Polymeric advanced delivery systems for antineoplasic drugs: doxorubicin and 5-fluorouracil
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Luis Jesús Villarreal-Gómez
Abstract
Conventional pharmaceuticals generally display the inability to transport active ingredients directly to specific regions of the body, amongst some of their main limitations. The distribution of the drugs in the circulatory system may lead to undesired toxicity, and therefore, adverse reactions. To address this situation, a selective transport of drugs is required, that is, releasing drugs specifically to the site of action in appropriate concentrations and in the right time. To achieve this goal, it is necessary to develop delivery systems that respond to several features, such as low toxicity, optimum properties for the transport and release of the drug, as well as a long half-life in the body. This feature paper critically provides an overview of different strategies of controlled drug release for two model antineoplasic drugs, i.e. doxorubicin (DOX) and 5-fluorouracil (5-FU). Any of the presented strategies for drug release possess advantages and disadvantages, and the selection of the strategy used will depend on the targeted tissue and nature of the drug.
1 Introduction
Neoadjuvant chemotherapy is a part of the conventional treatment in some stages of cancer. Often, the chemotherapy treatment is administered again after surgery (adjuvant chemotherapy). 5-Fluorouracil (5-FU) and doxorubicin (DOX) have been used among the more important chemotherapeutics. 5-FU is generally administered together with a vitamin-like drug, called leucovorin (or folinic acid), which improves its efficiency. When chemotherapy is given with radiation after surgery, a single drug can be used, such as 5-FU or capecitabine. For the chemotherapy before surgery, a combination called ECF (epirubicin, cisplatin and 5-FU) is most commonly employed, although other combinations can also be used in the treatment of stomach cancer (1).
Drugs used in chemotherapy generally destroy cancer cells but they may also damage some normal cells, which can result in side effects. The type of side effects depends on the type of drugs used, the amount, and the duration of treatment. Common consequences in short term of most chemotherapy drugs can include nausea, vomiting, diarrhea, lack of appetite, mouth sores and hair loss (2).
Because chemotherapy can damage the bone marrow, in which new blood cells are produced, the blood cell counts may drop. One such drop can result in increased risk of infections (low white blood cells), bleeding or bruising after minor cuts or injuries (due to a shortage of platelets), and tiredness and shortness of breath (due to the reduction in the red blood cell counts) (2).
Several approaches have been studied for the reduction of side effects and toxicity of antineoplasic drugs, vectorization of the drugs for delivery directly into the tumors. In this paper, we discuss several systems proposed for two of the most studied model drugs for delivery systems, namely DOX and 5-FU.
2 Model antineoplasic drugs
2.1 Doxorubicin (DOX)
DOX (Figure 1) (brand name Adriamycin) or hydroxyl daunorubicin, which belongs to the group of anthracyclines and was originally extracted from Streptomyces peucetius, is a drug widely used in cancer chemotherapy (3). It is an antibiotic of the anthracycline family (4), with a close structural relationship to daunomycin, the latter being an intercalating compound into the DNA.
Chemical structure of doxorubicin.
DOX is commonly used to treat many forms of cancer, including bladder, breast, stomach, lung, ovaries and thyroid, as well as some leukemias, Hodgkin’s lymphoma, soft tissue sarcoma and multiple myeloma (5). Anthracyclines are compounds which intercalate into DNA affecting many of its functions, including DNA and RNA synthesis (Figure 2). They can fractionate DNA in both ways, single and double chains, for example, in the crosslinking of the sister chromatids. Thus, the anthracyclines are both mutagenic and carcinogenic (6).
Biochemical steps necessary for cell division and drugs that interfere in it.
DNA cleavage is believed to be mediated by binding of a drug to DNA and inhibiting topoisomerase II enzyme, whose action prevents DNA breakage. The anthracycline through its quinone groups also generate free radicals, both in vitro (in solution) and tissues (either normal or malignant) that may contribute to DNA damage. Anthracyclines react with cytochrome P450 reductase in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) to form semiquinone radical intermediates which can react with oxygen to produce a superoxide radical anion (O2•−). This in turn can generate hydrogen peroxide and a hydroxyl radical (OH•) that damages the DNA by oxidizing the bases. The free radical production is significantly amplified by the interaction of DOX with iron. Additionally, the intracellular reaction of electron transferring of the semiquinone intermediate results in the generation of lipid peroxides, nitric oxide radicals, and other compounds harmful to the cell. Because of these and other effects, exposure of cells to anthracyclines promotes apoptosis. This process would be mediated by p53, which is a sensor for DNA damage and the activation for caspases.
The drug is administered by intravenous injection. The main benefit of this method of administration lies in reducing cardiotoxicity. Due to its adverse effects, particularly cardiotoxicity, it is very important to develop vehicles that allow drug vectorization to cancerous tumors. DOX is a basic drug poorly soluble at physiological pH, making it a good model of a hydrophobic drug substance. Its absorption spectrum in the visible light allows quantification while its fluorescent properties can locate its location on cells and tissues by fluorescence microscopy, which make it a model drug for evaluating antineoplastic delivery systems.
2.2 5-Fluorouracil (5-FU)
5-FU (Figure 3), it is an antimetabolite with a broad spectrum of activity against solid tumors (gastrointestinal tract, ovary, liver, brain, lung, etc.). Usually, cytotoxicity results in cell death by apoptosis. This is a form of cell death characterized by morphological and biochemical criteria. Morphologically, the cell shrinks and becomes denser, chromatin becomes pyknotic and packaged near the membrane creating images like a crescent or horseshoe. The nucleus is fragmented and the cell emits buds (process known as blebbing) containing nuclear and cytoplasmic fragments, these finally emerging from the cell, forming apoptotic bodies.
Chemical structure of 5-fluorouracil.
The clinical use of this drug has been limited due to development of resistance by tumorous cells. Moreover, 5-FU has a short half life time and variable bioavailability when administered orally due to metabolism in the gastrointestinal tract. In injectable solutions, from the degradation of 5-FU in basic media, byproducts are produced which are cardiotoxic (7). Therapy can enhance 5-FU effect and reduce its toxicity if drug accumulation in the infected tumor region is achieved, and the exposure of cells to this agent is prolonged. This requires the development of delivery systems for this drug in nanometric size. 5-FU is a slightly water-soluble drug with a pKa of 8.2 (weak acid), thus making it a good model of a unionized drug in physiological media.
3 Systems of controlled drug release
A system for controlled drug release is a system that releases a drug at a rate and/or at a given location according to the needs of an organism, for a period of time.
If the carrier has the potential to direct the drug to its site of action, an optimal pharmacological effect could be obtained and at the same time, the adverse effects of the drug may decrease.
The distribution of the drug once administered to the body may cause side effects in other areas. It must be established therefore an appropriate balance between the beneficial effects of the drug and the adverse reactions that can be triggered in different organs (Table 1).
| Advantages | Disadvantages |
|---|---|
| – Better compliance by the patient. Extension of the dosing interval. Less invasive. Complacency for the patient, as a single dosage, prolonged therapeutic effect is achieved | – Problems arising from the presence of the implant |
| – The system provides the degree of control necessary to achieve an order of release of the active substance close to zero | – High cost of a given polymer/drug formulation, due to the cost of the polymer or its preparation process |
| – The speed and duration of drug release in vivo can be determined by selection of particle size | – Guarantee adequate security characteristics, so that leaks or other factors leading to inadequate control are eliminated |
| – The particles are small enough to be administered via injection and biodegrade in the body without causing any undesirable effect on the site of injection or implantation | – In case any adverse reaction or complication occurs, you cannot remove the implanted system; only the initial state is recovered when the systems are fully degraded and released and completely delete the active ingredient |
| – A physical, chemical and microbiological stability. Economic benefits. Considers the costs of drugs, hospitalizations, analysis and control side effects. Patent and marketing | – Toxicity or lack of biocompatibility of the used polymer material |
| – Systemic drug concentrations are reduced and promote a local concentration in the target organ, so that the maximum pharmacological activity with minimal systemic side effects is obtained | – Formation of harmful by-products from the polymer, if it is biodegradable |
| – Protection of the active ingredient from potential inactivators in the biological medium before reaching the site of action | – The need in some cases of surgery to implant the polymer in an appropriate location |
| – Easy fabrication with good reproducibility | |
| – Reduction of the lethal dose of the drug: optimize. Minimize local and systemic side effects. Reduces the enhancement of the activity of the drug in chronic use. Reduces the accumulation of the drug in chronic use. Improve the effectiveness of treatment |
The action mechanisms of drugs used conventionally show a certain inability to transport active ingredients directly to specific regions of the body, among some of the main limitations. The distribution of drugs in the circulatory system may lead to unwanted toxicity and therefore adverse reactions. To resolve this situation, a selective transport of drugs is required, that is, release the drugs specifically to the site of action in appropriate concentrations and in the right time. To achieve this, it is necessary to develop delivery systems which must have several characteristics, such as low toxicity, optimal properties for transport and drug release and a long half-life in the body.
All these features can be provided by the applications of nanotechnology in this field, which allows for the manufacture of nanoscale devices, the drug to be released in the least invasive way and non-toxic to cells and tissues that do not need drug treatment (12). That is, the nanoscale enables one such transport, and interacts with cell membranes in a selective manner.
3.1 Nanometric systems studied for the release of DOX and 5-FU
3.1.1 Liposomes
In recent years, it has been reported a successful system for DOX release named as DOXIL® (DOX hydrochloride liposome), which is the first nanotechnology-based drug approved by the US Food and Drug Administration (FDA) for the treatment of patients with ovarian cancer, AIDS-related Kaposi’s sarcoma and multiple myeloma (13). DOXIL® is a PEGylated liposomal formulation of doxorubicin; the coating of poly (ethylene glycol) (PEGylation) helps in evading detection and clearance by the immune system; thus, increasing the circulation half-life of DOXIL® in blood. Due to their small size and surface coating, liposomes can penetrate compromised and leaky vasculature of tumors by a process known as enhanced permeation and retention (EPR) effect (14). EPR is a very noticeable phenomenon that occurs in solid tumors. In other words, the EPR effect is crucial as a basis for development of macromolecular anticancer therapy (15).
3.1.2 Polymeric micelles
Block copolymers formed by hydrophobic and hydrophilic segments are able to self-assemble into polymeric micelles with an inner hydrophobic layer and an outer hydrophilic layer in water. Polymeric micelles are more stable than surfactant micelles and can be used to solubilize hydrophobic substances. The hydrophilic shell prolongs circulation time, while their nanoscopic size permits accumulation in tumors by the EPR effect (16).
Moreover, pH-sensitive polymeric micelles have been studied for the release of DOX by the lower pH found in tumors. These micelles were made with block copolymers using a pH-sensitive linker. This study showed that cancer cells with endocytosed micelles, decrease pH in the lysosome, leading to the release of doxorubicin, thus activating its cytotoxic effect (17).
Further, a pH-responsive poly(ethylene glycol)-b-poly [2-(diisopropylamino)ethyl methacrylate] block copolymer (MPEG-PPDA) that can self-assemble into micelles at very low critical micelle concentration was investigated. These micelles were loaded with DOX and exhibited a superior stability in the physiological environment. Another important observation was that the non-loaded micelles showed no toxicity, and when loaded, they presented high cytotoxicity in cancer cells (18), (19).
3.1.3 Nanogels
Nanogels are among the more important delivery systems of existing drugs (Table 2). They are defined as lightly crosslinked polymer networks swollen in a solvent or a solution. It is necessary that nanogels have a size lower than 200 nm, so they may enter the cells by endocytosis through a mediated transmembrane molecules mechanism, while reducing the capture of the nanogels by phagocytic cells. Consequently, this will significantly increase the circulation time in the blood. The size should be large enough so that there is no leakage through healthy capillaries, but it should be small enough to escape the mononuclear phagocyte system. It is recommended to be between 10 and 100 nm (27).
Nanogels systems loaded with the antineoplasic drugs: doxorubicin and 5-Fluoroacil.
| Nanogel system (polymers) | Loaded drug | Treated disease | Ref. |
|---|---|---|---|
| Glycol chitosan (GCS) | Doxorubicin (DOX) | Various tumors | (20), (21) |
| Poly(N-isopropyl acrylamide-co-acrylic acid) nanogels (PNA) | Doxorubicin (DOX) | Various tumors | (22) |
| Bioreducible heparin (HEP)-based | Doxorubicin (DOX) | Various tumors | (23) |
| Methacrylic-based copolymers | 5-Fluorouracil (5-FU) | Human colon tumor colon cancer cell line (HCT-116) | (24) |
| Chitin nanogels (FCNGs) | 5-Fluorouracil (5-FU) | Skin cancers | (25) |
| N-isopropyl acrylamide (NIPAAm) 4-methacryloyloxy benzoic acid (4MBA) | 5-Fluorouracil (5-FU) | Various tumors | (26) |
Vectorizing the nanogels to the targeted tissues is achieved by merging the nanogel surface with specific ligands that can recognize specific receptors expressed only in tumorous cells. For vectorizing to cancer tissues, the effective ligands for tumor cells include folic acid derivatives, peptides, proteins and antibodies. It has been shown that nanogels can cross the cell membrane of tumor cells by passive diffusion. To take advantage of the EPR effect, nanogels with a diameter between 50 and 200 nm are useful for delivering drugs selectively in cancerous tumors (14), (28).
An essential feature of the nanogels with pharmaceutical applications is their biocompatibility. This can be achieved if the nanogels contain grafted PEG on their surface. The addition of PEG and PEG-containing copolymers to the surface of nanogels provoke an increase in the blood circulation half-life of the drug carrier. This strategy creates a hydrophilic protective layer around the nanogels that is able to repel the absorption of opsonin proteins via steric repulsion forces, thereby blocking and delaying the first step in the opsonization process (29), (30).
3.1.4 Polymeric vesicles
Polymeric vesicles are structures similar to lipid vesicles but created by self-assembly of amphiphilic block copolymers. They offer the possibility of simultaneous encapsulation of hydrophilic compounds in their aqueous cavities and the loading of hydrophobic compounds in its membranes. Surface functionalization of these nanocarriers allows specific targeting, using ligands, peptides, etc. (31), (32).
Polymer vesicles prepared with poly(styrene-b acrylic acid) were used to load DOX by a pH gradient method. Drug release was controlled by the addition of dioxane as plasticizer (33).
Polymeric vesicles (polymersomes) made of poly(ethylene glycol)-poly(lactic acid)/poly(ethylene glycol)-poly(caprolactone) mixtures were loaded with DOX and paclitaxel. The efficiency of the loaded polymersomes was twice that of the free drug in tumor cells. The carriers were innocuous and biodegradable (34).
DOX was also loaded by nanoprecipitation in poly (γ-benzyl L-glutamate)-block-hyaluronan (PBLG-b-HYA) based polymer vesicles. Intracellular delivery of DOX was investigated using CD44 expressing cancer cell models (MCF-7 and U87). High accumulation of the drug was observed in the nucleus of MCF-7 cells and in the cytosol of U87 cells, after been in contact with the loaded vesicles. The loaded vesicles suppressed growth of breast tumor on female Sprague-Dawley rats, with reduced cardiotoxicity compared to free drug (35).
A multifunctional stable and pH-responsive polymer vesicle nanocarrier system was developed for combined tumor-targeted delivery of DOX and superparamagnetic iron oxide nanoparticles. These multifunctional polymer vesicles were formed by amphiphilic triblock copolymers: folate (FA)-poly(ethylene glycol)-poly(glutamate hydrozone DOX)-poly(ethylene glycol)acrylate. The amphiphilic triblock copolymers self-assemble into stable vesicles in aqueous solution. It was found that the long PEG segments were mostly segregated into the outer hydrophilic PEG layers of the vesicles, thereby providing active tumor targeting via FA. Results from flow cytometry and confocal laser scanning microscopy analysis showed that FA conjugated vesicles exhibited higher cellular uptake than FA-free vesicles, which also led to higher cytotoxicity, via pH sensitive hydrolysis of DOX. The system simultaneously allows for ultrasensitive magnetic resonance imaging (MRI) detection (36).
5-FU has been loaded into polymeric vesicles formed by the UV cross-linked walls from poly[2-ethylhexylmethacrylate-co-(7-(4-trifluoromethyl) coumarin acrylamide)]. Drug release occurs slowly by diffusion through the pores of the vesicles. Fast drug release is achieved by UV irradiation, which disrupt the polymeric vesicles (37).
3.1.5 Polymeric prodrugs
Coupling anticancer drugs to synthetic polymers is a promising approach to improve the efficacy and reduce the side effects of these drugs. Seymour et al. made a polymeric prodrug of DOX by covalent conjugation to a copolymer based on N-(2-hydroxypropyl)methacrylamide (HPMA). The DOX-HPMA copolymer conjugate is unable to diffuse through cellular membranes and consequently display a lower volume of distribution and longer plasma half-life than free DOX. The poor membrane permeability of the conjugate also prevents its entry into cardiac tissue, reflected in decreased cardiotoxicity and, permitting administration of increased doses of DOX as a polymer conjugate. Treatment of mice with DOX-HPMA copolymer conjugate achieved treated/control lifespans up to 320%, compared with only 133% using aggressive regimens of free DOX (38).
pH-Activated polymers have been demonstrated to be a successful drug delivery vehicle system, as pH values in different tissues and cellular compartments vary tremendously. For example, the tumor extracellular environment is more acidic (pH 6.5) than blood and normal tissues (pH 7.4), and the pH values of endosome and lysosome are even lower at 5.0–5.5. For instance polymeric prodrugs with a pH sensitive linkage is a great strategy to release drugs from a carrier once the nanomaterial that have been accumulated in the tumor by the EPR effect.
Considering this approach, a dual pH sensitive polymer has been developed consisting of a parental diblock copolymer, monomethoxyl poly(ethylene glycol)-b-poly-(allyl ethylene phosphate) (mPEG-b-PAEP), bound by an hydrazone link to DOX. The polymer backbone is partially hydrolyzed at pH 6.8, when the hydrazone groups is hydrolyzed at pH 5, efficiently interiorizing DOX to cancer cells (39).
DOX was also attached through a hydrazone bond to a biodegradable polycarbonate: poly(5-methyl-5-allyloxycarbonyl-1,3-dioxan-2-one)-graft-12-acryloyloxy dodecyl phosphorylcholine-co-6-maleimidocaproyl-doxorubicin. The polymeric prodrug was synthesized by ring-opening polymerization and a highly efficient “click” reaction. The polymer self-assembled in a micellar structure, as confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Flow cytometry and fluorescence microscopy results demonstrated that prodrug micelles are internalized by cancer cells. In vitro drug release studies showed that the release of DOX was faster in an endosomal pH (pH=5.0) than in a normal physiological environment (pH=7.4). Moreover, this prodrug exhibited high cytotoxicity against HepG2 cells and HeLa cells, indicating its great potential for cancer therapy (40).
Wei et al. constructed reduction and pH dual-sensitive DOX-conjugated micelles from PEG-b-poly(methacrylic acid-g-hydrazone-DOX) diblock copolymer, using dithiodiethanoic acid as a crosslinker. The subsequent micelles exhibited the fastest DOX release in response to both stimuli (pH 4.0 and 15mM dithiothreitol, DTT) (41).
Hyaluronic acid (HA) prodrug micelles with pH and reduction responsiveness were prepared by chemical graft of phosphorylcholine and DOX to the backbone of HA. DOX was conjugated to HA by hydrazone bonds. Besides, the HA prodrug micelles were cross-linked via reduction responsive disulfide bonds to improve the stability of the micelles. The in vitro drug release studies showed that there was a dramatic release under endosome pH (pH=5.0), and reductive environment (10 mM DTT) than in a normal physiological environment (pH=7.4). Greater uptake of DOX from HA-prodrug micelles was observed in the CD44 receptor highly expressed MDA-MB-231 cell line, compared to the results from the CD44-negative cell line, NIH3T3 (42).
Coumarin functionalized block copolymers poly (ethylene oxide)-b-poly-(n-butyl methacrylate-co-4-methyl-[7-(methacryloyl)-oxyethyloxy] coumarin)) (PEO-b-P(BMA-co-CMA)) were synthesized via atom transfer radical polymerization (ATRP). 5-FU was attached directly to coumarin functionalized polymers via a [2+2] cycloaddition reaction under UV irradiation at wavelength 310 nm. The prodrug copolymer forms micelles of about 70 nm. In vitro drug release experiments showed the controlled release of 5-FU from the micelle-drug conjugates under UV irradiation (254 nm). These micelle-drug conjugates also showed excellent biocompatibility (43).
5-FU has also been attached to chitosan to form chitosan-1-acetic acid-5-fluorouracil (CS-FUAC) conjugates as a colon-specific prodrug. The conjugate was demonstrated to be more stable in solution than FUAC. The prodrug polymer was less hemolytic, but more cytotoxic on the human colorectal cancer cell line (HT-29) than the free drug (44).
3.1.6 Smart systems
When a biological system recognizes an external stimulus, it responds adaptively to external environmental changes. In recent years, researchers devoted to the design of intelligent polymers have sought to imitate this feature. These kinds of materials are defined as polymers which undergo reversible and significant changes, whether they are physical or chemical changes, in response to small changes of external conditions, such as temperature, pH, light, ionic strength, electrical and/or magnetic fields, action of biological molecules, etc.
Smart polymers have enormous potential applications in the biomedical field as systems for the controlled release of therapeutics, structural agents or bioactive scaffolds for tissue engineering, cell culture matrices, bioseparation devices, sensors or actuators, etc. (45).
Once bioactive nanoparticles penetrate the target tissue, a mechanism that allows for drug release is necessary. One strategy is the development of stimuli-responsive “PEGylated” nanoparticles by incorporating intelligent polymer segments that may induce significant changes in particle characteristics in response to external stimuli (i.e. ionic strength, temperature, pH stimuli, etc.) and metabolites. “PEGylated” nanogels have been designed to respond to pH for biomedical applications, considering that tumors, skin and endosomes/lysosomes have a pH that is more acid compared to normal tissue (pH 7.4) (46), (47). These nanogels which contain amino groups are ionized in acid and cause swelling of nanogels. This property has been used for drug delivery and as catalytic microreactors (48).
Another stimulus that is of great interest is the temperature, tumors have a higher temperature than healthy tissue, due to their rapid metabolism, and it is feasible to increase the temperature in a specific area of the body using an external heat source.
One of the most studied materials that is sensitive to stimuli is poly(N-isopropyl acrylamide) (NIPAAm), because linear polymers of this material undergo an expanded transition phase to a contracted vesicle (soluble to precipitated), whereas hydrogels undergo a swollen transition which collapses to a critical temperature (LCST) of about 32°C (46). Given the proximity of the LCST at body temperature (37°C), PNIPAAm is a potential candidate as a biomedical vector in the forms of linear polymers, copolymers or hydrogels. PNIPAAm has been studied for drug delivery to target tumors in thermosensitive coverings, in micelles for controlled drug release, and as attachment-detachment surface of living cells. PNIPAAm has also been used in ophthalmic solutions, as no in vitro cytotoxicity has been detected (49).
In addition, temperature-sensitive star polymers with a random number of arms and a crosslinked core were found by using PNIPAAm with ethylene glycol dimethacrylate (EGDMA) through the RAFT-technique. Nanometric star polymers were characterized by size exclusion chromatography (SEC), DLS and viscometry. These systems are potentially used for the release of DOX and 5- FU (50). A similar system has been studied in which the arms of the polymeric stars contain an amphiphilic acid that adjusts the transition temperature above the body temperature for positive release control (26).
3.1.6.1 Reduction-responsive polymeric delivery systems
The therapeutic effects of existing micellar and vesicular drug formulations are limited by slow and inefficient drug release at the pathological site. The development of smart polymeric nanocarriers that release drugs upon arriving at the target site has received a great amount of attention for cancer therapy. Hence, numerous reduction-sensitive polymeric micelles and vesicles have been designed and explored for triggered anticancer drug release. These reduction-responsive nanosystems have demonstrated several unique features, such as good stability under physiological conditions, fast response to intracellular reducing environment, triggering drug release right in the cytosol and cell nucleus, and significantly improved antitumor activity, compared to traditional reduction-insensitive counterparts (51).
As mentioned in Section 3.1.5, several delivery systems have been studied where release is triggered by low pH and a reductive environment. Furthermore, several strategies have been published using reduction responsive polymeric delivery systems, such as reduction sensitive shell sheddable micelles and polymersomes. Zhong et al. (52) reported that ligand-directed reduction-sensitive shell-sheddable micelles based on PEG-SS-PCL and galactose-PEG-PCL copolymers efficiently delivered and released DOX into the nuclei of target HepG2 cells, resulting in superior in vitro antitumor efficacy with a half maximal inhibitory concentration (IC50) comparable to free DOX.
Also, reduction-sensitive disassemblabled micelles with a reductively degradable core have been reported. In this case, reductively degradable poly(amide amine) (SSPAA) polymers based on the Michael addition reaction of cystamine bisacrylamide and primary amines have been applied for adaptable construction of reduction-sensitive disassemblable micelles. Sun et al. (53) reported that reduction-sensitive SSPAA-g-PEG micelles released DOX nearly quantitatively within 10 h in the presence of 1mM DTT.
Moreover, reduction-sensitive reversibly SCL micelles and polymersomes, where Xu et al. (54) found that SCL micelles based on PEG-b-PCL diblock copolymer with two lipoyl groups at its junction (PEG-L2-PCL) were readily crosslinked with DTT, showing markedly enhanced stability against dilution, whereas DOX was released rapidly in response to 10mM DTT, with about 75% release in 9h under the same conditions otherwise.
4 Controlled release systems through passive transport and active transport
Drug delivery systems may be designed in such a way that they penetrate the tissue and selectively release the drug where needed. One of the main factors that needs to be considered when designing a drug delivery system is whether drugs can be released through passive transport or active transport.
4.1 Passive transport of drugs
It is necessary to create strategies that will allow nano-carriers to stay for long periods for a sustained release of the drug or therapeutic component in a particular tissue. Usually, the nanoparticles are removed from the bloodstream and through an organ or tissue associated with the reticulum endothelial system (RES). This system consists of very large populations of mononuclear phagocytes that are associated with the reticular connective tissue and acts as a particulate filter. The main organs associated with this system are the bone marrow, intestines, kidneys, spleen and liver. Filtration of these nanocarriers is usually found in the spleen, liver and kidneys (55).
The tissue architecture of the main organs associated with RES determines their ability to act as filters. For example, the liver sinusoidal endothelium contains a porosity larger than 175 nm in diameter, thus allowing for a passive particle filtration. The size of these pores caused the perception that the maximum diameter of nanogels should be up to 200 nm in diameter, regardless of the deformability of the particles (56).
Strategies of passive drug transport are based on microarchitecture of irregular tumor masses. Tumor tissues have a nonfunctional system lymphatic drainage (leading to greater retention in tumor interstitial space), which causes increased vascular permeability of these tissues compared to healthy tissues. Based on this information, the drug delivery systems may be considered as colloidal systems that can be controlled by adjusting their size and their surface characteristics. This permits achieving a specific and massive accumulation in the tumor. To this purpose, one should consider the size of the nanogels containing anticancer drugs. The size should be large enough so that there is leakage through healthy capillaries, but small enough to escape the RES. The sizes that are adequate for this function are reported in the range between 10 and 100 nm. A typical example is constituted of nanocapsules composed of poly(D, L-Lactide) (PLA) and poly(D, L-lactide)-b-poly(ethylene glycol) diblock copolymer (PLA-PEG), which are loaded with an antitumor agent. Such nanocapsules are designed to administer anticancer drugs via topical ocular administration for the treatment of primary ocular lymphoma, their average sizes being of 146–246 nm. In in vitro studies, the drug was released with an efficiency comprised between 28 and 86% after 4 h (57).
Another important factor to consider is the shape of the nano-carriers, given that the erythrocytes are able to cross the liver porosity despite having a larger size, thanks to shape change. Strategies have been used with nanoparticles. For example, rod-shaped polystyrene nanoparticles loaded with therapeutic agents for the treatment of breast cancer gave successful results. The rodlike shape increases efficiency in drug release 1000 times compared to the spherical nanogels, in tests on cancer cells BT-474, SK-BR-3 and MDA-MB-231 (58).
On the other hand, phagocytic cells are the main obstacle of nanogels to remaining a long time in circulation, these cells are important for the immune system. Phagocytic cells cleaned circulation therapeutic nano-carriers, therefore these systems need camouflage release surfaces that cannot be recognized by the latter cells, preventing opsonization of serum proteins. A strategy to overcome this problem is to coat the nanoparticles with PEG. This polymer is widely used to prevent and decrease the time required for the nanoparticles to be opsonized into blood, and the functional groups of PEG may be able to block electrostatic and hydrophobic interactions with serum proteins that are also called opsonins. Then, opsonins bind to the surface of the nano-carriers (59). Rather than designing the nanogels with surfaces that prevent or change the opsonization pattern as PEG does, one of the reported strategies lies in performing a pretreatment in order to eliminate opsonins of the circulation (60).
4.2 Active transport of drugs through ligand-receptor interactions
Some strategies of drug release were reported by active transport through ligand-receptor interactions. One can enlist liposomes modified with anti-epidermal growth factor-2 (HER-2), the epidermal growth factor receptor 2 is a growth factor of human endodermal type. It is essential for normal growth and division of cells, which is why this abnormal expression is linked to cancerous processes. It has become an important marker and target for oncogenic treatment, especially in breast cancer. Such strategies allow liposomes to specifically bind to tumor tissues that over-express this receptor, specifically releasing their contents. Another approach lies in a system composed of nanoparticles of poly(D, L-lactide-co-glycolide) which contain a monoclonal antibody specific for cytokeratin and cystatin, i.e. an excellent protease inhibitor that can neutralize excessive proteolytic activity associated with breast tumor cells’ invasive metastases (61).
Another type of strategy involves the use of nanogels with a functionalized surface of antibodies, such as nanogel compounds of copolymers of poly(ethylene glycol)-b-poly(methacrylic acid) (PEG-b-PMA) with PEG functionalized with a terminal aldehyde. These copolymers were used to prepare nanogels via condensation of PEG-b-PMA with Ca2+ ions in the aggregates which resembles the mycelium. The resulting polyelectrolyte nanogels represented spherical particles with terminal free aldehyde in the PEG chains. A reductive amination reaction between the aldehyde groups and the amino groups of the antibodies results in an effective combination of the nanogels CC49 antibody against tumor-associated glycoprotein 72 (TAG-72) (62).
Another strategy is to use functionalized surfaces, such as those with the RGD peptide sequence (arginine-glycine-aspartic acid) which have a high affinity for integrins, the latter being “overexpressed” in the tumor neovasculature (63).
4.3 Active transport of drugs based on colloidal systems sensitive to stimuli
4.3.1 Active transport controlled by pH changes
Several nanocarrier systems that are sensible of pH changes can be found in the literature. For example, particles of poly(L-histidine) modified with PEG chains and the remains of folic acid have been reported to be a specific for DOX transport. In addition, co-polymers of poly(N-isopropyl acrylamide) and chitosan have been reported for the release of the anticancer drug with great delivery of this molecule on contact with pH <6.9 (typical of the tumor region) (64).
This is perhaps one of the most promising strategies for the active transport of drugs today. It is based on the use of materials for the formulation of colloids which are extremely sensitive to small changes in pH from natural blood (pH=7.4). For example, at the level of the tumor region, there are alterations in blood flow and metabolic characteristics (e.g. aerobic and anaerobic glycolysis) determining a pH≈6.6 in the tumor interstitium. Thus, the conveyor system will face a slightly acidic environment to which it is sensitive, so it will be destroyed while releasing the active substance transported specifically in its place (65), (66), (67).
Polymeric materials that are sensitive to acidic pH contain carboxyl or sulfonic groups, while the polymeric particles sensitive to basic pH contain ammonium salts in their chemical structure. In this regard, an alternative possibility may be to use sensitive conveying systems (such as liposomes) at pH between 4.5 and 5.0. These colloids after internalization by the tumor cells by endocytosis will degrade within the lysosomes in this acidic environment and under the action of hydrolytic enzymes, such as cathepsin B29 (68).
4.3.2 Active transport controlled by temperature changes
Magnetoliposomes for release of DOX have been reported. This system implies a lipid membrane consisting of 1, 2 dipalmitoyl-glycero-3 phosphocholine and cholesterol, a temperature range from 37°C to 41°C was applied to the site of action. The destruction of a magnetosome is shown in Figure 4. These magnetic nanoparticles consist of a core of magnetite (Fe3O4) and are coated with dextran-g-poly(N-isopropyl acrylamide-co-N,N′-dimethyl acrylamide) for DOX release. This strategy possesses the ability to be accumulated specifically at the site of action which is controlled by a magnetic field. Finally, it can be assumed, that the specific heat of the magnetic cores (hyperthermic effect) and thus the specific heating and polymer degradation, releases the antitumor agent (69).
Destruction of magnetosome for a drug delivery strategy.
Colloids made from heat-sensitive materials are characterized by having a process of destabilization/destruction to any slight changes in temperature (usually an increase). For example, DOXIL® is a drug delivery system acting on cells in three ways: it intercalates between DNA strands, inhibiting DNA and RNA synthesis in rapidly dividing cells. It also inhibits the enzyme topoisomerase II, preventing the relaxing of super-coiled DNA, blocking DNA and RNA synthesis. It finally forms iron-mediated free radicals, causing oxidative damage to DNA, proteins and cell membrane lipids (70). The polymer most often used in designing this type of conveyor systems is PNIPAAm. The main reason that motivates their widespread use is that the temperature causing destabilization is very close to the physiological temperature. It is even possible to control it (setting at ≈42°C) by forming copolymers with a hydrophilic monomer like N,N′-dimethyl acrylamide. Other thermosensitive polymers also under investigation are poly(N-(R)-1-hydroxymethyl-propyl methacrylamide), poly(2-carboxy-isopropylacrylamide), poly(N-acryl-N′-alkyl piperazine), and poly(N,N′-diethyl acrylamide) (66).
Table 3 summarizes the different strategies for active transport of drug molecules:
Other strategies under active transport.
| Type of control | Strategies | Ref. |
|---|---|---|
| Transport mediated by aptamers | Nucleic acid sequences capable of selectively binding to certain antigens located on the surface of tumor cells | (71) |
| Transport mediated by folic acid and derivatives | Folate receptors are abundant expression in cancer cells, as they have very important folic acid requirements for DNA synthesis | (72) |
| Transport mediated by transferrin | Transferrin receptors are located in large amount on the surface of a wide range of cancer cells | (73) |
| Active transport controlled by magnetic fields | The magnetic colloids are capable of carrying chemotherapeutic agents specifically to the site of action, as long as the applied magnetics gradient locates therein | (69) |
| Active transport controlled by light | Materials able to respond to light stimuli (ultraviolet or visible light) | (43) |
| Active transport controlled ultrasonic | Application of ultrasound in the tumor region causes an increase in the permeability of blood capillaries feeding the tumor, the thermal power generation and disruption of the membranes of malignant cells | (74) |
| Active transport controlled by enzyme systems | Based on the existence of natural enzymes in tumor region that have the ability to cause drug release by destruction/degradation of the conveyor system | (70) |
5 Electrospinning approach
In addition, biodegradable polymeric nanofibers fabricated by the electrospinning technique have been used as drug delivery systems (75). This technique uses an electrical field to form nanofibers from a polymeric solution with a relatively high viscosity and conductivity (Figure 5). These nanofibers can create a three-dimensional (3D) scaffold and can be used for a variety of applications in tissue engineering, purification, filtration and drug delivery (76). The main characteristic to be pursued is biocompatibility (77), (78), and in the case of drug delivery, the biodegradation rate of the nanofibers is also essential.
Co-axial electrospinning. Bioactive drugs can be loaded into a core shell nanofibers.
The main idea of using nanofibers made by biodegradable polymers is the release of the therapeutic drug depending on the degradation rate of the scaffolds; hence drug release kinetics can be controlled depending on the nature of the scaffolds.
The release of DOX from poly (lactic acid)-based electrospun nanofibers has been reported. In this study, the in vitro drug release in phosphate-buffered solution and acetate buffer for the optimized and non-optimized samples demonstrated that diffusion is the dominant drug release mechanism for drug-loaded fibers. The initial burst release was observed for non-optimized nanofibers compared to optimized nanofibers. Demonstrating that drug-loaded poly(lactic acid) nanofibers could be good candidates for biomedical applications (79).
Consequently, DOX has been loaded into gelatin nanofibers (80), multi-walled carbon nanotubes (MWCNTs)/PLGA hybrid nanofibers (81), nano-hydroxyapatite-poly(lactic-co-glycolic acid) composite nanofibers (82), poly(ethylene glycol)-poly(L-lactic acid) (PEG-PLA) diblock copolymer nanofibers (83), poly(ethylene oxide)/chitosan/graphene oxide nanocomposite nanofibrous scaffolds (84), carbon nanotubes incorporated into poly(lactic-co-glycolic acid) electrospun composite nanofibers (85).
In the case of 5-FU, several studies have been reported. This anticancer drug has been loaded into core/shell electrospun fibers. Shells made of Eudragit S100 (ES-100), and drug-loaded cores comprising poly(vinyl pyrrolidone), ethyl cellulose, ES-100, or drug alone (86), poly (lactide) nanofibers (87), chitosan/poly(ethylene oxide) electrospun nanofibrous membrane (88) and chitosan/hydroxy ethyl cellulose/poly(vinyl alcohol) nanofibers (89), among others.
6 Co-delivery of DOX and 5-FU
In recent years, combination therapy has been observed as a potential strategy for cancer treatment due to the enhanced anticancer effectiveness achieved by blocking multiple drug resistance pathways. In a published study, a drug carrier based on nanoscale ZIF-90 for the codelivery of DOX, attached to the surface of ZIF-90, and encapsulation of 5-FU into the pores of the framework was performed. These researchers demonstrated that the carrier had the potential of cancer-targeted delivery of drugs for the collapse of framework under the pH environment around cancer cells, and afterward releasing the drugs. Drug release at pH 5.5, simulating the environment of tumor, can reach over 95%, and the release time is less 16 h, meaning a more effective and faster release of the drugs around tumoral cells than that in a normal environment (90).
Also in the case of the co-delivery of DOX and 5-FU, it had been reported an amphiphilic dendritic nanomicelle-mediated system which co-deliver the drugs for enhanced therapeutic efficacy purposes. In this study, the unique nanomicelle is based on an amphiphilic dendrimer (AmD) which consists of a hydrophilic polyamidoamine dendritic shell and a hydrophobic poly(lactide) core for effectively loading and shuttling 5-FU and DOX) (91).
On the other hand, some PEGylated liposomes transformed the chemotherapeutic use of DOX by diminishing its cardiotoxicity; but, it remains unclear whether liposomal DOX is therapeutically superior to free DOX. Hence, it a novel liposome-encapsulated synergistic combination of DOX and 5-FU for low dose chemotherapy was reported. Delivery of synergistic ratios of this drug pair led to a greater than 90% reduction in tumor growth of murine 4T1 mammary carcinoma in vivo (92).
7 Conclusions
In conclusion, we believe that further studies should be made to find optimal strategies of release and to improve their efficiency. Also, as active transport require several proteins and enzymes to be active, genetic variability do not allow active vectorization to be effective. On the other hand, DOX and 5-FU have been used to treat different types of cancers in several zones of the body, it is necessary to consider more than one strategy to achieve the desired tissue, nevertheless, we can affirm that biodegradable polymers are necessary to deliver both drugs.
Acknowledgment
This work was supported by “Fondo Sectorial de Investigación y Desarrollo en Salud y Seguridad Social SS/IMSS/ISSSTE-CONACYT 2016” (Mexico) [grant number 272310]; 19th Call for Support Research Projects UABC [Grant number 4287].
References
1. Schott AF, Hayes DF. Defining the benefits of neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2012;30:1747–9.10.1200/JCO.2011.41.3161Search in Google Scholar PubMed
2. Perry CM. The chemotherapy source book. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.Search in Google Scholar
3. Zhu W, Soonpaa MH, Chen H, Shen W, Payne RM, Liechty EA, Caldwell RL, Shou W, Field LJ. Acute doxorubicin cardiotoxicity is associated with p53-induced inhibition of the mTOR pathway. Circulation 2009;119:99–106.10.1161/CIRCULATIONAHA.108.799700Search in Google Scholar PubMed PubMed Central
4. Pinedo HM, Smorenburg CH. Drugs affecting growth of tumours. 1st ed. Basel, Switzerland: Birkhäuser, Springer; 2006.10.1007/3-7643-7407-1Search in Google Scholar
5. Saffi J, Agnoletto MH, Guecheva TN, Batista LFZ, Carvalho H, Henriques JAP, Stary A, Menckd CFM, Sarasin A. Effect of the anti-neoplastic drug doxorubicin on XPD-mutated DNA repair-deficient human cells. DNA Repair 2010;9:40–7.10.1016/j.dnarep.2009.10.003Search in Google Scholar PubMed
6. Brunton LL, Chabner AB, Knollmann BC. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. San Diego, CA: Mc Graw Hill; 2011.Search in Google Scholar
7. Arias LJ. Novel strategies to improve the anticancer action of 5-fluorouracil by using drug delivery systems. Molecules 2008;13:2340–69.10.3390/molecules13102340Search in Google Scholar PubMed PubMed Central
8. Sáez V, Aldana R, Ramón JA, Páez R, Peniche C. Optimización de la encapsulación del factor de crecimiento epidérmico en microesferas de poli(lactida-co-glicolida) mediante un diseño factorial 32. Rev Iberoam Polim. 2008;9:505–11.Search in Google Scholar
9. Coelho JF, Ferreira PC, Alves P, Cordeiro R, Fonseca AC, Góis JR, Gil MH. Drug delivery systems: Advanced technologies potentially applicable in personalized treatments. EPMA J. 2010;1:164–209.10.1007/s13167-010-0001-xSearch in Google Scholar PubMed PubMed Central
10. Dikmen G, Genç L, Güney G. Advantage and disadvantage in drug delivery systems. J Mater Sci Eng. 2011;5:468–72.Search in Google Scholar
11. Bhagwat RR, Vaidhya IS. Novel drug delivery systems: an overview. Inter J Pharm Sci Res. 2013;4;970–82.Search in Google Scholar
12. Kabanov AV, Vinogradov SV. Nanogels as pharmaceutical carriers: finite networks of infinite capabilities. Angew Chem Int Ed. 2009;48:5418–29.10.1002/anie.200900441Search in Google Scholar PubMed PubMed Central
13. Mishra P, Nayak B, Dey RK. PEGylation in anti-cancer therapy: an overview. Asian J Pharm Sci. 2016;11:337–48.10.1016/j.ajps.2015.08.011Search in Google Scholar
14. Maeda H, Matsumura Y. EPR effect based drug design and clinical outlook for enhanced cancer chemotherapy. Adv Drug Deliv Rev. 2011;63:129–30.10.1016/j.addr.2010.05.001Search in Google Scholar PubMed
15. Fang J, Nakamura H, Maeda H, The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev. 2011;63:136–51.10.1016/j.addr.2010.04.009Search in Google Scholar PubMed
16. Jones M-C, Leroux J-C. Polymeric micelles – a new generation of colloidal drug carriers. Eur J Pharm Biopharm. 1999;48:101–11.10.1016/S0939-6411(99)00039-9Search in Google Scholar
17. Bae Y, Fukushima S, Harada A, Kataoka K. Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular ph change. Angew Chem Int Ed. 2003;115:4788–91.10.1002/ange.200250653Search in Google Scholar
18. Xu Z, Xue P, Gao Y-E, Liu S, Shi X, Hou M, Kang Y. pH-responsive polymeric micelles based on poly (ethylene glycol)-b-poly (2-(di isopropyl amino) ethyl methacrylate) block copolymer for enhanced intracellular release of anticancer drugs. J Colloid Interface Sci. 2017;490:511–9.10.1016/j.jcis.2016.11.091Search in Google Scholar PubMed
19. Khallaf RA, Salem HF, Abdelbary A. 5-Fluorouracil shell-enriched solid lipid nanoparticles (SLN) for effective skin carcinoma treatment. Drug Deliv. 2016;23:3452–60.10.1080/10717544.2016.1194498Search in Google Scholar PubMed
20. Oh NM, Oh KT, Baik HJ, Lee BR, Lee AH, Youn YS, Lee ES. A self-organized 3-diethylaminopropyl-bearing glycol chitosan nanogel for tumor acidic pH targeting: In vitro evaluation. Colloids Surf B Biointerfaces. 2010;78:120–6.10.1016/j.colsurfb.2010.02.023Search in Google Scholar PubMed
21. Soni G, Yadav KS. Nanogels as potential nanomedicine carrier for treatment of cancer: a mini review of the state of the art. Saudi Pharm J. 2016;24:133–9.10.1016/j.jsps.2014.04.001Search in Google Scholar PubMed PubMed Central
22. Xiong W, Wang W, Wang Y, Zhao Y, Chen H, Xu H, Yang X. Dual temperature/pH-sensitive drug delivery of poly (N-isopropylacrylamide-co-acrylic acid) nanogels conjugated with doxorubicin for potential application in tumor hyperthermia therapy. Colloids Surf B Biointerfaces. 2011;84:447–53.10.1016/j.colsurfb.2011.01.040Search in Google Scholar PubMed
23. Wu W, Yao W, Wang X, Xie C, Zhang J, Jiang X. Bioreducible heparin-based nanogel drug delivery system. Biomaterials 2015;39:260–8.10.1016/j.biomaterials.2014.11.005Search in Google Scholar PubMed
24. Ashwanikumar N, Kumar NA, Nair SA, Kumar GV. Methacrylic-based nanogels for the pH-sensitive delivery of 5-fluorouracil in the colon. Int J Nanomedicine 2012;7:5769–79.10.2147/IJN.S31201Search in Google Scholar PubMed PubMed Central
25. Sabitha M, Sanoj Rejinold N, Nair A, Lakshmanan VK, Nair SV, Jayakumar R. Development and evaluation of 5-fluorouracil loaded chitin nanogels for treatment of skin cancer. Carbohydr Polym. 2013;91:48–57.10.1016/j.carbpol.2012.07.060Search in Google Scholar PubMed
26. Sánchez-Bustos E, Cornejo-Bravo JM, Licea-Claverie A. Core cross-linked star polymers for temperature/ph controlled delivery of 5-fluorouracil. J Chem. 2016;2016:1–12.10.1155/2016/4543191Search in Google Scholar
27. Sáez-Fernández E, Ruiz Martínez MA, López-Ruiz A, Arias Mediano JL. Review of the “state of the art” and possibilities of the most significant approaches to the specific delivery of chemotherapy agents to tumor cells. Ars Pharm. 2010;51: 121–35.Search in Google Scholar
28. Kataoka K, Harada A, Nagasaki Y. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev. 2001;47:113–31.10.1016/S0169-409X(00)00124-1Search in Google Scholar
29. Oishi M, Nagasaki Y. Synthesis, characterization, and biomedical applications of core-shell-type stimuli-responsive nanogels – Nanogel composed of poly[2-(N,N-diethylamino)ethyl methacrylate] core and PEG tethered chains. React Funct Polym. 2007;67:1311–29.10.1016/j.reactfunctpolym.2007.07.009Search in Google Scholar
30. Owens III DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307(1):93–102.10.1016/j.ijpharm.2005.10.010Search in Google Scholar PubMed
31. Tanner P, Baumann P, Enea R, Onaca O, Palivan C, Meier W. Polymeric vesicles: from drug carriers to nanoreactors and artificial organelles. Acc Chem Res. 2011;44(10):1039–49.10.1021/ar200036kSearch in Google Scholar PubMed
32. Discher DE, Ortiz V, Srinivas G, Klein ML, Kim Y, Christian D, Cai S, Photos P, Ahmed F. Emerging applications of polymersomes in delivery: from molecular dynamics to shrinkage of tumors. Prog Polym Sci. 2007;32(8):838–57.10.1016/j.progpolymsci.2007.05.011Search in Google Scholar PubMed PubMed Central
33. Choucair A, Soo PL, Eisenberg A. Active loading and tunable release of doxorubicin from block copolymer vesicles. Langmuir 2005;21(20):9308–13.10.1021/la050710oSearch in Google Scholar PubMed
34. Ahmed F, Pakunlu RI, Brannan A, Bates F, Minko T, Discher DE. Biodegradable polymersomes loaded with both paclitaxel and doxorubicin permeate and shrink tumors, inducing apoptosis in proportion to accumulated drug. J Control Release 2006;116:150–8.10.1016/j.jconrel.2006.07.012Search in Google Scholar PubMed
35. Upadhyay KK, Bhatt AN, Mishra AK, Dwarakanath BS, Jain S, Schatz C, Le Meins JF, Farooque A, Chandraiah G, Jain AK, Misra A, Lecommandoux S. The intracellular drug delivery and anti-tumor activity of doxorubicin loaded poly(γ-benzyl l-glutamate)-b-hyaluronan polymersomes. Biomaterials 2010;31(10):2882–92.10.1016/j.biomaterials.2009.12.043Search in Google Scholar PubMed
36. Yang X, Grailer JJ, Rowland IJ, Javadi A, Hurley SA, Matson VZ, Steeber DA, Gong S. Multifunctional stable and pH-responsive polymer vesicles formed by heterofunctional triblock copolymer for targeted anticancer drug delivery and ultrasensitive MR imaging. ACS Nano. 2010;4(11):6805–17.10.1021/nn101670kSearch in Google Scholar PubMed
37. Sierant M, Kazmierski S, Rozanski A, Paluch P, Bienias U, Miksa BJ. Nanocapsules for 5-fluorouracil delivery decorated with a poly (2-ethylhexyl methacrylate-co-7-(4-trifluoromethyl) coumarin acrylamide) cross-linked wall. N J Chem. 2015;39(2): 1506–16.10.1039/C4NJ02053GSearch in Google Scholar
38. Seymour LW, Ulbrich K, Steyger PS, Brereton M, Subr V, Strohalm J, Duncan R. Tumour tropism and anti-cancer efficacy of polymer-based doxorubicin prodrugs in the treatment of subcutaneous murine B16F10 melanoma. Br J Cancer 1994;70:636–41.10.1038/bjc.1994.363Search in Google Scholar PubMed PubMed Central
39. Du JZ, Du XJ, Mao CQ, Wang J. Tailor-made dual pH-sensitive polymer-doxorubicin nanoparticles for efficient anticancer drug delivery. J Am Chem Soc. 2011;133(44):17560–3.10.1021/ja207150nSearch in Google Scholar PubMed
40. Wang H, Wang Y, Chen Y, Jin Q, Ji J. A biomimic pH-sensitive polymeric prodrug based on polycarbonate for intracellular drug delivery. Polym Chem. 2014;5(3):854–61.10.1039/C3PY00861DSearch in Google Scholar
41. Wang L, Wang Y, Jin Q, Jia F, Wang H, Ji J. Biomimic pH/reduction dual-sensitive reversibly cross-linked hyaluronic acid prodrug micelles for targeted intracellular drug delivery. Polymer (Guildf). 2015;76(Suppl C):237–44.10.1016/j.polymer.2015.09.003Search in Google Scholar
42. Wei C, Guo J, Wang C. Dual stimuli-responsive polymeric micelles exhibiting “DNA” logic gate for controlled release of adriamycin. Macromol Rapid Commun. 2011;32(5):451–5.10.1002/marc.201000708Search in Google Scholar PubMed
43. Jin Q, Mitschang F, Agarwal S. Biocompatible drug delivery system for photo-triggered controlled release of 5-fluorouracil. Biomacromolecules 2011;2(10):3684–91.10.1021/bm2009125Search in Google Scholar PubMed
44. Mohammed MO, Hussain KS, Haj NQ. Preparation and bioactivity assessment of chitosan-1-acetic acid-5-flurouracil conjugates as cancer prodrugs. Molecules 2017;22(11):1629.10.3390/molecules22111629Search in Google Scholar PubMed PubMed Central
45. Kopeček J, Yang J. Hydrogels as smart biomaterials. Polymer Int. 2007;56(9):1078–98.10.1002/pi.2253Search in Google Scholar
46. Serrano-Medina A, Oroz-Parra I, Gómez-Resendiz VE, Licea-Navarro A, Licea-Claverie A, Cornejo-Bravo JM. Temperature and pH sensitive core-shell nanogels as efficient carriers of doxorubicin with potential application in lung cancer treatment. Int J Polym Mater. 2018;67(1):20–6.10.1080/00914037.2017.1297938Search in Google Scholar
47. Oishi M, Nagatsugi F, Sasaki S, Nagasaki Y, Kataoka K. Smart polyion complex micelles for targeted intracellular delivery of pegylated antisense oligonucleotides containing acid-labile linkages. ChemBioChem 2005;6:718–25.10.1002/cbic.200400334Search in Google Scholar PubMed
48. Hayashi H, Iijima M, Kataoka K, Nagasaki Y. pH-Sensitive nanogel possessing reactive PEG tethered chains on the surface. Macromolecules 2004;37(14):5389–96.10.1021/ma049199gSearch in Google Scholar
49. Rzaev ZMO, Dinçer S, Pişkin E. Functional copolymers of N-isopropylacrylamide for bioengineering applications. Prog Polym Sci. 2007;32:534–95.10.1016/j.progpolymsci.2007.01.006Search in Google Scholar
50. Alvarez-Sánchez J, Licea-Claveríea A, Cornejo-Bravo JM, Frank CU. Star polymer with NIPAAm arms and crosslinked hydrophobic core for the release of 5 Fu. React Funct Polym. 2011;71(11):1077–108.10.1016/j.reactfunctpolym.2011.08.003Search in Google Scholar
51. Sun H, Meng F, Cheng R, Deng C, Zhong Z. Reduction-responsive polymeric micelles and vesicles for triggered intracellular drug release. Antioxid Redox Signal. 2014;21(5):755–67.10.1089/ars.2013.5733Search in Google Scholar PubMed PubMed Central
52. Zhong Y, Yang W, Sun H, Cheng R, Meng F, Deng C, Zhong Z. Ligand-directed reduction-sensitive shell-sheddable biodegradable micelles actively deliver doxorubicin into the nuclei of target cancer cells. Biomacromolecules 2013;14(10):3723–30.10.1021/bm401098wSearch in Google Scholar PubMed
53. Sun Y, Yan X, Yuan T, Liang J, Fan Y, Gu Z, Zhang X. Disassemblable micelles based on reduction-degradable amphiphilic graft copolymers for intracellular delivery of doxorubicin. Biomaterials 2010;31(27):7124–31.10.1016/j.biomaterials.2010.06.011Search in Google Scholar PubMed
54. Xu Y, Meng F, Cheng R, Zhong Z. Reduction-sensitive reversibly crosslinked biodegradable micelles for triggered release of doxorubicin. Macromol Biosci. 2009;9(12):1254–61.10.1002/mabi.200900233Search in Google Scholar PubMed
55. Knutson M, Wessling-Resnick M. Iron metabolism in the reticuloendothelial system. Crit Rev Biochem Mol Biol. 2003;38:61–88.10.1080/713609210Search in Google Scholar PubMed
56. Goldberg M, Langer R, Jia X. Nanostructured materials for applications in drug delivery and tissue engineering. J Biomater Sci Polym Ed. 2007;18:241–68.10.1163/156856207779996931Search in Google Scholar PubMed PubMed Central
57. de Faria TJ, de Campos A, Lemos Senna E. Preparation and characterization of poly(D, L-lactide) (PLA) and poly(D, L-lactide)-poly(ethylene glycol) (PLA-PEG) nanocapsules containing antitumoral agent methotrexate. Macromol Symp. 2005;229: 228–33.10.1002/masy.200551128Search in Google Scholar
58. Barua S, Yoo JW, Kolhar P, Wakankar A, Gokarn YR, Mitragotri S. Particle shape enhances specificity of antibody-displaying nanoparticles. Proc Natl Acad Sci. 2013;110:3270–5.10.1073/pnas.1216893110Search in Google Scholar
59. Naeye B, Raemdonck K, Remaut K, Sproat B, Demeester J, De Smedt SC. PEGylation of biodegradable dextran nanogels for siRNA delivery. Eur J Pharm Sci. 2010;40:342–51.10.1016/j.ejps.2010.04.010Search in Google Scholar
60. Moghimi SM, Szebeni J. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res. 2003;42:463–78.10.1016/S0163-7827(03)00033-XSearch in Google Scholar
61. Kos J, Obermajer N, Doljak B, Kocbek P, Kristl J. Inactivation of harmful tumour-associated proteolysis by nanoparticulate system. Int J Pharm. 2009;381:106–12.10.1016/j.ijpharm.2009.04.037Search in Google Scholar PubMed
62. Nukolova NV, Yang Z, Kim JO, Kabanov AV, Bronich TK. Polyelectrolyte nanogels decorated with monoclonal antibody for targeted drug delivery. React Funct Polym. 2011;71:315–23.10.1016/j.reactfunctpolym.2010.10.011Search in Google Scholar PubMed PubMed Central
63. Mitra A, Coleman T, Borgman M, Nan A, Ghandehari H, Line BR. Polymeric conjugates of mono- and bi-cyclic αVβ3 binding peptides for tumor targeting. J Control Release 2006;114(2): 175–83.10.1016/j.jconrel.2006.06.014Search in Google Scholar PubMed
64. Gao ZG, Lee DH, Kim DI, Bae YH. Doxorubicin loaded pH-sensitive micelle targeting acidic extracellular pH of human ovarian A2780 tumor in mice. J Drug Target 2005;13(7):391–7.10.1080/10611860500376741Search in Google Scholar PubMed PubMed Central
65. Licea-Claveríe A, Cornejo-Bravo JM, Salgado-Rodríguez R, Santos-Rosas D del R, Lugo-Medina E, Ramos-Ibarra MA, Arndt K-F. Temperature and pH-sensitive polymers with hydrophobic spacers for the controlled delivery of drugs. Macromol Symp. 2007;254(1):292–9.10.1002/masy.200750843Search in Google Scholar
66. Almeida H, Amaral MH, Lobão P. Temperature and pH stimuli-responsive polymers and their applications in controlled and selfregulated drug delivery. J App Pharm Sci. 2012;2(6):1–10.Search in Google Scholar
67. Licea-Claveríe A, Alvarez-Sánchez J, Picos-Corrales LA, Obeso-Vera C, Flores MC, Cornejo-Bravo JM, Hawker CJ, Frank CW. The Use of the RAFT-technique for the preparation of temperature/ph sensitive polymers in different architectures. Macromol Symp. 2009;283–284:56–66.10.1002/masy.200950909Search in Google Scholar
68. Barua S, Mitragotri S. Challenges associated with penetration of nanoparticles across cell and tissue barriers: a review of current status and future prospects. Nano Today 2014;9(2):223–43.10.1016/j.nantod.2014.04.008Search in Google Scholar PubMed PubMed Central
69. Sensenig R, Sapir Y, MacDonald C, Cohen S, Polyak B. Magnetic nanoparticle-based approaches to locally target therapy and enhance tissue regeneration in vivo. Nanomed Future Med. 2012;7:1425–42.10.2217/nnm.12.109Search in Google Scholar PubMed PubMed Central
70. Bacq ZM. Fundamentals of biochemical pharmacology: pergamon international library of science, technology, engineering and social studies, Oxford, UK: Elsevier; 2014.Search in Google Scholar
71. Ashrafuzzaman MD. Aptamers as both drugs and drug-carriers. Biomed Res Int. 2014;2014:1–21.10.1155/2014/697923Search in Google Scholar PubMed PubMed Central
72. Biswal BK, Verma RS. Differential usage of the transport systems for folic acid and methotrexate in normal human T-lymphocytes and leukemic cells. J Biochem. 2009;146:693–703.10.1093/jb/mvp130Search in Google Scholar PubMed
73. Luck AN, Mason AB. Transferrin-mediated cellular iron delivery. Curr Top Membr 2012;69:3–35.10.1016/B978-0-12-394390-3.00001-XSearch in Google Scholar PubMed PubMed Central
74. Gridi-Papp M, Feng AS, Shen J-X, Yu Z-L, Rosowski JJ, Narins PM. Active control of ultrasonic hearing in frogs. Proc Natl Acad Sci. 2008;105:11014–9.10.1073/pnas.0802210105Search in Google Scholar PubMed PubMed Central
75. Villarreal-Gómez LJ, Cornejo-Bravo JM, Vera-Graziano R, Grande D. Electrospinning as a powerful technique for biomedical applications: a critically selected survey. J Biomater Sci Polym Ed. 2016;27:157–76.10.1080/09205063.2015.1116885Search in Google Scholar PubMed
76. Velasco Barraza RD, Álvarez Suarez AS, Villarreal Gómez LJ, Paz González JA, Iglesias AL, Vera Graziano R. Designing a low-cost electrospinning device for practical learning in a bioengineering biomaterials course. Rev Mex Ing Biomédica. 2016;37:7–16.Search in Google Scholar
77. Villarreal-Gómez LJ, Vera-Graziano R, Vega-Rios MR, Pineda-Camacho JL, Mier-Maldonado PA, Almanza-Reyes H, Cornejo-Bravo JM. In vivo biocompatibility of dental scaffolds for tissue regeneration. Adv Mater Res. 2014;976:191–5.10.4028/www.scientific.net/AMR.976.191Search in Google Scholar
78. Villarreal-Gómez LJ, Vera-Graziano R, Vega-Rios MR, Pineda-Camacho JL, Mier-Maldonado PA, Almanza-Reyes H, Cornejo-Bravo JM. Biocompatibility evaluation of electrospun scaffolds of poly(l-lactide) with pure and grafted hydroxyapatite. J Mex Chem Soc. 2014;58:435–43.Search in Google Scholar
79. Doustgani A. Doxorubicin release from optimized electrospun polylactic acid nanofibers. J Ind Text. 2016;34:1047.10.1177/1528083716634033Search in Google Scholar
80. Mete D, Horzum N, Mohamed GS. Controlled release of doxorubicin from electrospun gelatin nanofibers, Proceedings of the World Congress on Recent Advances in Nanotechnology (RAN’16), Prague, Czech Republic. 2016.10.11159/nddte16.126Search in Google Scholar
81. Qi R, Tian X, Guo R, Luo Y, Shen M, Yu J, Shi X-Y. Controlled release of doxorubicin from electrospun MWCNTs/PLGA hybrid nanofibers. Chinese J Polym Sci. 2016;34:1047–59.10.1007/s10118-016-1827-zSearch in Google Scholar
82. Zheng F, Wang S, Shen M, Zhu M, Shi X. Antitumor efficacy of doxorubicin-loaded electrospun nano-hydroxyapatite-poly (lactic-co-glycolic acid) composite nanofibers. Polym Chem. 2013;4:933–41.10.1039/C2PY20779FSearch in Google Scholar
83. Xu X, Chen X, Ma P, Wang X, Jing X. The release behavior of doxorubicin hydrochloride from medicated fibers prepared by emulsion-electrospinning. Eur J Pharm Biopharm. 2008;70:165–70.10.1016/j.ejpb.2008.03.010Search in Google Scholar PubMed
84. Ardeshirzadeh B, Anaraki NA, Irani M, Rad LR, Shamshiri S. Controlled release of doxorubicin from electrospun PEO/chitosan/graphene oxide nanocomposite nanofibrous scaffolds. Mater Sci Eng C. 2015;48:384–90.10.1016/j.msec.2014.12.039Search in Google Scholar PubMed
85. Yu Y, Kong L, Li L, Li N, Yan P. Antitumor activity of doxorubicin-loaded carbon nanotubes incorporated poly(lactic-co-glycolic acid) electrospun composite nanofibers. Nanoscale Res Lett. 2015;10:343.10.1186/s11671-015-1044-7Search in Google Scholar PubMed PubMed Central
86. Illangakoon UE, Yu D-G, Ahmad BS, Chatterton NP, Williams GR. 5-Fluorouracil loaded eudragit fibers prepared by electrospinning. Int J Pharm. 2015;495:895–902.10.1016/j.ijpharm.2015.09.044Search in Google Scholar PubMed
87. Zhang J, Wang X, Liu T, Liu S, Jing X. Antitumor activity of electrospun polylactide nanofibers loaded with 5-fluorouracil and oxaliplatin against colorectal cancer. Drug Deliv. 2016;23:784–90.10.3109/10717544.2014.916768Search in Google Scholar PubMed
88. Li H, Hardy RJ, Gu X. Effect of drug solubility on polymer hydration and drug dissolution from polyethylene oxide (PEO) matrix tablets. AAPS Pharm Sci Tech. 2008;9:437–43.10.1208/s12249-008-9060-xSearch in Google Scholar PubMed PubMed Central
89. Ravikumar R, Peng MM, Abidov A, Babu CM, Vinodh R, Palanichamy M, Choi EY, Jang HT. Nanofibrous polymers blend of fluorouracil loaded chitosan hydroxy ethyl cellulose/ poly vinyl alcohol: synthesis and characterization. Int J Bio-Sci Bio-Tech. 2016;8:295–306.10.14257/ijbsbt.2016.8.2.28Search in Google Scholar
90. Han R, Sun Y, Kang C, Sun H, Wei W. Amphiphilic dendritic nanomicelle-mediated co-delivery of 5-fluorouracil and doxorubicin for enhanced therapeutic efficacy. J Drug Target. 2017;25(2):140–8.10.1080/1061186X.2016.1207649Search in Google Scholar PubMed
91. Camacho KM, Menegatti S, Vogus DR, Pusuluri A, Fuchs Z, Jarvis M, Zakrewsky M, Evans MA, Chen R, Mitragotri S. DAFODIL: A novel liposome-encapsulated synergistic combination of doxorubicin and 5FU for low dose chemotherapy. J Control Release. 2016;229:154–62.10.1016/j.jconrel.2016.03.027Search in Google Scholar PubMed PubMed Central
92. Zhang FM, Dong H, Zhang X, Sun XJ, Liu M, Yang DD, Liu X, Wei JZ. Postsynthetic modification of zif-90 for potential targeted codelivery of two anticancer drugs. ACS Appl Mater Interfaces. 2017;9(32):27332–7.10.1021/acsami.7b08451Search in Google Scholar PubMed
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Articles in the same Issue
- Frontmatter
- In this Issue
- Full length articles
- Synthesis, characterization and application of polypyrrole-cellulose nanocomposite for efficient Ni(II) removal from aqueous solution: Box-Behnken design optimization
- Biodegradable glucose and glucosamine grafted polyacrylamide/graphite composites for the removal of acid violet 17 from an aqueous solution
- Evaluation of activated composite membranes for the facilitated transport of phenol
- The effects of nanoparticles on morphology and thermal properties of erythritol/polyvinyl alcohol phase change composite fibers
- Rapid crystallization and mesophase formation of poly(L-lactic acid) during precipitation from a solution
- Structural deformation of PVDF nanoweb due to electrospinning behavior affected by solvent ratio
- Poly(vinyl amine) as a matrix for a new class of polymers
- Review
- Polymeric advanced delivery systems for antineoplasic drugs: doxorubicin and 5-fluorouracil
