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Behrooz, A.B.;  Talaie, Z.;  Syahir, A. Combination Therapy for Glioblastoma. Encyclopedia. Available online: (accessed on 20 April 2024).
Behrooz AB,  Talaie Z,  Syahir A. Combination Therapy for Glioblastoma. Encyclopedia. Available at: Accessed April 20, 2024.
Behrooz, Amir Barzegar, Zahra Talaie, Amir Syahir. "Combination Therapy for Glioblastoma" Encyclopedia, (accessed April 20, 2024).
Behrooz, A.B.,  Talaie, Z., & Syahir, A. (2022, November 02). Combination Therapy for Glioblastoma. In Encyclopedia.
Behrooz, Amir Barzegar, et al. "Combination Therapy for Glioblastoma." Encyclopedia. Web. 02 November, 2022.
Combination Therapy for Glioblastoma

Aggressive glioblastoma (GBM) has no known treatment as a primary brain tumor. Since the cancer is so heterogeneous, an immunosuppressive tumor microenvironment (TME) exists, and the blood–brain barrier (BBB) prevents chemotherapeutic chemicals from reaching the central nervous system (CNS), therapeutic success for GBM has been restricted. Drug delivery based on nanocarriers and nanotechnology has the potential to be a handy tool in the continuing effort to combat the challenges of treating GBM. Combination therapies may be enhanced by using nanotechnology-based delivery techniques. Nano-chemotherapy, nano-chemotherapy–radiation, nano-chemotherapy–phototherapy, and nano-chemotherapy–immunotherapy for GBM.

glioblastoma nanotechnology nanomedicine

1. Nano-Chemotherapies

Wnt signaling plays a crucial role in GBM, which affects apoptosis and autophagy by activating or inhibiting other pathways in the cell [1]. Curcumin (50 M), nanomicellar curcumin alone, and nanomicellar curcumin combination with TMZ were shown to dramatically reduce the invasion and migration of U-87 cells. Biomarkers of autophagy (Beclin 1 and LC3-I and -II) were found to be considerably elevated. As the levels of Bax protein decreased, those of apoptosis-related proteins Bcl-2 and caspase 8 increased. Genes related to the Wnt pathway (β-catenin, cyclin D1, Twist, and ZEB1) have drastically lower expression levels [2]. Apt-NPs, which were made from B19 aptamer (Apt)-conjugated polyamidoamine (PAMAM) G4C12 dendrimer nanoparticles (NPs) and used to deliver paclitaxel (PTX) and TMZ into U-87 stem cells, significantly reduced tumor growth in U-87 stem cells by inducing apoptosis and decreasing autophagy and multidrug resistance (MDR) gene expression [3]. YukinoriAkiyama and his colleagues found that, combining carmustine (BCNU) wafers and bevacizumab, newly diagnosed GBM patients treated with TMZ and radiation were shown to be safe. Patients with GBM responded better to the combination treatment than to normal therapy. This suggests that the combination treatment has a promising efficacy and side-effect profile [4]. An herbal polyphenolic molecule known as resveratrol (3,5,4′-trihydroxy-trans-stilbene) is found in red wine, peanuts, and soy. This herbal substance has some ability to destroy cancerous cells and enhance the tumor’s response to radiation or chemotherapy. The therapeutic effectiveness of resveratrol in GBM may be improved by its synergistic effects when combined with radiation and chemotherapy [5]. Nose-to-brain delivery of the conjugated NPs, which combine poly (D,L-lactic-co-glycolic acid) and chitosan nanoparticles with alpha-cyano-4-hydroxycinnamic acid (CHC) and cetuximab (CTX), was developed to treat GBM. EGRF activation was inhibited by CTX, which was shown to be covalently linked to NPs. When conjugated NPs were used in the chicken chorioallantoic membrane assay, there was a decrease in tumor size [6].
In a separate research project, scientists devised a liposomal delivery method that might be used to efficiently carry chemotherapy across the BBB to treat GBM. Tf-modified liposomes were used to target transferrin (Tf) and PFVYLI (PFV) cell-penetrating peptide (PFV) to boost the translocation of DOX and erlotinib across the BBB into U-87 tumor cells. In U-87 cells, brain endothelial cells, and glial cells, doxorubicin (DOX) and Erlo were efficiently absorbed. In addition, the apoptosis of U-87 cells was greatly increased by the use of dual-functionalized liposomes. Due to the increased BBB translocation of dual functionalized liposomes, around 52% tumor cell death was seen in in vitro brain tumor models employing the PLGA–chitosan scaffold-containing chemotherapy agents [7]. In order to achieve receptor-mediated transcytosis, a liposomal delivery method was produced that included a surface modified with transferrin (Tf) and a penetratin (Pen) cell-penetrating peptide. Loaded into liposomes, doxorubicin and the anti-glioblastoma drug erlotinib might more easily reach the cancerous tumor in the brain. There was a 15% increase in translocation across the coculture endothelium barrier when doxorubicin- and erlotinib-loaded Tf–Pen liposomes were delivered together to an in vitro brain tumor model, leading to tumor shrinkage and remission. Tf–Pen liposomes increased doxorubicin and erlotinib accumulation in the brains of mice by factors of 12 and 3.3, respectively, when compared to free medications. Tf–Pen liposomes regressed 90% of the tumor in mice brains, with a significant increase in median survival time (36 days) and no damage [8]. In comparison to their respective free drug formulations, codelivery of PTX- and methotrexate (MTX)-loaded PLGA NPs appear promising for the treatment of GBM [9].

2. Nano-Chemotherapy–Radiotherapy

Radiation therapy is one of the clinical therapies for GBM, and significant efforts have been undertaken to improve its effectiveness [10]. Radiation treatment, however, was ineffective because of the invasive tumor development of glioblastoma. Short-course radiation with the addition of TMZ in elderly patients with GBM resulted in longer survival than short-course radiotherapy on its own [11]. Humanized recombinant monoclonal antibody bevacizumab suppresses the proliferation and angiogenesis of vascular endothelial cells and has proven therapeutic effectiveness in the treatment of recurrent GBM [12]. One trial compared bevacizumab with RT/TMZ with RT/TMZ alone for newly diagnosed glioblastoma patients. There was no increase in overall survival (OS) but an improvement in progression-free survival (PFS). Additionally, the 6 month survival rate of rats given bevacizumab and radiotherapy/TMZ (RT/TMZ) was not improved. Adding bevacizumab to a radiotherapy/TMZ regimen may be a successful way to increase progression-free survival in patients [13]. An investigation showed that utilizing ionizing radiation (IR) in combination with the small-molecule inhibitor PLX3397 (a tyrosine-kinase inhibitor, CSF-1R inhibitor) was more effective than using IR alone in treating GBM intracranial xenograft mice [14]. Mice who received a combination of therapies had a considerably longer lifespan than those that received IR alone. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PNPs) attached to chlorotoxin (CTX), Ag-PNP-CTX, may irradiate tumor cells and reduce the extracellular activity of MMP-2, according to a study. The use of CTX nanovectors in conjunction with radiation therapy may offer a potential treatment for GBM by lowering MMP-2 activity and targeting scattered GBM cells. The combination of CTX nanovectors and radiation may be an effective treatment for GBM. Because CTX targeting increases the accumulation of nanovector therapeutic cargo in GBM cells and suppresses them by about 50%, it has a synergistic effect [15][16].
DC101, an anti-VEGFR2 antibody, was shown in a study by Kozin et al. to reduce the needed dosage of radiotherapy for tumor growth suppression by 1.3–1.7 times by lowering hypoxia. Radiation treatment has been shown to normalize the vasculature, according to a number of studies. Apoptosis of ECs is increased in a dose-dependent manner by high-dose stereotactic body radiotherapy (SFRT), resulting in the normalization of tumor vasculature [17]. According to Lan et al., hypofractionated radiotherapy (HFRT) considerably increases OS when compared to traditional radiation treatment. It is still unclear exactly how HFRT works in terms of radiobiology. There were more arteries covered and more perfusion after ablative hypofractionated radiation, demonstrating that HFRT restored the tumor’s vasculature [18]. Antitumor drugs conjugated with gold nanoparticles (AuNPs) represent a potential and new treatment option. Using the low-density growth test and irradiation, the antitumoral efficacy of AuNP-SI306 was investigated in vitro in the GBM model. In combination with radiotherapy (RT), the combination of AuNPs and SI306 was more effective in inhibiting tumor cell growth than the combination of AuNPs and free SI306 [19]. U87-MG human GBM xenografts in nude mice were treated with radiation and chemotherapy using pH-sensitive polymersomes, which resulted in significantly longer lifetimes for the xenografts. The BBB-crossing capacity of Au-DOX@PO-ANG is excellent, allowing it to effectively target tumors. The pH sensitivity of this delivery system and its capacity to adapt to the tumor microenvironment make it ideal for this application. The combination of gold nanoparticles with doxorubicin is a novel medication. The radiotherapy (RT) effect on GBM is improved with this sort of complicated medication. Tumor volume was significantly reduced in mice treated with Au-DOX@PO-ANG NPs [20] (Table 1).
Table 1. The studies reporting nano-chemotherapy–radiotherapy in GBM.
A potential noninvasive cancer treatment technique is the combination of photothermal therapy (PTT) with photodynamic therapy (PDT). As a result of light absorption, photothermal agents were used to create heat and destroy cancerous cells; as in the previous treatment, reactive oxygen species (ROS), free radicals, or peroxides were created to promote cell death [15]. Because of its selective therapeutic benefits, chemo-photothermal therapy (CPT) for cancer treatment is receiving increased interest. Fe3O4 magnetic nanoparticles drug-loaded with CPT have been shown to have anticancer effects on U-87 MG human GBM cells. Preparation of anticancer drug-loaded Fe3O4 MNPs by loading TMZ and indocyanine green (ICG) was carried out, and the samples were then examined using various techniques such as X-ray, UV–Vis spectroscopy and drug-loading capacity [21]. U-87 MG GBM cells died following MNP injection after being treated with near-infrared (NIR) light irradiation, resulting in the generation of reactive oxygen species (ROS). Researchers found that irradiating U-87 MG GBM cells with NIR laser-irradiated Fe3O4-TMZ-ICG MNPs significantly increased anticancer effects on Bcl-2-associated X protein, Bcl-2, cytochrome c, caspase-3, Fas-associated via the death domain, and caspase-8 genes, as shown by Western blot analysis and reverse transcription quantitative polymerase chain reaction. Using CPT, Fe3O4-TMZ-ICG MNPs may be a viable treatment option for patients with brain cancer [21]. Doxorubicin–curcumin–amino acid-based composite microbowls (CMBs) were created in 2021 by Chibh and coworkers using a miniaturized fluid flow-based self-assembly method. Dual chemo-photodynamic treatment was applied using CMBs on two- and three-dimensional (2D) spheroids of C6 glioma cells. CMBs with asymmetric holes showed promise as a combinatorial drug carrier for cancer treatment that might deliver chemo- and phototherapy at the same time [22]. PTT may be employed as a standalone therapy, guided by multimodal imaging, or used in combination with existing medicines for the treatment of cancer metastases, as shown by Zou et al. In several preclinical animal tests, a variety of photothermal nanotherapeutics (PTNs) have shown promising therapeutic effectiveness against metastatic cancer. PTT or a combination of PTT and other therapies may be an important and promising treatment option for cancer metastases [23].
By coating citrate-coated magnetic nanoparticles on rGO, researchers created an rGO-based magnetic nanocomposite (CMNP). To generate PEGylated mrGO for conjugation with gastrin-releasing peptide receptor (GRPR), phospholipid–polyethylene glycol was used to modify magnetic rGO (mrGOG). To transfer the anticancer medicine doxorubicin (DOX) into the endosome, the drug was coupled to mrGO (mrGOG) through π–π stacking interactions. It was shown that intravenous treatment of mrGOG/DOX under magnetic guidance reduced tumor growth and increased animal survival compared to groups that received free DOX or did not get magnetic guidance when using the U-87 tumor xenograft model developed in naked mice [24]. The anticancer effectiveness was greatly improved by increasing cell death and reducing cell proliferation when combined with a 5 min NIR laser therapy. Gold–silver nanotriangles (AuAgNTrs) that were stabilized by polyethylene glycol (PEG) were synthesized and used in photothermal treatment. Using the U-87 GBM cell model, a cell viability experiment was carried out. After just 10 min of laser irradiation at a power P = 3 W/cm2 that was shown to be nontoxic to the control cells, the excellent photothermal performance of AuAgNTrs was proven in suspension and in vitro [25]. Cell viability decreased by >80% after that time. The anti-EphA3-modified TMZ@GNPs (anti-EphA3-TMZ@GNPs) were synthesized for chemical and auxiliary plasma photothermal therapy (PPTT) in order to solve the issue of glioma resistance to TMZ, and to enhance GBM therapeutic benefits. TMZ@GNPs were used to treat GBM. In the anti-EphA3-TMZ@GNP-treated group, cytotoxicity and apoptosis were considerably greater than in the GNP and non-photothermal groups. Reversing drug resistance was shown by Western blot analysis, which indicated that the GNP–PPTT-mediated tumor cell death resulted in an increase in the production of antiapoptotic signaling molecules and cell-cycle inhibitors. After photothermal therapy, the anti-EphA3-TMZ@GNPs group survived 46 days longer (1.64-fold) than the TMZ group in the subcutaneous GBM model of nude mice [26]. For chemotherapy, a derivative of dicysteamine-modified hypocrellin (DCHB; a natural-origin photosensitizer) with a singlet oxygen quantum yield of 0.51 was used, together with a cyclic peptide (cRGD) as a targeting unit against GBM, to construct a multifunctional phototheranostic agent. As a result of the DCHB and TMZ-C18 assembly, the cRGD-decorated DTRGD NPs exhibited broad near-infrared absorption (peaking at 703 nm), NIR emission (peaking at 720 nm), strong photostability, a high photothermal conversion efficiency (peaking at 33%), and effective degradation of the TMZ-C18 compound. DTRGD NPs, on the other hand, may cross the BBB and target tumors directly. DTRGD NP-treated U-87MG tumor mice revealed that the targeted chemo/photodynamic/photothermal synergistic treatment may be accomplished with almost little harm [27].
uPAR, a plasminogen activator receptor of the urokinase type, is overexpressed in a variety of tumor species [28]. Indocyanine green (ICG)-conjugated peptide AE105, which targets the uPAR, has shown significant promise for fluorescence-guided surgery. During PTT, the photothermal abilities of ICG-Glu-Glu-AE105 led to tumor death and prolonged survival. Studies showed that apolipoprotein E peptide (ApoE), which targets the brain, grafted onto these nanoparticles, ApoE-Ph NPs, greatly increased PTT efficiency and the survival of mice with orthotopic GBM after mild irradiation (0.5 W·cm−2) [29]. It was shown that BK@AIE NPs, bradykinin aggregation-induced-emission nanoparticles, had a high photothermal conversion efficiency under 980 nm NIR laser irradiation, making them ideal for treating deep-seated malignancies. Tumor development can be significantly suppressed to lengthen the life span of mice following spatiotemporal PTT. Tissue necrosis factor and tumor-associated antigens may be eliminated and released by NIR irradiation. It was shown that the PTT treatment of GBM-bearing mice stimulated natural killer cells, CD3+ T cells, CD8+ T cells, and M1 macrophages in the GBM region, improving the therapeutic efficiency. BK@AIE NPs with NIR assistance were shown to be a potential technique for improving GBM clearance and activating local brain immune privilege in [30]. The hypoxic parts of tumors may be reached by macrophages that can penetrate blood vessel barriers. It has become a new trend to use macrophages as a medication delivery mechanism for tumor targeting. A photothermal agent, gold nanorods (GNRs), was effectively modified to boost cellular absorption and biocompatibility using monocyte chemoattractant protein-1 (MCP-1) and an iron-based metal–organic framework (MIL-100(Fe)). A xenograft model of U251 MG cells in nude mice was used to show the photothermal activity of MCP-1 and GNR@MIL-100 (Fe). After laser therapy, the tumor volume remained under 100 mm3 even after growth was reduced by further NIR treatment. Antitumor effectiveness of MCP-1/GNR@MIL-100 (Fe) coupled with laser therapy was shown by tumor histology, survival, and bioluminescence imaging [31]. Novel NPs for GBM PTT have been described in many articles; however, no clinical research has yet demonstrated their utility in GBM patients. Only a few researchers conducted in vitro analyses of GBM PTT, while others were able to overcome some of the fundamental problems of GBM PTT in vivo [32] (

3. Nano-Chemotherapy–Immunotherapy

Oncology immunotherapy has garnered significant interest in the last several decades. There is a possibility that it might engage the body’s immune system and produce particular immunological responses to eradicate the tumor cells [33][34]. EGFRvIII, a tumor-specific epitope expressed in GBM, the most frequent and deadly primary malignant neoplasm of the brain, is the target of the peptide vaccine rindopepimut (CDX-110) [35]. As part of a multi-immunotherapy strategy, rindopepimut exhibited considerable therapeutic benefit and effectiveness in clinical studies. In the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play a critical role. A shift from the protumor M2 (TAM2) to antitumor M1 (TAM1) phenotype lifts the immunosuppressive restrictions and enhances chemotherapy effectiveness [36]. It was shown that chemotherapy with macrophage-directed immunotherapy resulted in an improved therapeutic outcome. DOX@MSN-SS-iRGD&1MT nanoparticles were designed to simultaneously administer doxorubicin (DOX) and an immune checkpoint inhibitor (1-methyltryptophan, 1MT) into orthotopic glioma, where they showed promising results. To create the nanoparticle, silica nanoparticles loaded with DOX were coupled with Asp–Glu–Val–Asp (DEVD)-linked 1MT and then modified with iRGD, as shown in the figure. It was shown that these nanoparticles may pass across the BBB and reach the tumor site, where they significantly increase medication accumulation in orthotopic brain tumors while having common adverse effects [37]. Due to the active targeting of iRGD, the nanoparticles successfully crossed the BBB and boosted drug accumulation in orthotopic brain tumors [37]. DAMP emission from nano-DOX was shown to be more potent than that from doxorubicin. DTX-sHDL-CpG nanodisc administration into the tumor mass resulted in tumor regression and antitumor CD8+ T cell responses in the brain tumor microenvironment (TME), according to Kadiyala and her colleagues. In addition, 80% of GBM-bearing mice had tumor shrinkage and long-term survival after DTX-sHDL-CpG therapy combined with radiation (IR), which is the gold standard of care for GBM. For the treatment of GBM, the findings showed that nanodiscs in conjunction with IR led to tumor reduction, long-term survival, and immunological memory [38].
The tumor immune microenvironment may be altered, and chemotherapy’s efficacy may be improved by using RNAi-based immunomodulation, according to a study by Qiao et al. This system (Angiopep LipoPCB (TMZ + BAP/siTGF-β), ALBTA) was developed for the treatment of intracranial GBM with dual targeting and ROS response. Strong siRNA condensation, excellent drug loading efficiency, and good serum stability are among the properties of traceable nanoparticles. Through receptor-mediated transcytosis, they can penetrate the BBB and effectively target GBM cells. ALBTA’s zwitterionic lipid (distearoyl phos phoethanol-amine-polycarboxybetaine lipid) boosts TMZ’s cytotoxicity and improves the gene silencing efficacy of siTGF-β by promoting endosomal/lysosomal escape. ALBTA significantly improves the improved immunosuppressive microenvironment of glioma-bearing mice [39]. To change the immunological milieu of GBM and enhance the efficiency of TMZ, siRNA against tumor growth factor (siTGF-β) was used. 
Galstyan et al. investigated the potential of targeted nanoscale immunoconjugates (NICs) produced utilizing poly(l-malic acid), a naturally occurring polymeric scaffold covalently labeled with a-CTLA-4 or a-PD-1, by examining their systemic distribution across the blood–brain barrier (BBB). The local anticancer immune response in the brain demonstrated that the checkpoint blockade drug was delivered across the BBB to the tumor location, implying the induction of a systemic and local immune response in glioblastoma therapy [40]. Another intriguing study on immune nanoconverters encapsulating a resiquimod- and doxorubicin-loaded scaffold demonstrated the polarization of immunosuppressive tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells into tumoricidal APCs, as well as in situ vaccination via in vivo mechanisms for the activation of neoantigen-specific T cells [41]. Chemotherapy and PDT (photodynamic treatment) in conjunction with ICB (immune checkpoint blockade) are also commonly used in many malignancies. Combining local chemotherapy and anti-PD-1 therapy may improve antitumor immune responses and prolong overall survival in glioblastoma treatment. Notably, the chemo- and immunotherapy sequence is essential for defining the anti-PD-1 antibody’s activity [42][43].
Gold nanoparticles (AuNPs) and outer membrane vesicles (OMVs) from E. coli were successfully used to construct an Au–OMV complex. For both subcutaneous G261 tumor-bearing C57BL/6 mice and in situ (brain) tumor-bearing C57BL/6 mice, the combination of radiation and Au–OMV induced radiosensitizing and immunomodulatory effects that effectively reduced tumor development. In situ tumor-bearing mice treated with Au–OMV and radiation had a longer survival time. The treatment’s mechanisms of success were examined. Au–OMV and radiation enhanced intracellular ROS in G261 glioma cells [44].
Furthermore, it was shown that the vitality of G261 glioma cells was linked to macrophage chemotaxis and the generation of TNF-α in the presence of RAW 264.7 macrophages [44]. Increasing the immunogenicity of GBM cells (GC) is a promising strategy for overcoming the immunosuppression associated with GBM. An immunosuppressive microenvironment in GBM was efficiently altered by nanodiamonds containing doxorubicin (Nano-DOX), which was shown to stimulate the GC’s immunogenicity and start anti-GBM immune responses [45]. Researchers discovered that Nano-DOX induced GC to release antigens and damage-associated molecular patterns (DAMPs), which operate as potent adjuvants, rather than apoptosis. As a consequence, dendritic cells (DC) were more activated. In Nano-DOX-treated GC, an increase in autophagosome release was noted. However, it was shown to be a minor source of antigen donation. Nano-DOX-induced GC antigen donation and DAMP emission were decreased by blocking autophagy in GC, although DC activation was also effectively suppressed by Nano-DOX-treated GC. These data imply that Nano-DOX increases GC immunogenicity primarily via activation of autophagy. By leveraging autophagy in cancer cells, nanotechnology may be used to alter the GBM immune microenvironment therapeutically [46][47]. Immunosuppression and treatment resistance in GBM are mainly attributed to tumor-associated myeloid cells (TAMCs). Since up to 50% of the brain tumor mass is composed of TAMCs, it is imperative that a treatment approach for targeting TAMCs in GBM be developed. These studies showed that an LNP platform can recognize highly expressed programmed death-ligand 1 (PD-L1) in tumor-associated macrophage cells, which allows it to selectively target and deliver drugs to tumors in mice and humans. Dinaciclib-encapsulated lipid nanoparticles (LNPs) effectively eliminated TAMCs from tumors and dramatically improved the survival of mice in glioma models (GL261 and CT2A) when used in conjunction with radiation treatment. This nanomedicine platform has the potential to revolutionize the treatment of GBM and speed up its adoption in clinical practice [48].


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