they can reduce the recurrence of these cancer cells by eliminating the disease without resorting to other therapies, or, that these are less harmful to the human body. As we can see in this review, both the nanoparticles and the fibers can be directed or complement each other to increase the release efficiency and protein-receptor specificity, and thus decrease the resistance that cancer cells have shown to have. Some articles lack in vivo models, where they show that the nanoparticles or that the free drug in blood does not reach other organs not affected by cancer cells; and that these have no greater short-term and long-term side effects than chemotherapy.
REFERENCES
1) Aspectos básicos sobre el cáncer. 2016.
Sociedad Americana contra el cáncer.
https://www.cancer.org/es/cancer/aspectos- basicos-sobre-el-cancer/que-es-el-cancer.
html. Revisado el 15 de Junio del 2019.
2) Hyndman, I. J. 2016. Review: the
Contribution of both Nature and Nurture to Carcinogenesis and Progression in Solid Tumours. Cancer Microenviron. 9: 63–69.
doi: 10.1007/s12307-016-0183-4.
3) International Agency for Research on Cancer.
2018. Globocan 2018 México Report. 283, 2. Retrieved from http://gco.iarc.fr/today/
data/factsheets/populations/484-mexico- fact-sheets.pdf.
4) Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, & Jemal, A. 2018. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68: 394–424. doi:
doi:10.3322/caac.21492.
5) Yabroff K, Lund J, Kepka D, & Mariotto, A. 2014. Economic Burden of Cancer in the US. Cancer Epidemiol Biomarkers Prev., 10.11(301): 1–18. doi: 10.1158/1055-9965.
EPI-11-0650.
6) Vicente J & Guillén A. 2017. Problemas y factores psicologicos en el retorno al trabajo tras incapacidad temporal prolongada por cáncer de mama. Med Segur Trab. 63(248):
245-259.
7) Cancer Research UK. 2013. How many different types of cancer are there?
[internet] http://www.cancerresearchuk.
org/aboutcancer/cancers-in-general/cancer- questions/how-many-differenttypes-of- cancer-are-there. Accessed June 2018.
8) Nurgali K, Jagoe R, & Abalo R. 2018.
Adverse effects of cancer chemotherapy:
Anything new to improve tolerance and reduce sequelae? Frontiers in Pharmacology, 9:1–3. doi: 10.3389/fphar.2018.00245.
9) Nonnekens J & Hoeijmakers J. 2016. After surviving cancer, what about late life effects of the cure? EMBO Molecular Medicine.
9(1): 1 –3. doi: 10.15252/emmm.201607062 10) Zugazagoitia J, Guedes C, Ponce, S, Ferrer
I, Molina-Pinelo S, & Paz-Ares L. 2016.
Current Challenges in Cancer Treatment.
Clinical Therapeutics, 38(7): 1551–1566.
doi:10.1016/j.clinthera.2016.03.026.
11) HAAGENSEN, C. D. (1947). Recent advances in cancer therapy. Bulletin of the New York Academy of Medicine, 23(3), 123–135.
12) Fonseca A, Serra A, & Coelho J. 2015.
Bioabsorbable polymers in cancer therapy:
Latest developments. EPMA Journal, 6(1), 1–18. doi: 10.1186/s13167-015-0045-z.
13) Senapati S, Mahanta A, Kumar S, & Maiti P. 2018. Controlled drug delivery vehicles for cancer treatment and their performance.
Signal Transduct Tar. 3(1): 1–19. doi:
10.1038/s41392-017-0004-3.
14) Jahangirian H, Ghasemian E, Webster T, Moghaddam R & Abdollahi Y. 2017. A review of drug delivery systems based on nanotechnology and green chemistry: green nanomedicine. Int J Nanome. 12: 2957-2978.
doi:0.2147/IJN.S127683.
15) Talebian S, Foroughi J, Wade S, Vine K, Dolatshahi-Pirouz A, Mehrali M, Wallace G. 2018. Biopolymers for Antitumor Implantable Drug Delivery Systems: Recent Advances and Future Outlook. Adv Mater.
30(31):1–31. doi: 10.1002/adma.201706665 16) Raghavendra G, Varaprasad K, Jayaramudu
T. 2015. Biomaterials: Design, Development and Biomedical Applications. In:
Nanotechnology Applications for Tissue Engineering. 1st Ed. ELSEVIER.
17) Pan J, Rostamizadeh K, Filipczak N, &
Torchilin V. 2019. Polymeric co-delivery systems in cancer treatment: An overview on component drugs’ dosage ratio effect.
Molecules, 24(6): 1 – 32. doi:10.3390/
molecules24061035.
18) Niaounakis, M. 2015. Definitions of Terms and Types of Biopolymers. In Biopolymers:
Applications and Trends. doi:10.1016/b978- 0-323-35399-1.00001-6.
