Jurnal PVA Cancer

International Journal of Pharmaceutics 600 (2021) 120478
Contents lists available at ScienceDirect
International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm
Polyvinyl alcohol based-drug delivery systems for cancer treatment

Gabriela Rivera-Hernández a, d, Marilena Antunes-Ricardo a, Patricia Martínez-Morales b, Mirna
L. Sánchez c, *
a
Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias, Centro de Biotecnologia-FEMSA, Ave. Eugenio Garza Sada 2501, Monterrey, Mexico
b
CONACYT- Centro de Investigación Biomédica de Oriente-IMSS, Km 4.5 Carretera Federal Atlixco-Metepec, 74360 Metepec, Puebla, Mexico
c
Laboratorio de Materiales Biotecnológicos (LaMaBio), Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, IMBICE-CONICET, Bernal, Argentina
d
Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Argentina
A R T I C L E I N F O A B S T R A C T
Keywords: Polyvinyl alcohol (PVA) is a biodegradable semicrystalline synthetic polymer that has been used for biomedical
Cancer applications for several years. In the pharmaceutical area, PVA has been widely used to prepare solid dispersions
Hydrogel to improve the solubility of drugs. Furthermore, it has been demonstrated that PVA is highly biocompatible and
Microparticles
non-toxic in in-vitro and in-vivo studies. Several reports provided in this review suggest a promising strategy for
Nanoparticle
Polyvinyl alcohol
cancer treatment. Thus far, the current therapy includes a combination of surgery, chemotherapy, and radio
therapy, the effectivity can be limited due to the heterogeneous manifestations of the disease, dose-related
toxicity, and side effects. A promising strategy is the implementation of a targeted therapy using hydrogels,
microparticles, or nanoparticles (NPs), capable of encapsulating, protecting, transporting, and targeted admin
istration of a therapeutic agent. Considering the relevance of the PVA in conjunction with their copolymers, it has
become a promising biodegradable material to build novel functional composites used in the fabrication of
hydrogels, microparticles, nanoparticles, and nanocomposites for drug delivery systems in cancer treatment.
1. Introduction treatment drug delivery systems approved for sale, 81 nanoparticles,

and 13 hydrogels (ClinicalTrials.gov, 2020). The nanoparticles drug
According to the World Health Organization (WHO), cancer is one of delivery systems (NDDS) include gold nanoparticles, oxide nano
the leading causes of death in the world, with an estimated 9.6 million particles, nanoliposomes, collagen matrix (Rexin G), bioadhesive
deaths in 2018. In 2020, the most common mortal cancers were lung nanoparticles, super magnetic iron oxide nanoparticles, stable nucleic
(1.76 million deaths), colorectal (862,000 deaths), stomach (783,000 acid nanoparticles and the albumin stabilized nanoparticles (Nab-
deaths), liver (782,000 deaths), and breast (627,000 deaths) (IARC, paclitaxel) (ClinicalTrials.gov, 2020). Nowadays, the NDDS’s are used as
2020). Unfortunately, treatment is limited due to the heterogeneous alternatives of treatment for carcinomas of thyroid, lung, prostate,
manifestations of the disease, dose-related toxicity, and side effects ovarian pancreatic, cervical, gastric skin, head and neck, brain, lym
(Olov et al., 2018; Saklani and Kutty, 2008). A promising strategy to phoma sarcoma, and in a greater number of cases on breast cancer
limit the adverse effects of these treatments is the implementation of a (ClinicalTrials.gov, 2020). The results of clinical trials have suggested
targeted therapy through the use of nanoparticles (NPs) and hydrogels, some advantages of NDDS’s such as a higher response, longer time to
capable of encapsulating, protecting, transporting, and administering a tumor progression, and, in patients receiving second-line or greater
therapeutic agent (Pandey et al., 2014). Encapsulated drug delivery therapy, a longer median survival (Tran et al., 2017; Yardley, 2013). For
systems also offer the possibility of liberation of adequate concentra example, Nab-paclitaxel a formulation of paclitaxel in the presence of
tions in localized areas, maximizing the effect against cancer cells while serum albumin in a nanoparticle colloidal suspension (average size of
reducing the side effects and cytotoxicity in healthy cells. Although only 130 nm), has the advantage in comparison with the application of
a relatively small number have been approved, these are likely to be an Cremphor-EL-paclitaxel (Paclitaxel + 50% Cremophor EL (CrEL)/abso
increasing part of oncological therapies in the coming years (Iturrioz- lute ethanol) of a shorter infusion time (30 min), it no need for pre
Rodríguez et al., 2019; Sunderam et al., 2019). Now, there are 94 cancer medication for hypersensitivity reactions and utilizes the endogenous
* Corresponding author.
E-mail address: mirna.sanchez@unq.edu.ar (M.L. Sánchez).
https://doi.org/10.1016/j.ijpharm.2021.120478
Received 4 October 2020; Received in revised form 23 February 2021; Accepted 6 March 2021
Available online 12 March 2021
0378-5173/© 2021 Elsevier B.V. All rights reserved.
G. Rivera-Hernández et al. International Journal of Pharmaceutics 600 (2021) 120478
albumin transport mechanisms to concentrate nab-paclitaxel within the 2.1. Physico-chemical properties
tumor (Chao et al., 2005; Stinchcombe, 2007). Another example is Rexin
G target gene therapy, which is encapsulated in a collagen matrix Generally, PVA is soluble in water, slightly soluble in ethanol and
nanoparticle and administered intravenously. It was the first approved insoluble in other organic solvents. It is tasteless and odorless. Other
therapy for clinical trials in the treatment of metastatic cancers. Rexin G properties such as pH, viscosity, drying, melting point, refractive index,
accumulates in cancerous lesions, enhancing local drug concentration and residue on ignition are based on molecular weight and hydrolysis
within tumors. It is used in the treatment of Sarcoma, osteosarcoma, and percentage. For example, the partially hydrolyzed PVA (87–89%) is
pancreatic cancer (Chawla et al., 2019). more soluble in water and it has more flexibility and adhesion to hy
In the pharmaceutical area, polyvinyl alcohol (PVA), a biodegrad drophobic surfaces. On the other hand, highly hydrolyzed PVA
able semicrystalline synthetic polymer, had been widely used to prepare (91–99%) is more stable in the presence of organic solvents and has
solid dispersions in order to improve the solubility of drugs and prevent more tensile strength and adhesion onto hydrophilic surfaces (Rowe
crystal transformation. Furthermore, the PVA is used as a granulating et al., 2009; Marin et al., 2014; Saxena, 2003). The specific values of
liquid to prevent nucleation, slow crystal growth and remove water PVA physico-chemical properties are shown in Table 1.
excess by absorption (Gaaz et al., 2015; Vaidya et al., 2008). In addition, Hydroxyl groups of PVA produce inter and intramolecular hydrogen
PVA has been used as an embolic agent since the 1970s and current bonding. They have an important effect on the rheological and me
intravascular use is primarily in the form of microparticles (Córdoba- chanical properties of the polymer, which is determined by the density
Esquivel et al., 2019). Lately, the PVA in conjunction with their co and spatial arrangement of hydroxyl groups (Gao et al., 2010). These
polymers, had been used to control drug delivery, as it can be useful for bonding are also responsible for phenomena such as phase separation
both, hydrophilic and hydrophobic drugs. It is a common excipient for and gelation, which means the solution properties are time-depending.
drugs administered by the ophthalmic, vaginal, and transdermal route Rheological and viscoelastic properties of the PVA solutions are
and it is considered as non-toxic by oral administration because of its affected by the effectiveness of the physical bonding and polymerization
high median lethal doses [LD50] in rats (15–20 g/kg) (Gaaz et al., 2015; degree and the molecular orientation is developed easier by steady shear
Marin et al., 2014). (Gao et al., 2010; Song and Kim, 2004).
The aim of this review is to provide a summary of the uses of PVA as a In addition, it has been demonstrated that PVA solutions in water are
component of biomaterials used in the fabrication of delivery systems rheological heterogeneous. It measured the rheological properties of
nanoparticles, hydrogels, and nanocomposites used in cancer treatment. PVA with 1300, 1700, 2000, and 2400 degrees of saponification
In addition, this review supplies novel information about the in-vitro and (transesterification reaction). It was found that with a higher saponifi
in-vivo biocompatible studies, and the state of art in the clinical trials cation degree, the PVA solution exhibits greater values of the complex
that involve the PVA biomaterials before mentioned. viscosity. Furthermore, PVA-1700, PVA-2000, and PVA-2400 solutions
had a non-Newtonian flow behavior, while PVA-1300 showed an almost
2. Polyvinyl alcohol properties Newtonian behavior (Gao et al., 2010).
PVA is a synthetic polymer represented by the formula (C2H4O)n. 3. PVA in biomedical area
According to the length of the initial vinyl acetate polymer and the
degree of hydrolysis, the PVA products can have different molecular It is important that a polymeric drug delivery system overcomes all
weights (20,000–400,000 g/mol). It is classified into two groups, the limitations and disadvantages related to conventional therapeutic
partially hydrolyzed and fully hydrolyzed. PVA chemical structures are agents and must be biodegradable, biocompatible, and non-toxic. The
shown in Fig. 1 (Gao et al., 2010; Rowe et al, 2009; Song and Kim, 2004). most representative delivery systems are hydrogels, microparticles, and
PVA was initially obtained in 1924 by Hermann and Haehnel, after loaded polymeric nanoparticles. It has been proved that the individual
hydrolyzing polyvinyl acetate in ethanol with potassium hydroxide properties of polymers are key for their use for specific targets (Hossen
(Chemical and Technical Assessment 61st JECFA, 2004). In 1960, it was et al., 2019; Lagoa et al., 2020; Marin et al., 2014).
reported the preparation of PVA by alkaline catalyzed alcoholysis of In this regard, PVA is one of the most used polymers in the
methanol solutions of polyvinyl acetate at temperatures in the range biomedical filed based on its mechanical properties, high ability to form
between about 30 to 60 ◦ C (Snyder, 1954). After, Inskip et al, (Marin films, nontoxicity, water-solubility, no carcinogenicity, hydrophilicity,
et al., 2014), report an alkali-catalyzed alcoholysis of polyvinyl esters to good compatibility and biodegradability in human tissues and fluids
produce polyvinyl alcohol with a better yield with the addition of (Hassan and Peppas, 2000; Luo et al., 2018; Rolim et al., 2019). As well
formaldehyde before the alcoholysis. The aggregation of polycarboxylic PVA has three remarkable properties for a polymer to be used as a de
acid was incorporated in order to neutralize the alkaline reaction, livery system: high surface stabilization, chelation properties (Fatema
increasing the thermal stability of the PVA in 1973 (Subramanian, et al., 2018; Kadhim et al., 2016)and low protein adsorption properties
1972). Nowadays PVA is produced commercially from polyvinyl ace resulting in low cell adhesion compared with other hydrogels (Baker
tate. The acetate groups are hydrolyzed by ester interchange with et al., 2012). All previous mentioned properties made that PVA would be
methanol in the presence of anhydrous sodium methylate or aqueous extensively used in many biomedical applications, including wound
sodium hydroxide (Marin et al., 2014). dressings (Badawy, 2014; Fatema et al., 2018; He et al., 2017).
Table 1
Properties values of polyvinyl alcohol (Rowe et al, 2009; Marin et al., 2014;
Saxena, 2003).
Properties Values
Flash Point 79 ◦ C
Melting Point 180–190 ◦ C
Boiling Point 340 ◦ C
Decomposition temperature >200 ◦ C
Viscosity >4,8–5,8 mPa.s (4% solution)
Density 1.19–1.31 g/cm3
pH 5,0–6,5 (4% solution)
Fig. 1. Partially hydrolyzed structural formula and fully hydrolyzed structural
Refractive Index 1.49–1.53
formula of polyvinyl alcohol.
2
A highlight is the use of PVA in many medical devices, including of physically cross-linked is based on the physical interactions (hydro
contact lenses, orthopedic devices and drug delivery systems, which had phobic, electrostatic, and hydrogen bonding) between the different
been approved by the U.S. Food and Drug Administration (Bolto et al., polymer chains as well as, for example, proteins interactions (Parhi,
2009; Bourke et al., 2003; Kobayashi et al., 2001; Yamagata et al., 1979; 2017). The protein interaction involves block copolymers, which can be
Yon et al., 1994). Also, PVA has been used in many non-implanted crystallized in physiological conditions, and determine film network
medical materials as a tissue adhesion barrier, to treat vascular embo formation and properties (Husain et al., 2018; Maitra and Kumar Shukla,
lism and to improve neurologic regeneration. Furthermore, it had been 2014). These physical and protein interactions can be destabilized by
reported the use of PVA in implantable medical materials to replace variations in pH, ionic strength, or temperature. For example, Xu et al.,
meniscus tissues and cartilage. These varied applications of PVA have 2018 report a protein engineered multinetwork physical hydrogel con
demonstrated its safety for human use, especially where the adsorption formed by tannic acid (TA), PVA and bovine serum albumin (BSA). They
of host protein is unwanted (Baker et al., 2012). treat a PVA/BSA solution by the freeze-thaw method and forms the first
This review addresses the use of PVA as delivery systems for cancer hydrogel network. Then, the TA was added, and a secondary hydrogel
treatment. It includes historical use of PVA as delivery system in cancer network based on the noncovalent interaction (hydrogen bond and hy
treatment, and in vitro and in vivo biocompatibility studies. drophobic interaction) was formed. This hydrogel shows high mechan
ical strength, good water- retention ability, and the mechanical property
of hydrogel can be well-regulated by varying the concentration of TA
3.1. Hydrogels
and BSA proteins.
The most common methods reported for obtaining physically cross-
The hydrogels are cross-linked polymer particles with a high-water
linked hydrogels are freeze-thawing (crystallization) (Sanchez et al.,
content and three-dimensional structure. They are biocompatible, and
2019) stereo complex formation (Wang et al., 2019), charge interaction
they had a swelling degree which allows drug delivery (Escalona Rayo
(Drozdova et al., 2017) and hydrogen bonding (Parhi, 2017; Xu et al.,
et al., 2014). Drug delivery from hydrogels can be classified in diffusion-
2018). Especially, crystallization is a widely used method for the syn
controlled, swelling-controlled, and chemical-controlled and it could be
thesis of PVA hydrogels. This method consists of the formation of mi
controlled by the response to the external stimuli like pH, temperature,
crocrystals and hydrogen bonding interactions in the polymer structure
ionic strength, and electric field (Maya et al., 2013). An example of the
due to the exposure of PVA solutions to cycles of freezing-thawing. The
release for stimuli is schematized in Fig. 2.
properties of these PVA hydrogels formed will depend on the number of
The hydrogels can be classified into crystalline, semi-crystalline and
freeze-thaw cycles, the concentration of the polymer solution, the mo
amorphous (non-crystalline), depending on the chemical composition
lecular weight of PVA, the temperature (generally − 20 ◦ C) and time of
and their physical structure. There are two methods used for hydrogel
the freezing (Rodríguez-Rodríguez et al., 2020). For example, (Sanchez
preparation, chemical (radical polymerization, chemical reaction with
et al., 2019) synthetized an eco-friendly hydrogel based on PVA and
functional groups, irradiation with high energy, and reaction with the
different contents of acid-treated bentonite (1–5 wt%). The free
enzyme) and physical methods (hydrogen bonding, ionic bonding, mo
zing–thawing method was chosen because it is a non-toxic technique.
lecular entanglements, or physical interaction) (Ghawanmeh et al.,
In the case of the stereo complex formation method, the hydrogels
2019).
are formed by a crosslinking between lactic acid oligomers of opposite
chirality (Maitra and Kumar Shukla, 2014). Wang et al., 2019 fabricated
3.1.1. Methods of synthesis of PVA hydrogels
an advanced injectable thermogel formed by poly(ethylene glycol)–
Synthesis of hydrogels is based on cross-linking networks and can be
polylactide (PEG–PLA) modified with cholesterol by stereo complex
classified into three main categories, physically cross-linked (self-
formation method. The hydrogel shows higher mechanical strength,
assembled hydrogel), chemically cross-linked and cross-linking by
lower critical gelation temperature, better chondrocyte adhesion, larger
irradiation (Sharma and Tiwari, 2020).
pore size, and slower degradation, compared with the PEG-PLA
hydrogel.
3.1.1.1. Physically cross-linked hydrogels. The physically cross-linked is
On the other hand, the hydrogels synthetized by charge interactions
a reversible method of hydrogels formation, where the network forma
are based on the use of amphiphilic blocks or graft copolymers which
tion is only physical. Recently, it has been increased interest in them,
contain different segments of hydrophobic and hydrophilic nature
because of their relatively easy synthesis and their main advantage of
which result in swelling and uptaking water that forms the hydrogel
avoiding toxic residues by keep away the use of cross-linking agents
(Maitra and Kumar Shukla, 2014). For example, Drozdova et al., 2017
during their synthesis process (Sharma and Tiwari, 2020). The principle
Fig. 2. Drug delivery of PVA hydrogel after a variation of pH or temperature.
3
synthetized hydrogels based on low molecular weight acrylated PVA chemically cross-linked hydrogels is the enzymatic reaction, which re
copolymerized with either negatively charged acrylic acid (AA) or quires slight reaction conditions, such as neutral pH, aqueous environ
positively charged 2-(diethylamino) ethyl methacrylate (DEAEMA) ment and mild temperature (Nguyen et al., 2015; Ogbeide Ebhodaghe,
monomers. The structure of the obtained hydrogels was studied in 2020). Some of the most used enzymes are horseradish peroxidase,
function of the co-monomer content and it was concluded that the tyrosinase, transglutaminase, lysyl oxidase and, phosphopantetheinyl
proposed modifications improved cell adhesion (mouse fibroblast and transferase. This method has the main advantage of the substrate spec
human mesenchymal stem cells), spreading and proliferation. ificity of the enzyme, which can prevent toxicity caused by side re
Finally, the hydrogen bonding method consists of the interaction of actions (Nguyen et al., 2015).
the hydrogen bonds, formed after the protonation of carboxylic acid
groups at a low pH. This method, brings the characteristic of show pH- 3.1.1.3. High-energy irradiation hydrogels. Finally, hydrogels could be
dependent swelling in hydrogels and it is used for the improvement of synthesized by the high-energy irradiation with gamma or electron
the physical and mechanical strength (Husain et al., 2018). For example, beam as well (Ogbeide Ebhodaghe, 2020). This method allows the cre
Liu et al. (2020) developed a hydrogel composed of PVA and poly ation of radicals in the polymer chain of hydrogel inducing the forma
(acrylic acid) (PAA). This material was prepared by immersing a PVA tion of covalent bonds between their functional groups without the
hydrogel into an aqueous PAA solution, forming the H-bonds between addition of a crosslinker. Gamma and electron beam polymerizations
the PAA and PVA chains. The facility of breakage and reformation of H- implicates the initiation, propagation, and termination steps similar to
bonding bring to the hydrogel network a very effective energy- the radical polymerization. The process begins when the hydroxyl rad
dissipating mechanism. The application proposed for these hydrogels icals are created and start free radical polymerization between the vinyl
are in biomaterials, sensors, and actuators, soft machines, and flexible monomers which proliferate in a quick chain addition. The hydrogel is
electronics Another example, are the pH-responsive supramolecular synthetized once the network reaches the critical gelation point (abrupt
hydrogels based on PVA with small phenolic biomolecules synthesized change in viscosity) (Maitra and Kumar Shukla, 2014; Rodríguez-
by (Euti et al., 2019). The structure and type of functional groups of Rodríguez et al., 2020). The main advantages of this method, are the
different phenolic molecules allow the formation of hydrogen bonding, control of pore size of hydrogels by varying the irradiation dose and the
which provided them the characteristics of controlled low phase tran possibility to perform at room temperature and in physiological pH
sition temperature, and pH-dependent swelling behavior. Some of the (Maitra and Kumar Shukla, 2014; Rodríguez-Rodríguez et al., 2020). For
applications proposed for these hydrogels include the 3D bioprinting example, Khozemy et al. (2019) synthetized a crosslinked hydrogel
and topical drug delivery of thermolabile biomolecules. Nowadays, this composite membrane based on PVA, vitamin E and chitosan-loaded
pH-dependent swelling characteristic in hydrogels is already explored in AgNO3 using gamma irradiation for potential use in wound dressings.
the oncologic area for the creation of smart materials for drug delivery It was found that increase of the irradiation dose improves radical for
(Fan et al., 2019). mation in the reaction mixture. For consequence, more crosslinking
occurred with a higher gelation percent. In other study, a Zinc oxide
3.1.1.2. Chemically cross-linked hydrogels. The chemically cross-linked (ZnO)/PVA hydrogel was created using gamma irradiation for being
hydrogels are formed by polymer networks cross-linked by covalent used in drug release. It was found that interaction between ZnO with the
bonds between pendant hydroxyl (–OH) groups present in PVA chains. hydroxyl group of the PVA produce a decrease in the equilibrium degree
They are stable, possess a higher mechanical strength than physical of swelling percentage in the ZnO/PVA hydrogel nanocomposites in
hydrogels and cannot be dissolved (Wang et al., 2018). The chemically comparison with pure PVA hydrogel (Kumaraswamy et al., 2017).
cross-linked hydrogels can be synthetized by chemical reaction of Nowadays, the existence of diverse synthesis techniques, allows the
complementary groups, where covalent bonds between polymer chains generation of a great variability of hydrogels, with different character
of hydrogels can be created by the reaction of their functional groups istics and applications. Specially, the biomedical area has become in a
with crosslinker agent, such as N, N-(3-dimethylaminopropyl)-N0-ethyl tendency for the innovation procedures of synthesis.
carbodiimide, tetraethoxysilane (TEOS), borates, glyoxal, glutaralde
hyde and other monoaldehydes, in conjugation with either methanol, 3.1.2. Use of PVA hydrogels for cancer treatment
acetic acid or sulfuric acid (Kumar and Han, 2017; Rodríguez-Rodríguez Because of its controlled release applications, and the kinetics of the
et al., 2020). However, this chemically crosslinking has the disadvan entrapped drugs which can be monitored by the regulation of the water
tage of the production of toxic radicals and monomers, which make uptake of the polymer or by crosslinking it, PVA hydrogels have become
these hydrogels unacceptable for biomedical applications (Kumar and a tendency as potential cancer treatment for different tissues (Chao
Han, 2017; Rodríguez-Rodríguez et al., 2020). For example, Liu et al. et al., 2020). For that reason, numerous studies are underway in human
(2020), design an ethylene glycol/PVA hydrogel to be used in a highly cancer cells lines, as it is shown in Table 2. The studies show promising
compressible and superior low temperature tolerant supercapacitor. preliminary results, and more test are required to determine other pa
This hydrogel shows a significant improvement of compressive stress rameters such as human doses and best administration route.
(15.5 MPa), excellent shape recovery property and high ionic conduc
tivity (0.48 S m− 1). In another research, a chemical-physical crosslinked
triple-network hydrogel was prepared using PVA, poly(N-vinyl-2- 3.2. Microparticles
pyrrolidone) (PVP) and AA as raw materials. This hydrogel showed a
fracture stress of 1.87 MPa, strain rate of 175%, and compressive stress Microparticles are characterized by their size, which is ranging from
of 3.5 MPa under 80% compressive deformation. The application pro 50 μm to 1200 μm. They have become a trend in material research due to
posed for this hydrogel is to develop a supercapacitor for compression- their simplicity and versatility. Nowadays, microparticles from different
resistant electronics (Li et al., 2019). materials already exist in the market for different therapeutic applica
An alternative method to produce chemically cross-linked hydrogels tions(Luz et al., 2020; Piacentini et al., 2020). Nevertheless, micropar
is the chain-growth polymerization, which includes anionic and cationic ticles synthesized from PVA (commonly called drug eluting beads
polymerization, free radical polymerization and controlled free radical (DEBs) have been specially put in the light because of their clinical use in
polymerization (Ogbeide Ebhodaghe, 2020). This method is performed the unresectable hepatocellular cancer treatment (ClinicalTrials.gov,
in three steps process, initiation, propagation, and termination, where a 2020).
free radical active site is created where monomers are added in a chain The PVA microspheres have been synthesized towards nucleophilic
form (Maitra and Kumar Shukla, 2014). Another method to produce substitution reaction with carbonyl diimidazole or carbodiimide. They
are conformed by functional groups on a preformed crosslinked PVA
4
Table 2
Different drugs used in chemotherapy loaded in polyvinyl alcohol hydrogels and polyvinyl alcohol composite hydrogels for cancer treatment in different cell lines.
Composite Loaded molecule Technique Application in vitro Reference
CMCh/PVA Oxaliplatin Modified free radical polymerization technique HCT-116 Colorectal cancer (Ullah et al., 2019)
Sulfoacetic acid/PVA Metotrexate Chemically crosslinked MDA-486 Mammary gland (Hou et al., 2016)
Gelatin/ PVA Cisplatin Dissolution and stirring A2780/CP70 Ovarian cancer (Oun et al., 2014)
Poly(methacrylate)/PVA Doxorubicin Polymer/polymer/water emulsion method LoVo Colon cancer (Cavalieri et al., 2008)
Hyaluronic acid/PVA-styrylpyridinium Paclitaxel Photocrosslinking reaction U-87 Glioblastoma (Tao et al., 2012)
Chitosan/PVA Doxazocin Chemically crosslinked HeLa Cervix Cancer (Jamal et al., 2018)
Polyvinyl pyrrolidone/PVA IkBa protein Repeated freeze thaw method HeLa Cervix Cancer (Banerjee et al., 2018)
hydrogel (Dreher et al., 2014). These microspheres are capable of being chloroform and dichloromethane (DCM). In addition, co-solvents, as
loaded with specific therapeutic agents and then deliver a high intra methanol, can be added (Floyd et al., 2015; Paulo and Santos, 2019).
tumoral drug concentration while reducing plasma drug levels, reducing The coacervation, also called phase separation, this technique in
systemic toxicity. Their therapeutic function is the delivery of chemo volves the dissolution of the polymer in an organic non-solvent that
therapeutic agents and generate ischemia, resulting in tumoral necrosis contains the drug to be encapsulated. This mixture is added to a vege
(Sottani et al., 2012). The most commercially available microspheres are table oil to induce polymer phase separation. Then, the polymer-solvent
from Merit medical, Boston Scientific, and Biocompatible UK labora is extracted before hexane or heptane is added to achieve the final
tories, which are used in process such as transarterial chemo sphere hardening, Finally, the microspheres are collected and washed
embolization (TACE), targeting intratumoral lactic acidosis (TILA) and (Floyd et al., 2015). This technique does not have the requirement of
drug-eluting bead (DEB). The microparticles characteristics are shown complex machines in high-pressure homogenization or high tempera
in Table 3. tures to melt the lipid matrix (Chirio et al., 2011).
Since the microparticles shown in Table 2 have been approved by The spraying drying is a well-established method of powder prepa
FDA a long time ago, (“510(k) Premarket Notification,” n.d.), they are ration from a liquid phase for a wide range of drugs in the pharma
the most used in clinical practice. Exist in numerous studies where a ceutical industry. In this technique, the polymer and drug are dissolved
comparison is made, between them and other materials, showing the in a solvent and passed through a spray dryer. A stream of heated air
advantages and disadvantages of each one (Bishay et al., 2014; Spies breaks the polymer solution into droplets, forming microspheres that are
et al., 2004). However, nowadays the researchers are focusing on the dried and collected (Chirio et al., 2011; Sham et al., 2004). Its main
replication microparticles drug delivery system, but in the nanoscale. advantages are the particle formation in a single-step continuous and
scalable process and the manipulation of the process parameters (Lee
3.2.1. Methods of synthesis of PVA particles et al., 2011).
Some of the techniques used to prepare micro and nanoparticles In addition, results suggest that the incorporation of PVA in the
include the single emulsion, double emulsion, coacervation and spray particle formulation from microscale to nanoscale range process may
ing drying. The single emulsion, also known as the oil-in-water (O/W) lead to the formation of mucoadhesive particles for many nano
emulsion or solvent extraction, it is a common method used to form drug particulate systems (Yang et al., 2014).
encapsulated polymeric microspheres for pharmaceutical purposes. The
process consists of forming the microsphere, dissolving the polymer in 3.2.2. Use of microparticles of PVA for cancer treatment
an organic solvent with the drug to be encapsulated. This combination is Until now, the most used form of PVA in the treatment of cancer is
added to an aqueous solution containing a stabilizer (PVA) and after the microparticles. TACE, TILA and DEB are used alone or in conjunction
they are homogenized. The organic solvent is then removed by evapo as an alternative of treatment in gastrointestinal, liver, hepatocellular,
ration and the drug encapsulated microspheres are recovered. A varia thorax, peritoneal and uterine cancer (ClinicalTrials.gov, 2020?).
tion of the single emulsion method can use an acetone/mineral oil Nowadays, the brands commercially available have been used specially
emulsion instead of the organic and water system (Floyd et al., 2015). to treat the unresectable liver cancer (Table 4). For example, it was re
The double emulsion known as the water-in-oil-in-water (W/O/W) ported a study which evaluated safety and efficacy of TACE-DEB PVA
emulsion, allows the efficient encapsulation of hydrophilic compounds. microparticles loaded with doxorubicin in patients with unresectable
The process consists in the dissolution of the drug to be encapsulated in a hepatocellular carcinoma. The results show a partial response of (10%),
small volume of water and the later addition of an organic solution, and the maintain a stable disease of (90%). Treated tumors demon
containing the dissolved polymer. This is emulsified and produces the strated a mean decrease in contrast enhancement of 64% (P < 0.0001).
first water-in-oil emulsion (W/O). The first W/O emulsion is then added Non-present progression of a treated lesion while undergoing treatment.
to an aqueous phase, containing PVA, forming a double emulsion of At 6 months, the disease control rate was 95%; median overall survival
water-in-oil-in-water (W/O/W). Finally, the organic solvent is evapo was 26 months (Reyes et al., 2009).
rated, and the microspheres are recovered. The most used solvents are The efficiency of PVA microparticles has also been compared with
Table 3
Characteristics of different PVA microparticles used in TACE, TILA and DEB for cancer treatment disponible in market.
Brand Hydrolysis Polymerization Gelling agent Viscosity (CSt) Crosslinking International patent
(%) degree Type reference
Merit Medical 1–25 67,000 Sodium acrylate 0–50 Physical (Cryo) US10265271B2
(HepaSphere)
Boston Scientific 80–99 9000–186,000 Sodium alginate 20–80 (20 ◦ C) Chemical US7901770B2
Merit Medical 80–99 – Acrylic copolymer – Chemical US9439861B2
(Embosphere) (trisacryl)
Biocompatibles UK – 200 to 2,000 Sodium alginate 150–200 Chemical WO2014152488A2
(40 ◦ C)
*CSt (Centipoise).
**DMSO (Dimethylsulfoxide).
5
Table 4
Different PVA microparticles used in TACE, TILA and DEB for cancer treatment are available in the market.
Brand Size Range Encapsulated Drug Interventions Type of cancer International patent
(μm) reference
Merit Medical 30–200 Doxorubicin HCl or Irinotecan DEB-TACE Hepatocellular Carcinoma; Metastatic Colorectal US10265271B2
(HepaSphere) Cancer to the liver.
Boston Scientic 45–1180 Oxaliplatin, Raltitrexed and DEB-TACE Colorectal cancer with Liver Metastasis; Liver US7901770B2
Doxorubicin Cancer
Merit Medical 50–900 – TILA-TACE Hepatocellular Carcinoma US9439861B2
(Embosphere)
Biocompatibles UK 70–700 Doxorubicin DEB-TACE Unresectable Liver Metastases from WO2014152488A2
Neuroendocrine Tumors
*DEB (Drug-eluting bead).

**TACE (Transarterial chemoembolization).
***TILA (Targeting intratumoral lactic acidosis).
other materials. For example, Shlansky-Goldberg et al., 2014 publish an of microparticles, for example PLGA/PVA nanoparticles used to control
study with the objective of make a comparison between spherical PVA the delivery of doxorubicin are made by single emulsion (Siddharth
microsphere (SPVA) (size 700–900 μm and 900–1,200 μm) with tris- et al., 2017). Another example is the use of double emulsion technique to
acryl gelatin (TAG) microsphere (size 500–700 μm) used for the treat synthesize drug-loaded polymeric nanoparticles for intracranial tumor
ment of symptomatic uterine fibroids with uterine fibroid embolization therapy, encapsulating chemotherapeutics such as 5-fluorouracil,
(UFE). The study shows that both products have an equal reduction in camptothecin, imatinib mesylate, C-terminal fragment of platelet fac
the symptom severity and the improvement of quality of life at 3 and 12 tor 4 (PF-4/CTF), hemopexin (PEX), doxorubicin, radio iodinated IUdR,
months. Complications were minor in both groups. antisense oligonucleotides, and mitoxantrone (Floyd et al., 2015). Also
Because of the promising preliminary results, the use of PVA mi Spray drying technique has been successfully used to encapsulate
croparticles had become an important research line, which according to paclitaxel and doxorubicin in PLA/PVA and PLGA/PVA nanoparticles
the base data of the National Institute of Cancer exist thirty-two clinical for brain tumor treatment (Floyd et al., 2015).
trials using PVA for oncological purposes.
3.3.1. Use of PVA nanoparticles for cancer treatment
3.3. Nanoparticles Although clinical trials have shown some chemotherapies as a safe
drug even at high doses, poor bioavailability and suboptimal pharma
Nanoparticles are systems that range in size from 1 to 300 nm and cokinetics largely moderated its anti-cancer activity in pre-clinical and
contain a therapeutic agent. They can be synthesized from a diversity of clinical models (Yallapu et al., 2010). In recent years, polymeric nano
substances, such as polymers, lipids, ceramics, and carbon nanotubes. particles have become the most promising and viable technology plat
Polymer nanoparticles are stable and allow high loading of agents, form for targeted and controlled drug delivery systems for anti-cancer
which brings the opportunity to control the drug release kinetics and drugs. They accumulate in cancer tissues through the enhanced
displays a variety of surface-attached ligands (Feng et al., 2010). For permeability and retention effect, reducing the toxicity in non-target
example, silk/PVA nanoparticles could be loaded with a therapeutic tissues, and protecting drugs from preliminary inactivation (Pieper
drug and show pH-dependent release in-vitro. It had been reported a new et al., 2019). The nanoparticles should possess high drug loading levels,
aqueous-based method of preparation, called polyvinyl alcohol blends, deliver drugs to the specific pathological site, and target cells without
used for silk spheres synthesis with controllable size and shape. In these drug leakage on the way (Cheng et al., 2013). Nanoparticles with a
systems, the drug distribution and loading efficiency depend on their hydrophobic surface are early absorbed by the liver, spleen, and lungs,
hydrophobicity and charge, which leads to different drug release pro while those with a hydrophilic surface show an increased circulation
files (Cao et al., 2017). The PVA is widely used as a surfactant during time in the body (Cheng et al., 2013).
particle formulation by the nanoprecipitation or emulsion methods Regarding PVA nanoparticles, they have become a tendency in
leads to the formation of nanoparticles (Yang et al., 2014) and to cancer treatment for different tissues because of the relatively low cost
encapsulate metallic nanoparticles (Khanna et al., 2005). Some exam and high biocompatibility (Pieper et al., 2019). For example, Yallapu
ples of this formulation are shown in Fig. 3. et al. (2010) developed PLGA nanoparticles, in the presence of PVA and
Synthesis methods of nanoparticles are similar to synthesis methods PLL stabilizers, using a nanoprecipitation technique to encapsulate
Fig. 3. a) Polymer nanoparticle coated with polyvinyl alcohol. b) Polyvinyl Alcohol coated mesoporous silica nanoparticles. c) Polyvinyl Alcohol coated metallic
nanoparticle.
6
curcumin to improve its applicability in cancer therapy. In this study as a part of diabetes therapying in animals models (Cai et al., 2016).
nanoparticles demonstrated two and sixfold increases in the cellular Because of its biocompatibility, PVA has been widely used as an
uptake performed in cisplatin-resistant A2780CP ovarian and metastatic excipient in biomedical and pharmaceutical drug delivery systems
MDA-MB-231 breast cancer cells, respectively, compared to free cur administered by ophthalmic, vaginal, and transdermal routes (Gaaz
cumin. Also, Hu et al. (2008) report the synthesis of a self-assembled et al., 2015).
PVA-Iron oxide/silica core-shell nanocarriers for the controlled release Thus far, some studies for cell absorption are described for epithelial
of therapeutic agents by an external magnetic field. The nanoparticles lung cells and cancer cells. Because of the highly glycosylated segments
present a high-efficiency uptake by HeLa cervical cancer cells and interspersed by hydrophobic, lipid-coated domain, present in mucus,
exhibit excellent cytocompatibility, implying the nanoparticles are PVA particles could be trapped through steric obstruction and adhesion
potentially capable of offering highly efficient and accurate release of of constituents through hydrophobic, electrostatic and hydrogen
therapeutic agents for anti-cancer applications. In addition, De Patricio bonding interactions (Yang et al., 2014), however, Madlova et al. (2009)
et al. (2014) prepared PLA/PVA nanoparticles charged with confirmed qualitatively by confocal images that PVA nanoparticles are
Phosphorus-32 orthophosphate, strontium-89 Chloride, and internalized by epithelial lung cells, independently of surface charge, or
ethylenediamine-tetra-methylenephosphonic acid (EDTMP) using a particle hydrophobicity. Concerning PVA absorption by cancer cells, the
double emulsion-solvent evaporation method. Nanoparticles were mechanism depends on particle properties. For example, Rejman et al.
characterized by atomic force microscopy (AFM), showing spherical in (2004), showed that bigger particles (>200 nm) are mainly internalized
shape with a heterogeneous surface and with a size ranging from 200 to via clathrin-coated pits, while small particles with (<200 nm) are
500 nm. After an in-vivo study of biodistribution was performed in rats, it absorbed via caveolae-mediated endocytosis by skin cancer cells. This
was observed that they have controlled-release and greater stability than biological process is shown in Fig. 4.
the administration of EDTMP alone. Some examples of in-vitro studies Evaluation of potential oral toxicity of PVA and its intravenous in
which use chemotherapy encapsulated in nanoparticles with PVA, are jection pharmacokinetics had been tested in animal models in past de
shown in Table 5. cades (DeMerlis and Schoneker, 2003; Kaneo et al., 2005; Kelly et al.,
Although there exist a growing number of in-vitro studies of nano 2003; Rodwell et al., 2003). Thus, the potential systemic and neuro
particles synthesized with PVA, nowadays, there does not exist PVA toxicity of PVA was assessed when fed in the diet rats (Kelly et al., 2003).
nanoparticles charged with anticancer encapsulated drugs in the It was not found evidence of reproductive, neurological or systemic
market. toxicity after 70 and 90 days; moreover, it was not observed alterations
in macro- and microscopic examinations, mortality, motor activity,
4. Biocompatibility and routes of administration/ adsorption of ophthalmology, hematology, clinical chemistry, organ weights, urinal
PVA compounds ysis, and functional observation assessments. The no-adverse-effect-
level (NOAEL) was very high, stablished on 5000 mg/kg/day in this
In humans, several evidence support the biocompatibility of PVA study (Kelly et al., 2003). In another study it was determined the oral
since the late 1980s (Hulman and Kirkham, 2007; Lanman et al., 1988) LD50 of PVA of 10 g/kg body weight in male albino rats (Nair, 1998).
and some biomedical application includes ophthalmic solutions con Regarding oral toxicity of PVA, a review revealed that acute oral toxicity
taining 1.4% polyvinyl alcohol of tear replacement solutions without of PVA is very low and it is very poorly absorbed from the gastrointes
experiencing any ocular discomfort (Fassihi and Naidoo, 1989). tinal tract; moreover, the compound does not accumulate in the body
In this decade, it had increased the number of studies where PVA when administered orally and does not display a mutagenic or clasto
hydrogels are used with biomedical applications, such as replacing part genic effect (DeMerlis and Schoneker, 2003). Furthermore, 98% of PVA
of the articular cartilage (Yuan et al., 2013) a tissue sealant in a poly is excreted in feces and 0.2% in urine (DeMerlis and Schoneker, 2003).
meric hydrogel therapy for advanced emphysema (Ingenito, 2013), Other pharmacokinetics and biodisposition studies indicate that PVA
wound dressing containing healing agents (Nasef et al., 2019) and disappears slowly from the blood circulation with a half-life of 7 h after
wound dressings which absorb wound fluid and act as an effective intravenous injection (Kaneo et al., 2005). Moreover, its presence in
barrier against secondary infections (Singh et al., 2016). More applica blood circulation, in tissue distribution and, the urinary and fecal ex
tions include drug delivery in wound dressing (Hamedi et al., 2018), cretions suggest that PVA is eliminated exclusively by the mechanisms
drug delivery systems to enhance the delivery of antimicrobials for the that do not involve saturable transport processes (Kaneo et al., 2005;
treatment chronic infections (Wan et al., 2015), drug delivery of insulin Sun et al., 2012). Furthermore, it was found that PVAs are very stable in
Table 5
Chemotherapy loaded in PVA nanoparticles and PVA composite nanoparticles to be used in cancer treatment in different tissues.
Nanoparticles Size (nm) Technique Type of Cancer Encapsulated Reference
Drug
PLA/PVA, PLGA/PVA, >200 Emulsion diffusion UKF-NB-3 Neuroblastoma Doxorubicin (Pieper et al.,
PLGA-PEG/PVA 2019)
PLGA/PVA 145.2–208.4 Emulsion-solvent evaporation A549 Lung cancer cells Disulfiram (Najlah et al.,
2017)
PLGA/PVA 257.1 Emulsification and solvent Hep-G2 Human Liver cancer Betulinic acid (Padhy et al.,
evaporation 2018)
PVA/CD coating of 130 ± 10 Precipitation HEK 293 Camptothecin (Selvam et al.,
Magnesium 2018)
PLGA/PVA 220–270 Solvent evaporation from oil-in- SCC7 Squamous cell carcinoma, A549 Human lung Artesunate (Nassir et al.,
water (O/W) emulsion adenocarcinoma, MCF-7 Human breast cancer 2018)
PLGA/PVA 202.8 ± 2. Nanoprecipitation LNCaP Human prostate epithelial cancer Resveratrol (Nguyen et al.,
64 2015)
Poloxamer/PVA 110.4 Nanoprecipitation HT 29 Colon Cancer Capecitabine (Padhy et al.,
2018)
PCL/PVA <1000 Solvent evaporation Caco-2, Colon cancer 5-fluorouracil (Öztürk et al.,
2017)
PVA-Coated Magnetite 50 Chemical co-precipitation Hl-60, Leukemia 6- (Moustafa et al.,
Mercaptopurine 2018)
7
Fig. 4. The mechanism of absorption of different size PVA nanoparticles.
the body because no degradation product was detected in the urine and 5. PVA future trend forecast
feces (Kaneo et al., 2005; Sun et al., 2012). Moreover, the participation
of parenchymal, Kupper, and endothelial liver cells was suggested in the The application of PVA in the synthesis and development of nano
clearance of PVAs after intravenous injection in mice (Kaneo et al., materials for drug delivery in the oncological area had been historically
2005), indicating that liver is the main site of accumulation after applied. However, the recent advances in biomedicine have led to the
administration of PVA-based nanocarriers (Sun et al., 2012). Regarding discovery of new molecules for therapeutic purposes such as growth
genotoxicity, Ames test using some Salmonella typhimurium and Escher factors, proteins, peptides, and nucleic acids which need a more highly
ichia coli strains indicate there is no evidence of mutagenicity (Nair, developed drug delivery system. For that reason, the design of new
1998). Furthermore, tests in animals, showed no evidence of carcino pharmaceutical excipients and their delivery systems, which can in
genic activity of PVA (Nair, 1998). crease the drug specificity while reducing possible side effects, are a very
At cellular level some studies evaluated the putative toxicity effects important aspect for future enhancement.
of nanoparticles PVA coated with superparamagnetic iron oxide nano Numerous developments are being researched in the area of smart
particles (SPION) on some human cell lines (Schulze et al., 2014; Strehl nanomaterials, self-assembled hydrogels, and the combined approaches
et al., 2015). Results showed any observable toxic effects to human using microengineering and 3D matrices in order to generate safer and
mesenchymal stromal cells and immune cells (Schulze et al., 2014; custom drug delivery systems.
Strehl et al., 2015). Despite the PVA coated nanoparticles increased the
migration of mesenchymal stromal cells (Schulze et al., 2014) and 6. Conclusion
promoted cell differentiation and increased survival of immune cells
(Strehl et al., 2015). It is not clear whether the effect on these pheno Cancer is one of the most challenging and deadliest illnesses in the
types can be due to the SPION nanoparticles coated with PVA or to the world with the disadvantage of non-standard treatment because of its
PVA (Schulze et al., 2014; Strehl et al., 2015). heterogeneous manifestations. The polymeric materials have become a
Regarding toxicity to the environment and, since PVA, widely used in promising research area, because they bring the possibility of encapsu
many industrial applications, can result in the release of harmful heavy lating, protecting, transporting and administering a therapeutic agent.
metals from sediments (Giroto et al., 2006), several studies had evalu Specially, PVA and its properties have been deeply studied, since the
ated the efficiency of its degradation by several methods (Chou et al., PVA is a traditional material used as an excipient in numerous phar
2010; Sun et al., 2012; Ye et al., 2017); some of them include the maceutical formulas. PVA is commonly used in conjunction with other
combination of UV/chlorine oxidation working in synergy for effective polymers or materials with the purpose of enhancing the composite
degradation (Ye et al., 2017). properties and improving its absorption. It has been demonstrated that
In summary, for years PVA has been widely used in many products PVA is highly biocompatible and non-toxic in in-vitro and in-vivo studies.
without any report of damage. The safety and biocompatibility of PVA Nowadays the PVA is widely used in many products without any
had been demonstrated in different studies in animals and currently report of damage. The most representative use of PVA in drug delivery
there are many clinical trials using PVA microparticles for cancer systems include hydrogel, microparticles and loaded nanoparticles.
treatment. At this moment, several evidence of the use of PVA nano However, only the microparticles synthesized from PVA are available in
particles charged with drug for cancer support a promising technology the market. They have been specially used in the unresectable hepato
platform that offer a highly efficient therapeutic agent. cellular cancer treatment. Nevertheless, the hydrogels have become in a
8
tendency in research because of its controlled delivery applications, as Cao, Y., Liu, F., Chen, Y., Yu, T., Lou, D., Guo, Y., Li, P., Wang, Z., Ran, H., 2017. Drug
release from core-shell PVA/silk fibroin nanoparticles fabricated by one-step
well as the kinetics of the entrapped drugs. In a similar way, the nano
electrospraying. Sci. Rep. 7, 1–9. https://doi.org/10.1038/s41598-017-12351-1.
particles have been put in the light because of their enhanced perme Chao, T.C., Chu, Z., Tseng, L.M., Chiou, T.J., Hsieh, R.K., Wang, W.S., Yen, C.C., Yang, M.
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The widespread review of the literature in this article resumes the containing less Cremophor EL as first-line therapy for advanced breast cancer: a
phase II trial. Invest. New Drugs 23, 171–177. https://doi.org/10.1007/s10637-005-
data available of state of art of PVA based-drug delivery systems for 5863-8.
cancer treatment. Cavalieri, F., Chiessi, E, Villa, R., Viganò, L., Zaffaroni, N., Telling, M.F., Paradossi, G.,
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Biomacromolecules 9 (7), 1967–1973. https://doi.org/10.1021/bm800225v. In
strated its safety, biocompatibility and non-toxicity properties to be a press.
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negative cyclin G1 inhibitor for advanced pancreatic cancer. Mol. Ther. - Oncolytics
Authors acknowledge the financial support from the Consejo 12, 56–67. https://doi.org/10.1016/j.omto.2018.12.005.
Chemical and Technical Assessment 61st JECFA, 2004.
Nacional de Ciencia y Tecnología (CONACYT Gabriela Rivera Hernán Cheng, R., Meng, F., Deng, C., Klok, H.A., Zhong, Z., 2013. Dual and multi-stimuli
dez scholarship 966895). responsive polymeric nanoparticles for programmed site-specific drug delivery.
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technique. J. Microencapsul. 28, 537–548. https://doi.org/10.3109/
Gabriela Rivera-Hernández: Investigation, Writing - original draft, 02652048.2011.590615.
Chou, W.L., Wang, C.T., Huang, K.Y., 2010. Investigation of process parameters for the
Writing - review & editing. Marilena Antunes-Ricardo: Writing - re removal of polyvinyl alcohol from aqueous solution by iron electrocoagulation.
view & editing. Patricia Martinez-Morales: Writing - review & editing. Desalination 251, 12–19. https://doi.org/10.1016/j.desal.2009.10.008.
Mirna L. Sánchez: Conceptualization, Supervision, Writing - review & Córdoba-Esquivel, J.A., Guerrero-Avendaño, G.M.L., Enríquez-García, R., 2019.
Influencia de los materiales embolizantes en el tamaño de los miomas posterior a la
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De Patricio, B.F.C, De Albernaz, M.S, Sarcinelli, M.A, De Carvalho, S.M., Santos-
Oliveira, R., Weissmüller, G., 2014. Development of novel nanoparticle for bone
Declaration of Competing Interest cancer. J. Biomed. Nanotechnol. 10 (7), 1242–1248. https://doi.org/10.1166/
jbn.2014.1812. In this issue.
DeMerlis, C.C., Schoneker, D.R., 2003. Review of the oral toxicity of polyvinyl alcohol
The authors declare that they have no known competing financial
(PVA). Food Chem. Toxicol. https://doi.org/10.1016/S0278-6915(02)00258-2.
interests or personal relationships that could have appeared to influence Dreher, M., Wood, B., Negussie, A., Lewis, A., Tang, Y., 2014. Imageable Embolic
the work reported in this paper. Microsphere.
Drozdova, M.G., Zaytseva-Zotova, D.S., Akasov, R.A., Golunova, A.S., Artyukhov, A.A.,
Udartseva, O.O., Andreeva, E.R., Lisovyy, D.E., Shtilman, M.I., Markvicheva, E.A.,
Acknowledgments 2017. Macroporous modified poly (vinyl alcohol) hydrogels with charged groups for
tissue engineering: preparation and in vitro evaluation. Mater. Sci. Eng. C 75,
1075–1082. https://doi.org/10.1016/j.msec.2017.03.017.
Authors acknowledge the financial and institutional support from Escalona Rayo, O., Quintanar Guerrero, D., n.d. Nanogeles poliméricos: una nueva
the Consejo Nacional de Ciencia y Tecnología, Research Chair Funds of alternativa para la administración de fármacos [WWW Document]. 2014. URL http
://www.scielo.org.mx/scielo.php?script=sci_arttext&pid=S1870-01952014
NutriOmics from Tecnológico de Monterrey, the Consejo Nacional de 000300003 (accessed 9.30.20).
Investigaciones Científicas y Tecnológicas (CONICET), Laboratorio de Euti, E.M., Wolfel, A., Picchio, M.L., Romero, M.R., Martinelli, M., Minari, R.J.,
Materiales Biotecnológicos (LaMaBio), Departamento de Ciencia y Igarzabal, C.I.A., 2019. Controlled thermoreversible formation of supramolecular
hydrogels based on poly(vinyl alcohol) and natural phenolic compounds. Macromol.
Tecnología, Universidad Nacional de Quilmes, Bernal, Argentina Rapid Commun. 40, 1900217. https://doi.org/10.1002/marc.201900217.
IMBICE-CONICET, Bernal, Argentina. PMM thanks the support of the Fan, D.Y., Tian, Y., Liu, Z.J., 2019. Injectable Hydrogels for Localized Cancer Therapy.
Cátedras CONACYT program. Front. Chem. https://doi.org/10.3389/fchem.2019.00675.
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International Journal of Pharmaceutics 600 (2021) 120478

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

Polyvinyl alcohol based-drug delivery systems for cancer treatment

1. Introduction treatment drug delivery systems approved for sale, 81 nanoparticles,

Fig. 2. Drug delivery of PVA hydrogel after a variation of pH or temperature.

*DEB (Drug-eluting bead).

Fig. 4. The mechanism of absorption of different size PVA nanoparticles.

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