INTRODUCTION
Gliomas are the most frequent primary malignant brain tumors in adults. Their incidence is approximately 81% of all malignant brain tumors and 45% of all primary central nervous system (CNS) tumors.[1] The World Health Organization classification divides brain tumors according to the constituent cells of the CNS, such as astrocytes, oligodendrocytes, and ependymal cells, and further sub-classifies according to the presumed level of differentiation, which is determined based on morphological abnormalities. Recently, genetic/epigenetic features that can identify numerous tumor histotypes have also been included.[2] Glioblastoma multiforme (GBM), the most malignant occurring type of glioma, shows an incidence of around 60% of all brain tumors in adults.[3] Patients show a median survival of 14–15 months from the diagnosis.[4] The choice of optimal treatment depends on several factors, such as size of the lesion, patient's age, and neurological status.[5] The standard treatment of gliomas is multimodal that includes surgical resection, radiotherapy, and chemotherapy. The extent of resection is considered a prognostic factor. However, radical resection is not always achievable, both due to the extensive infiltration of the tumor and as an attempt to preserve the functional areas. Several techniques have been designed to improve tumor detection and to increase the possibility of total tumor resection, such as neuronavigation, use of 5-aminolevulinic acid, and intraoperative magnetic resonance imaging (MRI). There is evidence that the combined use of these techniques improves the success rate of complete resection of tumors to 96.2%.[6] Radiotherapy and chemotherapy are related to important side effects, such as postradiation leukoencephalopathy, nerve damage, hair loss, vomiting, infertility, and skin rash. Moreover, the effectiveness of chemotherapy is limited by various factors such as toxic effects on healthy cells, tumor cell chemoresistance, and poor selectivity of anticancer drugs. Moreover, the blood–brain barrier (BBB) limits the delivery of many chemotherapeutic agents.
Angiogenesis, the proliferation of new blood vessels from preexisting vessels, is an index of malignancy.[7] This process consists of various steps including endothelial cell proliferation, stimulation of endothelial cells by endogenous growth factors, cell migration, and capillary tube formation. Tumor progression could be slowed down by hindering the formation of blood vessels inside the tumor. The major advantage of _targeting angiogenesis is better accessibility of a drug into the tumor vasculature. This event can decrease tumor drug resistance, and at the same time, it increases the efficacy of the drug. However, this approach showed significant limitations associated with the physicochemical properties of the compounds and related toxicity, systemic degradation, and optimal concentrations.
Nanotechnology is considered as an emerging field with potential application in cancer research and therapy. In particular, nanoparticles (NPs) allow entry of drugs within the BBB reducing doses administered, side effects, and resistance.[8] Their nanometric size, electrostatic charge, and lipophilic characteristics allow them to freely penetrate into the brain tissue [Figure 1]. NPs can be structured to carry therapeutic drugs and imaging agents, which are loaded on or within the nanocarriers, by chemical conjugation or encapsulation. This review shows recent studies concerning NPs drug-delivery systems (DDSs) which utilized novel _targeted biomarkers in the treatment of gliomas.
Figure 1: Nanoparticle properties
NANOTECHNOLOGY STRATEGIES TO OVERCOME THE BLOOD–BRAIN BARRIER
BBB is a physical barrier which protects the brain and the spinal cord from passage of drugs, neurotoxins, and invading organisms and regulates the movement of nutrients between the systemic circulation and the brain tissue.[8,9] Novel drugs require effective delivery technologies that are suitable to minimize side effects, leading to better patient compliance. Efficacious doses are obtained with high concentrations and administered alone; these drugs lack specificity and cause significant damage to noncancerous tissues. Moreover, most chemotherapeutic agents have poor solubility and are mixed with toxic solvents.[10] NP-based DDSs provide better penetration of therapeutic and diagnostic agents enabling achievement of efficacy with reduced doses and systemic concentration of drugs. Nanostructure-mediated drug delivery shows the possibility to enhance drug bioavailability, improve time of release of drug molecules, and enable precision drug _targeting without altering the structural integrity of the BBB.[11] Surface property modifications allow a more accurate tumor _targeting, conferring advantageous properties to the particle.[12]
NPs may be delivered to specific sites by size-dependent passive _targeting or by active _targeting. Passive _targeting consists of chemical modifications of the NPs to increase permeability or stability. The most common surface modification of different NPs is the insertion of ethylene oxide polymers, known as poly (ethylene glycol) (PEG). PEG is able to mask the NP charge and hide _targeting ligands, directly attached to NPs. PEG increases half-life of nanocarrier DDSs by decreasing their uptake by macrophages due to steric repulsion effects and inhibition of plasma-protein adsorption. PEGylation has been successfully applied in the majority of DDSs, including lipid, polymeric NPs, and inorganic NPs.
Active _targeting is usually achieved by incorporation of a receptor-specific ligand that can promote _targeting of the drug-containing NP toward specific cells. The term “active _targeting” refers to the use of peripherally conjugated _targeting moieties for enhanced delivery of NP systems. This method has been performed to obtain a high degree of selectivity to specific tissues and to enhance the uptake of NPs into cancer cells and angiogenic microcapillaries.[12]
Absorptive-mediated transcytosis is to deliver drugs by NP system, functionalized with cell-penetrating peptides or cationic proteins via electrostatic interactions. However, because it is a nonspecific process, the adsorptive process also occurs in the blood vessels and also in other non_target organs. This evidence results in a reduced concentration of the drug in the brain. Cell-penetrating peptides (CPPs) and cationic proteins are investigated to enhance drug delivery to the brain via adsorptive-mediated transcytosis. A large variety of cargo molecules/materials have been effectively delivered into cells via CPPs, including small molecules, proteins, peptides, fragments of DNA, and NPs. The transcription factor transactivator protein (TAT), involved in the replication cycle of human immunodeficiency virus, was demonstrated to penetrate cells.[13] One of the most interesting demonstrations of the effectiveness of TAT-shuttled nanocarriers across the BBB was accomplished by TAT-conjugated CdS: Mn/ZnS quantum dots.[14] Histological data showed that TAT-Q dots migrated beyond endothelial cells and reached the brain parenchyma.
Transporters for the nutritive substances into the brain are overexpressed on the BBB and can be used for brain-_targeted delivery.[15] The glutathione transporter is highly expressed on the BBB. Systemic administration of glycosyl cholesterol-derived liposomes containing coumarin-6 displayed reduced cytotoxicity and 3.3-fold higher Cmax compared to control liposomes _targeting glucose transporters on BBB.[16]
Receptor-mediated transcytosis across the BBB shows a high specificity. Molecules necessary for the normal function of the brain are delivered to the brain by specific receptors expressed on the BBB endothelial cells. Therapeutic compounds are able to cross the BBB after association/conjugation to these specific ligands. Receptor-mediated transcytosis has been demonstrated for transferrin, insulin, insulin-like growth factors (IGF-1 and IGF-2), and the low-density lipoprotein receptor-related protein (LRP).[17] Transferrin receptor (TR) is a transmembrane glycoprotein overexpressed in GBM cells. Drug _targeting to the TR can be achieved using the endogenous ligand transferrin or using antibodies directed against the TR. Doxorubicin-loaded TR-NPs showed antitumor effect in brain tumor-bearing rats, who survived 70% longer than those treated with the doxorubicin solution.[18] The endogenous ligands may bind with the receptors hindering the binding efficiency of ligand-modified NPs. To avoid this, antibodies against these receptors were developed. Ulbrich et al.[19] developed human serum albumin NPs, coupled to transferrin or TR-mAbs, (OX26) for delivery of loperamide and showed efficiency in transporting the drug to the brain using mice, in which OX26 was conjugated to HAS-NPs. OX26 mAb can avoid competition with endogenous transferrin in the circulation system because it binds to an extracellular domain of TR.[19] LRPs 1 and 2 (LRP1 and LRP2) are multifunctional receptors. Polysorbate 80, a nonionic surfactant, could adsorb ApoE in serum when it was conjugated on to NPs, and polysorbate 80-coated NPs have been also evaluated as a brain-_targeting delivery system by many groups.[20,21] Several drugs that do not cross the BBB, including tubocurarine, loperamide, dalargin, and doxorubicin, show higher concentrations in the brain when associated with polysorbate 80-coated NPs.
ANTIANGIOGENIC STRATEGY IN THE TREATMENT OF GLIOMAS
Angiogenesis is a physiological process that plays an important role during embryonic development, tumor growth, organ growth and repair, and wound healing. The microvascular proliferation of gliomas is structurally and functionally abnormal, and it correlates to vasogenic edema, increased interstitial pressure, and heterogeneous delivery of oxygen and drugs.[22] The blood vessels formed by tumor cells are leaky and enlarged with morphologically aberrant endothelial cells and an incomplete basement membrane. These abnormalities lead to an abnormal tumor microenvironment characterized by interstitial hypertension, hypoxia, and acidosis.[23] Vascular endothelial growth factor (VEGF) and angiopoietin families are predominant angiogenic factors in glioblastoma.[24] The control of the various phases of the angiogenesis can represent a valid approach in tumor therapy. It can prevent the development of tumors and can act as a complementary therapy in cancer treatment. The antiangiogenic approach can be directed to a specific biomarker so as to inhibit or alter a specific pathway, where it can extrinsecate through a link with specific membrane receptors overexpressed by glial cells, thus allowing the _targeted release of the pharmacological compound.
VEGF is expressed in gliomas and directly correlates to tumor grading, vascularity, and clinical behavior while inversely correlates to prognosis.[25] Bevacizumab (Avastin®; Hoffman-La Roche Ltd., Basel, Switzerland) is a humanized monoclonal antibody _targeting VEGF and approved in the US for GBM in 2009. Bevacizumab interferes with the VEGF pathway, thus counteracting the angiogenic processes, reducing vascular permeability and cerebral tributary blood flow of the tumor. However, clinical studies conducted on human subjects have yielded little encouraging results. The phase III “Avaglio” trial, conducted on 921 patients with newly diagnosed GBM, resulted in no overall survival benefit in bevacizumab-treated versus placebo-treated patients (median overall survival of 16.8 months for bevacizumab-treated patients and 16.7 months for placebo-treated patients).[26] A second phase III trial, the RTOG 0825 trial, produced similar results.[27] Recently, a new technology called coacervation has been developed for solid-lipid NPs preparation.[28] Through this technique, different hydrophilic drugs have been loaded into solid-lipid NPs using the hydrophobic ion-pairing technique. A recent experimental study showed an increase in bevacizumab activity when combined with solid-lipid NPs structured by the coacervation technology. The activity of bevacizumab, evaluated using four different in vitro tests on human umbilical vein endothelial cells (HUVEC) cells, increased by 100-fold to 200-fold when delivered in solid-lipid NPs.[29] In a recent study on rat glioma model, the authors describe the possibility to downregulate the expression of VEGF by a compound formed by lipid NPs carrying VEGF antisense oligonucleotides, both in vitro and in vivo.[30] In another study, the authors evaluated a liposomal DDS combined with cisplatin analog, cis-diamminedinitratoplatinum (II), and antibodies against the native form of VEGF or VEGFR2. The results evidenced sustained drug release profile, high affinity to antigens, and increased uptake by glioma C6 and U87MG cells.[31] Cerium oxide NP treatment caused decreased expression levels of VEGF in the human astrocytoma cell line (MOG-G-CCM) associated with reduced motility and capacity of endothelial cells to form new capillaries.[32] Chwalibog et al.[33] reported the action of diamond-NPs on VEGF-A and VEGF-receptor in human U87 glioblastoma cells. After diamond-NPs treatment, the authors demonstrated a reduced fibroblast growth factor 2 and VEGF expression, and a decreased development of blood vessels in GBM. An interesting study evaluated the action of magnetic NPs as (MRI) agents for in vivo visualization of gliomas.[34] Monoclonal antibodies against VEGF were conjugated to ferric oxide-bovine serum albumin (Fe3O4-BSA) through a PEG linker. The results showed that these _targeted NPs are effective in visualization of gliomas under MRI.
Overexpression of epidermal growth factor receptor (EGFR) on blood–brain–tumor barrier (BBTB) allows a selective _targeting of EGFR. EFGR is highly expressed in cancer cells, in more than 40% of GBM cases, and the mutated form EGFRvIII is expressed in more than 40% of GBM cases. A compound structured by PEGylated immunoliposomes (ILs) conjugated with anti-human EGFR antibodies cetuximab (α-hEGFR-ILs) was developed.[35] The affinity of the α-hEGFR-ILs for the EGFR was evaluated in vitro using U87MG and U251MG cells and in vivo using an intracranial U87MG xenograft model. The in vitro studies revealed significantly higher binding of α-hEGFR-ILs, while the in vivo study evidenced a more efficacious collect of α-hEGFR-ILs inside the tumor. A clinical study on animals showed the effectiveness of anti-EGF nanomedicine in GBM.[36] The therapeutic agent used was cetuximab (that binds both EGFR and EGFRvIII deletion mutant) conjugated with iron oxide NPs (IONPs). The result was an increase in survival. The use of an interesting pharmacological compound formed by transferrin-conjugated lipopolyplex nanoparticles (Tf-NPs) causes inhibition of migration and expression of EGFR;[37] these NPs can act both on cancer stem cells (CSCs) and on differentiated cancer cells. In an interesting study, the authors describe the phase I results of EnGeneIC delivery vehicle minicells coupled with doxorubicin, in patients with recurrent GBM.[38] They utilized the anti-EGFR monoclonal antibody Vectibix to _target the EGFR protein on cancer cells, thus releasing doxorubicin. The compound was well tolerated with no dose-limiting toxicity.
Integrins play prominent roles in tumor invasion and angiogenesis. In GBM, αvβ3 and αvβ5 are overexpressed on brain tumor cells and on brain tumor neovessels, favoring interaction between glial cells and the extracellular matrix. These integrins could be specifically _targeted with arginine-glycine-aspartic acid (RGD) peptide. Cyclic RGD and peptide-22 dual-modified liposomes loaded with doxorubicin showed to overcome BBB/BBTB, inhibiting the growth of GBM.[39] The compound paclitaxel (PTX)-loaded c (RGDyK)-PEG -block-poly (lactic acid) micelle (c [RGDyK]-PEG-PLA-PTX) was tested in U87MG cells.[40] Cilengitide (cyclo [RGDfV]) is a cyclic peptide that selectively binds αv integrins. c (RGDyK)-PEG-PLA micelle when loaded with PTX demonstrated the strongest tumor growth inhibition among the studied PTX formulations. The compound increased the overall median survival time of treated mice (48 days). In recent research, a pharmacological compound characterized by a platinum anticancer drug-incorporating polymeric micelle with cyclic RGD showed a high permeability and storage capacity into the tumor tissue.[41]
Glioma cells show an upregulation of expression of interleukin-13 (IL-13) receptor α2 (IL-13rα2) on their surface cells. A novel compound structured with Pep-1 and CREKA peptides GBM _targeting nano-DDS (PC-NP) was designed.[42] Pep-1 was used to overcome the BBTB and interfere with glioma cells via IL-13rα2-mediated endocytosis, and CREKA was utilized to bind to fibrin-fibronectin complexes expressed in tumor microenvironment. The results showed that the cellular uptake of PC-NPs by U87MG cells was significantly enhanced as compared to non_targeting NPs. In accordance with the increased cellular uptake, PC-NPs remarkably increased the cytotoxicity of its payload PTX against U87MG cells. In a recent study, Madhankumar et al.[43] showed the improvement of internalization of doxorubicin-loaded nanoliposomes, _targeted with conjugated IL-13, and cytotoxicity in U251 glioma cells. Bernardi et al.[44] conjugated gold-silica nanoshells to an antibody specific to IL-13rα2 demonstrating that these immunonanoshells are capable of inducing cell death in U373MG and U87MG cell lines. A significant therapeutic effect was found after convection-enhanced delivery (CED) of both IONPs and EGFRvIIIAb-IONPs in mice.[45] Use of bioconjugated magnetic NPs may permit the advancement of CED in the treatment of malignant gliomas due to their sensitive imaging qualities on standard T2 weighted MRI and therapeutic effects.
Curcumin is a polyphenolic compound derived from the Indian spice turmeric. It presents proapoptotic, antiangiogenic, anti-inflammatory, immunomodulatory, and antimitogenic effects.[46] NanoCurc™, a polymeric-NP formulation of curcumin, was used to treat medulloblastoma and glioblastoma cells. This compound caused a dose-dependent decrease in growth of multiple brain tumor cell cultures, including the embryonal tumor-derived lines DAOY and D283Med, the glioblastoma neurosphere lines HSR-GBM1 and the JHH-GBM14 cell lines.[47] The effect was associated with a combination of G2/M arrest and apoptotic induction. Furthermore, curcumin has been utilized in a spherical core-shell nanostructure, formed by amphiphilic methoxypolyethylene glycol-poly (caprolactone) (mPEG-PCL) block copolymers, delivered into C6 glioma cells through endocytosis. In vitro studies proved that the cytotoxicity of these nanoconjugates would be the result of a pro-apoptotic effect against rat C6 glioma cell line, in a dose-dependent manner.[48]
The combination of silver NPs (AgNPs) with magnetic NP hyperthermia (MNPH) treatment has been used as treatment in glioma model. AgNPs had significant effect on enhancing thermoinduced killing in vitro. In the glioma-bearing rat model, AgNPs combined with MNPH enhance Bax (Bcl-2-associated X protein) expression in cancer cells, which was correlated with cell apoptosis induction. The mechanism of thermosensitization by AgNPs might be related to the release of Ag+ cation from the silver nanostructures inside cells.[49]
p53 is currently established in multiple clinical trials. Some authors have developed a nanocomplex structured by a cationic liposome with the surface modified with an anti-TR encapsulated with wtp53 plasmid DNA.[50] The compound, named SGT-53, is designed to _target tumor cells via receptor-mediated endocytosis. As a result, temozolomide-resistant GBM would become more sensitive, resulting in a significant apoptosis of CD133-positive CSCs, and an increase in median survival time.[50]
CONCLUSIONS
Recent studies have shown that nanotechnology could be used to both improve the treatment efficacy and to reduce the adverse side effects. Nanotechnology-based approaches to _targeted delivery of therapeutic compounds may potentially be engineered to carry out specific functions as needed. New NPs DDSs are providing innovative, controlled, and _targeted techniques, resulting in a considerable decrease in therapy-associated side effects while increasing antitumor efficacy. It is also possible to take novel selective contrast enhancement molecules into the brain and in particular into neoplastic brain tissue, to visualize brain tumor and to study in vivo almost all of its aspects, such as cellular proliferation, angiogenesis, necrosis, tumor-safe tissue interface, and edema. This approach could permit the use of a lower total dose of drug, a selective drug delivery to _target brain tumor cells, both into the central core of tumor and into the distal foci of tumor cells within areas often characterized from integrity of BBB. This last aspect is very interesting in the future challenges of multimodal brain tumor diagnosis and treatment, such as precocious diagnosis, preoperative histological and grade diagnosis, preoperative treatment planning, follow-up, and recurrence diagnosis and treatment. Notwithstanding, there are potential risks related to these novel approaches. Some cancer cells could develop drug resistance making the drugs released from the _targeted NPs ineffective. Moreover, NPs might change stability, solubility, and pharmacokinetic properties of the carried drugs. In addition, some materials used to create NPs possess low toxicity but quickly degrade and do not circulate in tissues long enough to warrant a sustained drug/gene delivery. Objects of debate are the long-term effects of interactions between NPs and coating of molecules and _target cells.
Cerebral gliomas represent, to date, a still unresolved challenge for the medical community. There are several factors underlying the disappointing results in brain cancer therapeutics, including limited cell drug uptake, intracellular drug metabolism, inherent tumor sensitivity to chemotherapy, and cellular mechanisms of resistance. Prognosis remains poor and the mortality is still high. New biomolecular studies have allowed identifying novel biomarkers and pathways of various phases of tumor progression. Therefore, new treatments have been proposed with the aim of interacting, in a specific way, with such _targets. The molecules that participate in the angiogenesis, a mechanism that allow and promote neoplastic progression, appear to be of interest. The main limitation of this approach is linked to the identification of the most suitable _target. Furthermore, due to the numerous pathways activated during tumor progression, hypothetical _target may be subject to cyclic re-activation, making the treatment practically ineffective. Identification of multiple _targets could be a more viable option and so is to _target the activated molecules in the early stages of tumor progression.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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