January 01, 2018. doi:10.12123/npcd201801005
BIOWED January 01, 2018
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Ran Chen, Yi Li, Rennan Weng*
Department of Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510275, P. R . China
Keywords: Nanotechnology; Brain glioma; Treatment
Received: September 01,2017 Accept: November 01,2017 published:January 01,2018
With its highly proliferative, infiltrative, and invasive properties, glioma is the most common malignant primary brain tumor, and 57% of them are glioblastoma multiforme, with a median survival time of only 18 months. However, facing the great challenges from blood-brain barrier and blood-brain tumor barrier, the drug treating for glioma remain non-targeted with low efficiency, which urgently need a new drug. Due to its plastic, low-toxic, targeted nature, nanotechnology brings hope to glioma treatment. In this review, we will discuss the potential possibility of nanoparticles in the treatment of gliomas based on targeted drug delivery system.
The incidence of malignant primary brain tumor is 5.03-8.84 per 100,000. Glioblastoma accounts for 8% of all intracranial tumors. Glioblastoma multiforme (GBM) is the most common, aggressive, and malignant form of astrocytomas, which originate in the brain. The 5-year relative survival rate for patients with GBM is lower than 5%(1), and the standard clinical treatment of GBM consists of maximal surgical resection, chemotherapy, and radiotherapy. However, the resistance of GBM towards the chemotherapy and radiotherapy leads to aggressive tumor relapse as well as poor convalescence, and the median survival of GBM patient is only 18 month(2,3).
Currently, the most critical challenge of treating for GBM is the poor drug penetration over the body barrier, including blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). The BBB isolates the central nerve system and blood-borne substances through the enzymatic barrier, cell-cell tight junction, immunological barrier, and diffusion barrier, while the BBB allows the liposoluble or small hydrophilic to pass through(4). The BBTB, on the other hand, is the barrier between brain tumor and blood-borne substance, the permeability processes the apparent heterogeneity. Usually, due to the high metabolic demand of tumor cells, the tumor vasculature is highly enriched and contributes to the high permeability of the barrier, which is in favor of the drug aggregation. However, although the core portion of GBM has the abundant blood vessels supply as well as high BBTB permeability, the BBTB surrounded the tumor edge has similar low permeability as the complete BBB. Therefore, the concentration of drug penetrated into the brain tumor is still low(5,6).
Recently, the application of nanotechnology has drawn extensive attention from researchers in the medical science. The nanomaterial is readily degradable in vivo, which can be used as a delivery system of a lot of medicine. With the application of nanotechnology as drug delivery system, we can improve the drug administration: make the drugs more peculiar to the targets, decrease the side effects, better monitor the concentration, and easier design the drug construct(7). As we all know, the major potential mechanism of nanotechnology in the drug delivery system is enhancing the permeability and retention effect (EPR)(8). Therefore, during the process of the nanoparticle drug cross the BBB, on one hand, the nanoparticle reagents indirectly increase the drug concentration in the cerebrospinal fluid by enhancing the BBB permeability; On the other hand, the nanoparticles can cross the BBB through active and passive transportation, and the receptor-mediated nanoparticle endocytosis is the most accepted pathway(9). The nanocarrier consists of polymer nanoparticles, nanoscale liposomes, and carbon nanotubes, etc(10). Although there are several nanoparticle drugs are currently approved in the market for cancer treatment, the study of the application of nanotechnology in GBM is lagging behind.
In the studies of nanoparticle and GBM, the nanoscale liposome is the relatively mature carrier than the others. Some drugs have been already approved for phase I and phase II clinical trial such as polyethylene glycol liposomal adriamycin DepoCyt®, liposomal daunoXome ®, and other types of vectors are in preclinical trial(11,12). In this paper, we will review the nanotechnology in the treatment of GBM, imaging and diagnosis field based on the characteristics of the properties of nanoparticles and their function in the targeted drug delivery system.
Application of Organic Nanoparticles in the Treatment of GBM
Organic nanoparticles, according to the composition and structural trait can be categorized to high molecular polymer nanoparticles, biomaterial nanoparticles, micellar nanoparticles, dendrimer, and etc.(10).
High Molecular Polymer Nanoparticles
Micellar nanoparticles are composed of an amphiphilic macromolecule polymer. Amphiphilic molecules can spontaneously assemble and form the hydrophobic core to encapsulate the hydrophobic particles. According to the animal study, based on ERP effect, the convection-enhanced delivery of paclitaxel can extend the survival period of rat glioma model by using the polyether Nano microsphere as carriers(13). Interestingly, polyether nanoparticles themselves have the ability to prevent the drug from clearance out(14). The in vitro study of human glioblastoma cells indicates that the combination of the acid-labile groups and the nanomicrosphere polymers has the advantage of rapidly reaching and maintaining the effective plasma concentration(15). After binding to the acid-labile groups, the nanomicrosphere polymers can be not only structurally stable in the physiological environment of pH=7.4 but also be able to load the doxorubicin; and then release the doxorubicin under the acidic conditions (e.g. Lysosomes). What's more, the release is biphasic, the nanomicrosphere polymer release the doxorubicin at a high rate during the first phase (pH>5); while during the second phase (pH<5), the release is slow but stable. However, for the in vitro study, the physiological environment of the pH is relatively consistent. While in the actual human body, the pH of the tumor microenvironment is usually lower than the normal tissue (pH=6~7). The glioblastoma tumor tissues are highly heterogeneous, the elevated metabolism of rapidly growing tumor results in the release of various acidic metabolites, which lower the pH of the tumor microenvironment, contributing to the complexity of microenvironmental pH(16). Taken together, the pH-dependent sustained release system needs further studies. In addition, an Star-branched amphiphilic copolymers can transport chemotherapeutic drugs as well as genes, which offers better treatment than the microsphere with single agents. This combination therapy broadens the horizon of nanotechnology in terms of cancer treatment(17).
Due to the EPR effect, the nano-agents have a higher concentration in the tumor tissue compared to normal tissue, called passive targeting(16). However, elevated levels of drug concentration in the tumor site are not equivalent to the elevated level of drug internalization, whereas the latter has a greater biological significance(18). Based on this, we can bind specific ligands to the surface receptor on the nano-agents to achieve the active targeting. Currently, the ligands of active targeting are generally those overexpressed in the tumor cells such as folic acid, transferrin, EGFR, glycoprotein receptor, etc., or tumor endothelial cells such as VEGF, avb3 integrin, VCAM-1, MMP(16). Thus, in the course of the treatment of the tumor, in order to enhance the target specificity, on the one hand, we can co-target two ligands of tumor cells and tumor endothelial cells; on the other hand, we can target the common ligand of tumor cell and endothelial cell(19,20). For example, the cRGD peptide is a class of short peptides containing the Arg-Gly-Asp sequence that can be used as a recognition site for certain integrins and their ligands to mediate the cell interaction. Thus, its application in targeted therapy has become a new research focus. The cRGD peptide targeting drug loading primarily based on the precursor microsphere which consists of amphoteric macromolecule polymer that contains abundant surface functional groups binds to the sulfhydryl group of cRGD. In addition, some studies used nuclear magnetic resonance (NMR) to analyze the effect of the microsphere with drugs and ligands loaded, based on EPR theory, and compared the drug concentration inside U87MG cells before and after the drug treatment. They found the drug concentration inside the cells was higher when drug and ligand were both loaded. At the same time, as to the efficacy, Miura et al.(21) found that the cRGD peptides could use endocytosis to cross the BBTB by observing the tumor growth on the glioma BALB/c nude mice model, therefore, increase the target binding efficiency and drug concentration, and provide the extraordinary anti-tumor effect. Above is the general idea of studying the application of nanocarrier in terms of target therapy on the tumor. Conventional models and techniques are shown in Table 1. (See supplemental data)
However, in the nano-agent experiment of tumor drugs, although the EPR effect has been tested in the animal model and achieved expected results, most of the clinical trials are not successful. This is due to the huge difference between the mouse tumor model and human tumors. The mouse tumor progresses faster than the human tumor, and mouse tumor and blood vessel are less heterogeneous, the individual difference cause to the inconsistency of mouse and human experiment results(22). Nevertheless, nanotechnology has a great potential for tumor treatment. On the one hand, some applications, for example, low toxicity (assuming that the drug has low toxicity, can sustain low concentration yet effective without the EPR effect.), local medication and diagnosis do not rely on the EPR effect. On the other hand, the concept of personalized therapy is still lagging behind, and the application of Nano-agent will be the solution to such problems(8).
Nano dendrimers, as the name suggests, consists of dendrimer polymers, highly branched, radially, and have a large number of surface groups. Due to its particular dendritic structure, this particle has a high drug load and versatility, and the transport efficiency of the drug is related to the size and configuration of the particles(18). The most studied nano-dendrimers are polyamide amines (PAMAM) particles(19,20,23), which are ideal for cationic multimers and transport vectors(24). The versatility is mainly due to its ability to combine a variety of functional materials to achieve targeted transport protein and BBB permeability changes. For example, in addition to binding to specific ligands such as Angiopep-2(20), transferrin(19), etc. to achieve "active targeting"; the combination with magnetic fluorescent materials can also achieve in vivo positioning, in Agrawal et al.(23), the use of MRI targeting targeted transporter siRNA could inhibit the expression of tumor cell epidermal growth factor to treat glioblastoma. In addition, studies(19) show that nano dendrimers can also achieve biphasic binding, that is, internal binding of specific molecules such as tamoxifen, externally binding specific ligands, thereby reducing cell efflux to drugs and increasing drug intake of the cell.
In addition to nanospheres and nano dendrimers, other polymeric nanoparticles also include PLGA particles, which can also bind to specific ligands such as nucleic acid(25), transferrin(26), and even magnetic Silica(26) to achieve targeted drug delivery to glioma.
However, despite the fact that specific ligands increase the efficacy of drug administration, but the "off-target" problem is still unavoidable. In vitro study(27) showed that after the drug entering the body, the transferrin group on the surface of the nanoparticles would interact with the proteins in the medium and form a protein "crown," thereby preventing the aggregation of the drugs in the non-target site. Although the study only reported the transferrin, it is reasonable to suspect that other ligands will also present this kind of issue.
Biomaterial nanoparticles are made up of natural polymers such as polysaccharides and proteins. In essence, they are macromolecule polymer. Biomaterial nanoparticles have multiple advantages including low cell toxicity, abundant surface functional groups, high drug affinity, and excellent target cells absorption(28). Animal natural proteins include albumin, gelatin, elastin, polysaccharides such as chitosan can be used as ligands or as nanoparticle skeletons(28). Natural proteins, compared to the artificial proteins, will attain better bioactivity. When the natural proteins bind to the receptors on the cell surface, they can activate endocytosis while the artificial proteins' abilities to activate endocytosis are limited. Therefore, even to the same receptor, the natural protein and artificial protein will trigger different signaling pathways(29).
The liposome is a synthetic spherical structure with the lipid bilayer, also composed of amphiphilic molecule. Unlike the monolayer nanomicrosphere that forms a hydrophobic core, the bilayer nanomicrosphere can form a hydrophilic core in the liquid phase which is in favor of the transport of small hydrophilic molecules. Indeed, the nano-liposomes provide the potential solution to the rapid metabolism, poor absorption, and high toxicity of conventional liposome application(30).
Compared with other nano-agent, liposomes have the disadvantages such as low clearance rate, and low transportation rate. Therefore, the liposomes usually bind with polyethylene glycol (PEG), APMP (acting on GLUT-1, which favors the cell uptake of nanoparticles)(31), RGD peptides(32), transferrin(33), and other specific ligands. Among those ligands, PEG can escape the reticuloendothelial system, reduce the phagocytosis of macrophages(34), reduce the antigenicity of liposomes in order decrease the clearance of immune system(35), prolong the circulatory time in the body(36), and increase the drug concentration on the tumor site. Thus, PEG conjugated liposomes are called "stealth liposomes"(37).
As TPGS (an amphoteric copolymer material) is increasingly used in liposome and microsphere cell skeletal synthesis(37,38), studies have found that TPGS (PEGylated Vitamin E) Nano-agents have a greater toxicity to tumor cells while showing a higher packaging efficiency to drugs, cell uptake rate is also higher(39). TPG is likely to overcome the multidrug resistance of tumor cells as a P-glycoprotein inhibitor(39). Due to the TPGS is more conducive to be uptaken by cell and the TPGS does not bind ligands causes poor targeting, the side effects will be more severe than other liposomes reagents.
In recent years there comes out a kind of theranostic liposomes, integrated with the imaging and treatment as a whole, not the only save the time of patients, but also reduce the toxicity of contrast agent, thereby is safer than traditional imaging technology. For example, the quantum dots (QD) contain heavy metals, which are toxic, but it degrades less after encapsulating into the liposomes, so that make sure the harmful substances in the body can be maintained within the human safety range(37,38).
Solid Lipid Nanoparticles
Solid lipid nanoparticles (SLNs) take advantage of nanoscale liposomes and polymeric macromolecules. The major differences between SLNs and nanoscale liposomes are (1) solid structure, a solid lipid core matrix, can dissolve lipophilic substances; (2) composed of solid natural or synthetic lipid, so the biocompatibility is high, and the cell Toxicity is minimal. Studies have shown that SLNs with ligand folate and APMP loaded can enhance the transport efficiency of etoposide in vitro to achieve targeted delivery(40). Also, somatostatin receptors, particularly type 2, are overexpressed in neovascular endothelial cells and glioma cells in gliomas. Therefore, by constructing Tyr containing paclitaxel (PTX) -3-octreotide-modified SLNs can act on both cells simultaneously to achieve "double-targeted" therapy(41).
Inorganic Nanoparticles in the Treatment of Brain Gliomas
Inorganic nanoparticles include magnetic nanoparticles, carbon nanotubes, etc. Compared to organic nanoparticles, inorganic nanoparticles have better physical properties and play a unique role in thermotherapy.
Magnetically-responsive Nanoparticles (MNP)
MNP consists of magnetic cores (composed of iron, manganese, cobalt, nickel and their respective oxides) and a biocompatible polymer shell, which is noninvasive and can be administered orally(42). On the one hand, it can use its magnetic field to manipulate an external magnetic field such as MRI to accurately reach the organs with the tumors, reduce the side effects of the drug concentration in the non-lesion site while maintaining the external magnetic field to allow the residence time of the nanomaterials in the tumor site to be prolonged sufficient time to release the drug. The animal study found that the turnover time of MNP in the tumor site can be up to 150 min, and it took 60 min to release all the drugs(43). On the other hand, studies have shown that thermotherapy as adjuvant therapy can improve the survival rate of patients with recurrent pleomorphic glioblastoma(44). MNP magnetic field energy can be converted into heat; alternating magnetic field of local heat can be applied to the treatment of thermotherapy to achieve the purpose of treating tumor(45). At the same time, external thermal effects can also improve tissue permeability and increase the plasma drug concentration. MNP can also be combined with heat-sensitive materials to "guard" the release of drugs(46).
Currently, MNP has been shown to be non-toxic and well-tolerated in preclinical and clinical studies of solid tumors(47,48). However, due to MNP requires high magnetic field control, has low biocompatibility, and limited targeting ability, intracarotid drug administration will cause vessels clotting and therefore leads to the risk(49). Mohammed et al.(50) found that the polymer coating could prevent particle aggregation and improve biocompatibility to some extent. Therefore, the magnetic field controlled MMPs still needs to be further improved. The limited targeting is that the magnetic field is localized to local organ levels with limited fineness and can further bind to specific ligands to increase the targeting of magnetic nanoparticles at the cellular level(51).
Carbon Nanotubes (CNTs)
CNTs are a kind of nano-material with cylindrical structure, which can be separated into single-walled nanotubes (SWNTs) and Multi-walled nanotubes (MWNTs), which is a good gene therapy drug carrier. In the targeted drug delivery studies, CNTs can bind with specific ligands such as angiopep-2 to achieve target therapy(52), and can also bind other ligands and fluorescent markers to achieve a simultaneous diagnosis and treatment(53). In addition, studies have found that with the addition of the glioma inhibitor, CNT can significantly enhance the ability of inflammatory cells (such as macrophages) to uptake CpG oligodeoxynucleotide and activate the intracellular receptor TLR9, and then cause a series of immune responses such as increased NK cells, more effectively inhibit tumor growth(54). Ouyang et al.(55) also found that CNTs combined with TMZ chemotherapy had better anti-tumor effects.
In addition, CNT-Mediated Thermal Therapy (CNMTT) is also a research hotspot in recent years. The principle is that carbon nanotubes can convert electromagnetic radiation (such as internal infrared rays) into heat and cause apoptosis. SWNTs and MWNTs are both used in thermotherapy of the tumor, and MWNs is more commonly used(56). However, the application of CNMTT not only need to fully consider the precise mode of administration, CNT structural characteristics, and physical/chemical properties; but also to evaluate its cytotoxic effect on tumor cells and cytogenetic and acquired heat-resistant treatment(57,58).
At present, the difficulty of CNMTT application is mainly on how to accurately administer the drug and overcome the tumor cell self-protection mechanism - heat shock reaction (HSR). To achieve local administration without damage to other intracranial tissue, the intracranial catheter can be used for External Collection Devices (ECD), but because the ECD method is still in the study, there is not enough data to prove its feasibility in CNMTT while the evaluation of HSR is mainly based on the expression of heat shock protein. Eldridge et al.(57) used the transient heating method to induce stress in the cells to simulate acquired heat resistance and found that PEG phospholipids encapsulated MWNTs did not induce cell production of HSR. TMZ chemotherapy is commonly used in patients with glioma, and whether TMZ will affect the acquired heat resistance of tumor cells needs further analysis(57).
In addition, gold nanoparticles can also be used for thermotherapy; the basic principle is similar to carbon nanotubes. In comparison, carbon nanotubes have the wider absorption spectrum, higher energy efficiency(59), and less temperature distortion(60), and the potential for thermotherapy is much greater than that of gold nanoparticles.
Application of Nanotechnology in the Diagnosis and Imaging of Brain Glioma
Brain glioma, especially GBM, shows strong aggressiveness, rapid development, which makes the early clinical diagnosis and treatment very important. MRI is a fundamental and sensitive method to diagnose a brain tumor, but its sensitivity highly relies on the quality of contrast agents(61). Conventional contrast agent has several problems such as low contrast and high toxicity, while the imaging technology is closely related to diagnostic accuracy.
In MRI imaging, the common nanomaterial is a nano contrast agent and common nanocarrier(61). The nano contrast agent is a superparamagnetic iron oxide (SPIO), including ferumoxides (Feridex in the USA, Enodorem in Europe) with a particle size of 120 to 180 nm, and ferucarbotran (Resovist) with a particle size of about 60nm, which are clinically approved and on the clinical trial(62). In addition, other than SPIO, carbon nanotubes as nano contrast agent still under clinical trial(63). For carbon nanotubes, as conventional nanocarrier of contrast agent, it contains toxic substance gadolinium. Therefore, the PS80 nanoparticle(64), PAMAM dendrimers molecule(61) can be used as a carrier to lower the toxicity. There are studies have shown that human glioblastoma will continue to shed some specific cells into the blood of microbubbles, so antibody can be used to label cell microbubbles and mark the magnetic nano-cell microbubbles. Micronuclear magnetic resonance (μNMR) detection can also mark cell signal strength and sensitively reflect the blood cell microbubble level, which provides a promising glioma prospective to glioma diagnosis and treatment(65).
Conclusion and Prospect
Due to the high aggressiveness of glioma to BBB and BBTB, the progression of glioma is complicated, which brings the great challenge to the treatment. Compare to conventional drugs, the advantages of nano-agent are highly specific to the targets, and low toxicity. On the one hand, the microenvironment of glioma is very complex, it can interact with the nano-agent to form a protein crown, resulting in the off-target of the drug. What's more, glioma is highly heterogeneous, and cannot be simulated by the in-vitro study. On the other hand, glioma cells express diverse cell surface protein, so it is important to select appropriate ligands. At the same time, the application of nano technology in the diagnosis and treatment of glioma began relatively late. Although the animal study of EPR effect broadens the horizon of diagnosis and treatment. However, with the failure of more and more nano-agent on the clinical trial, we found EPR effect is highly heterogeneous in human. Hopefully, in the future, there will be better clinical glioma model to boost the development of nanotechnology in glioma treatment.
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