Glioblastoma(GBM) is the most common malignant brain tumor. Although current treatment strategies, including surgery, chemotherapy, and radiotherapy, have achieved clinical effects and prolonged the survival of patients, the gradual development of resistance against current therapies has led to a high recurrence rate and treatment failure. Mechanisms underlying the development of resistance involve multiple factors, including drug efflux, DNA damage repair, glioma stem cells, and a hypoxic tumor environment, which are usually correlative and promote each other. As many potential therapeutic targets have been discovered, combination therapy that regulates multiple resistance-related molecule pathways is considered an attractive strategy. In recent years, nanomedicine has revolutionized cancer therapies with optimized accumulation, penetration, internalization, and controlled release. Blood-brain barrier(BBB) penetration efficiency is also significantly improved through modifying ligands on nanomedicine and interacting with the receptors or transporters on the BBB. Moreover, different drugs for combination therapy usually process different pharmacokinetics and biodistribution, which can be further optimized with drug delivery systems to maximize the therapeutic efficiency of combination therapies. Herein the current achievements in nanomedicine-based combination therapy for GBM are discussed. This review aimed to provide a broader understanding of resistance mechanisms and nanomedicine-based combination therapies for future research on GBM treatment.
Silantyev AS, Falzone L, Libra M, Gurina OI, Kardashova KS, Nikolouzakis TK, et al. Current and future trends on diagnosis and prognosis of glioblastoma: from molecular biology to proteomics. Cells. 2019; 8: 863.
Delgado-López P, Corrales-García E. Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol. 2016; 18: 1062-71.
Stupp R, Mason WP, van Den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352: 987-96.
Giese A, Bjerkvig R, Berens M, Westphal M. Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol. 2003; 21: 1624-36.
Ashby LS, Smith KA, Stea B. Gliadel wafer implantation combined with standard radiotherapy and concurrent followed by adjuvant temozolomide for treatment of newly diagnosed high-grade glioma: a systematic literature review. World J Surg Oncol. 2016; 14: 1-15.
Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS, Khasraw M. Management of glioblastoma: state of the art and future directions. CA Cancer J Clin. 2020; 70: 299-312.
Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley D. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010; 37: 13-25.
Arvanitis CD, Ferraro GB, Jain RK. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer. 2020; 20: 26-41.
da Ros M, Iorio AL, Lucchesi M, Stival A, de Martino M, Sardi I. The use of anthracyclines for therapy of CNS tumors. Anticancer Agents Med Chem. 2015; 15: 721-7.
Von Holst H, Knochenhauer E, Blomgren H, Collins V, Ehn L, Lindquist M, et al. Uptake of adriamycin in tumour and surrounding brain tissue in patients with malignant gliomas. Acta Neurochir(Wien). 1990; 104: 13-6.
Löscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. Neuro Rx. 2005; 2: 86-98.
Goldwirt L, Beccaria K, Carpentier A, Farinotti R, Fernandez C. Irinotecan and temozolomide brain distribution: a focus on ABCB1. Cancer Chemother Pharmacol. 2014; 74: 185-93.
Ostermann S, Csajka C, Buclin T, Leyvraz S, Lejeune F, Decosterd LA, et al. Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res. 2004; 10: 3728-36.
Osuka S, Van Meir EG. Overcoming therapeutic resistance in glioblastoma: the way forward. J Clin Invest. 2017; 127: 415-26.
Jänne PA, Shaw AT, Camidge DR, Giaccone G, Shreeve SM, Tang Y, et al. Combined pan-HER and ALK/ROS1/MET Inhibition with dacomitinib and crizotinib in advanced non-small cell lung cancer: results of a phase I study. J Thorac Oncol. 2016; 11: 737-47.
Zhao M, van Straten D, Broekman MLD, Preat V, Schiffelers RM. Nanocarrier-based drug combination therapy for glioblastoma. Theranostics. 2020; 10: 1355-72.
Zhao X, Bai J, Yang W. Stimuli-responsive nanocarriers for therapeutic applications in cancer. Cancer Biol Med. 2021; 18: 319-35.
Ward RA, Fawell S, Floc'h N, Flemington V, McKerrecher D, Smith PD. Challenges and opportunities in cancer drug resistance. Chem Rev. 2021; 121: 3297-351.
Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002; 2: 48-58.
Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer. 2018; 18: 452-64.
van Tellingen O, Yetkin-Arik B, de Gooijer M, Wesseling P, Wurdinger T, de Vries H. Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. Drug Resist Updat. 2015; 19: 1-12.
Schaich M, Kestel L, Pfirrmann M, Robel K, Illmer T, Kramer M, et al. A MDR1(ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann Oncol. 2009; 20: 175-81.
Munoz JL, Rodriguez-Cruz V, Greco SJ, Nagula V, Scotto KW, Rameshwar P. Temozolomide induces the production of epidermal growth factor to regulate MDR1 expression in glioblastoma cells. Mol Cancer Ther. 2014; 13: 2399-411.
Zhang J, Stevens MFG, Bradshaw TD. Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2012; 5: 102-14.
O'Regan CJ, Kearney H, Beausang A, Farrell MA, Brett FM, Cryan JB, et al. Temporal stability of MGMT promoter methylation in glioblastoma patients undergoing STUPP protocol. J Neurooncol. 2018; 137: 233-40.
Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller M, et al. Correlation of O6-methylguanine methyltransferase(MGMT)promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol. 2008; 26: 4189-99.
Cho DY, Lin SZ, Yang WK, Lee HC, Hsu DM, Lin HL, et al. Targeting cancer stem cells for treatment of glioblastoma multiforme. Cell Transplant. 2013; 22: 731-9.
Lytle NK, Barber AG, Reya T. Stem cell fate in cancer growth, progression and therapy resistance. Nat Rev Cancer. 2018; 18: 669-80.
Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, et al. Analysis of gene expression and chemoresistance of CD133+cancer stem cells in glioblastoma. Mol Cancer. 2006; 5: 67.
Po A, Ferretti E, Miele E, De Smaele E, Paganelli A, Canettieri G, et al. Hedgehog controls neural stem cells through p53-independent regulation of Nanog. EMBO J. 2010; 29: 2646-58.
Carballo GB, Matias D, Ribeiro JH, Pessoa LS, Arrais-Neto AM, Spohr TCLSE. Cyclopamine sensitizes glioblastoma cells to temozolomide treatment through Sonic hedgehog pathway. Life Sci. 2020; 257: 118027.
Lambiv WL, Vassallo I, Delorenzi M, Shay T, Diserens AC, Misra A, et al. The Wnt inhibitory factor 1(WIF1) is targeted in glioblastoma and has a tumor suppressing function potentially by induction of senescence. Neuro Oncol. 2011; 13: 736-47.
Musah-Eroje A, Watson S. A novel 3D in vitro model of glioblastoma reveals resistance to temozolomide which was potentiated by hypoxia. J Neurooncol. 2019; 142: 231-40.
Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance(MDR1) gene. Cancer Res. 2002; 62: 3387-94.
Ulasov IV, Lenz G, Lesniak MS. Autophagy in glioma cells: an identity crisis with a clinical perspective. Cancer Lett. 2018; 428: 139-46.
Seidel S, Garvalov BK, Wirta V, von Stechow L, Schänzer A, Meletis K, et al. A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain. 2010; 133: 983-95.
Persano L, Pistollato F, Rampazzo E, Della Puppa A, Abbadi S, Frasson C, et al. BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1α stability and MGMTexpression. Cell Death Dis. 2012; 3: e412.
Rausch V, Liu L, Apel A, Rettig T, Gladkich J, Labsch S, et al. Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment. J Pathol. 2012; 227: 325-35.
Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015; 33: 941-51.
Tu L, Luo Z, Wu YL, Huo S, Liang XJ. Gold-based nanomaterials for the treatment of brain cancer. Cancer Biol Med. 2021; 18: 372-87.
Christian DA, Cai S, Garbuzenko OB, Harada T, Zajac AL, Minko T, et al. Flexible filaments for in vivo imaging and delivery: persistent circulation of filomicelles opens the dosage window for sustained tumor shrinkage. Mol Pharm. 2009; 6: 1343-52.
Xiao K, Li Y, Luo J, Lee JS, Xiao W, Gonik AM, et al. The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials. 2011; 32: 3435-46.
Hui Y, Wibowo D, Liu Y, Ran R, Wang HF, Seth A, et al. Understanding the effects of nanocapsular mechanical property on passive and active tumor targeting. ACS Nano. 2018; 12: 2846-57.
Wu H, Lu H, Xiao W, Yang J, Du H, Shen Y, et al. Sequential targeting in crosslinking nanotheranostics for tackling the multibarriers of brain tumors. Adv Mater. 2020; 32: e1903759.
Zheng M, Liu Y, Wang Y, Zhang D, Zou Y, Ruan W, et al. ROS-responsive polymeric siRNA nanomedicine stabilized by triple interactions for the robust glioblastoma combinational RNAi therapy. Adv Mater. 2019; 31: e1903277.
Fan K, Jia X, Zhou M, Wang K, Conde J, He J, et al. Ferritin nanocarrier traverses the blood brain barrier and kills glioma. ACSNano. 2018; 12: 4105-15.
Xu Y, Shen M, Li Y, Sun Y, Teng Y, Wang Y, et al. The synergic antitumor effects of paclitaxel and temozolomide co-loaded in mPEG-PLGA nanoparticles on glioblastoma cells. Oncotarget. 2016; 7: 20890.
Zhang Z, Yue YX, Xu L, Wang Y, Geng WC, Li JJ, et al. Macrocyclicamphiphile-based self-assembled nanoparticles for ratiometric delivery of therapeutic combinations to tumors. Adv Mater. 2021; 33: e2007719.
Liu Q, Zhang TX, Zheng Y, Wang C, Kang Z, Zhao Y, et al. Calixarene-embedded nanoparticles for interference-free genedrug combination cancer therapy. Small. 2021; 17: e2006223.
Herrlinger U, Tzaridis T, Mack F, Steinbach JP, Schlegel U, Sabel M, et al. Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter(Ce Te G/NOA-09): a randomised, open-label, phase 3 trial. Lancet. 2019; 393: 678-88.
Chong DQ, Toh XY, Ho IA, Sia KC, Newman JP, Yulyana Y, et al. Combined treatment of Nimotuzumab and rapamycin is effective against temozolomide-resistant human gliomas regardless of the EGFR mutation status. BMC Cancer. 2015; 15: 1-13.
Brandes AA, Basso U, Reni M, Vastola F, Tosoni A, Cavallo G, et al. First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase Ⅱ study of the Gruppo Italiano Cooperativo di Neuro-Oncologia. J Clin Oncol. 2004; 22: 1598-604.
Zou Y, Wang Y, Xu S, Liu Y, Yin J, Lovejoy DB, et al. Brain co-delivery of temozolomide and cisplatin for combinatorial glioblastoma chemotherapy. Adv Mater. 2022; 34: e2203958.
Lu G, Wang X, Li F, Wang S, Zhao J, Wang J, et al. Engineered biomimetic nanoparticles achieve targeted delivery and efficient metabolism-based synergistic therapy against glioblastoma. Nat Commun. 2022; 13: 4214.
Zhao YZ, Shen BX, Li XZ, Tong MQ, Xue PP, Chen R, et al. Tumor cellular membrane camouflaged liposomes as a non-invasive vehicle for genes: specific targeting toward homologous gliomas and traversing the blood-brain barrier. Nanoscale. 2020; 12: 15473-94.
Xu AM, Huang PH. Receptor tyrosine kinase coactivation networks in cancer. Cancer Res. 2010; 70: 3857-60.
Meng X, Zhao Y, Han B, Zha C, Zhang Y, Li Z, et al. Dual functionalized brain-targeting nanoinhibitors restrain temozolomide-resistant glioma via attenuating EGFR and METsignaling pathways. Nat Commun. 2020; 11: 594.
Li LN, Zhang HD, Yuan SJ, Tian ZY, Wang L, Sun ZX. Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway. Int J Cancer. 2007; 121: 1360-5.
Ismail M, Yang W, Li Y, Chai T, Zhang D, Du Q, et al. Targeted liposomes for combined delivery of artesunate and temozolomide to resistant glioblastoma. Biomaterials. 2022; 287: 121608.
Kumar V, Radin D, Leonardi D. Probing the oncolytic and chemosensitizing effects of dihydrotanshinone in an in vitro glioblastoma model. Anticancer Res. 2017; 37: 6025-30.
Cao Y, Huang B, Gao C. Salvia miltiorrhiza extract dihydrotanshinone induces apoptosis and inhibits proliferation of glioma cells. Bosn J Basic Med Sci. 2017; 17: 235-40.
Wang R, Liang Q, Zhang X, Di Z, Wang X, Di L. Tumor-derived exosomes reversing TMZ resistance by synergistic drug delivery for glioma-targeting treatment. Colloids Surf B Biointerfaces. 2022; 215: 112505.
Floyd SR, Pacold ME, Huang Q, Clarke SM, Lam FC, Cannell IG, et al. The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature. 2013; 498: 246-50.
Lam FC, Morton SW, Wyckoff J, Vu Han TL, Hwang MK, Maffa A, et al. Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles. Nat Commun. 2018; 9: 1991.
Behrooz AB, Vazifehmand R, Tajudin AA, Masarudin MJ, Sekawi Z, Masomian M, et al. Tailoring drug co-delivery nanosystem for mitigating U-87 stem cells drug resistance. Drug Deliv Transl Res. 2022; 12: 1253-69.
Lee SW, Kim HK, Lee NH, Yi HY, Kim HS, Hong SH, et al. The synergistic effect of combination temozolomide and chloroquine treatment is dependent on autophagy formation and p53 status in glioma cells. Cancer Lett. 2015; 360: 195-204.
Golden EB, Cho HY, Jahanian A, Hofman FM, Louie SG, Schönthal AH, et al. Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy. Neurosurg Focus. 2014; 37: E12.
Ruan S, Xie R, Qin L, Yu M, Xiao W, Hu C, et al. Aggregable nanoparticles-enabled chemotherapy and autophagy inhibition combined with anti-PD-L1 antibody for improved glioma treatment. Nano Lett. 2019; 19: 8318-32.
Xie Y, Lu X, Wang Z, Liu M, Liu L, Wang R, et al. A hypoxiadissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma. Biomater Sci. 2022; 10: 6791-803.
Wang K, Kievit FM, Chiarelli PA, Stephen ZR, Lin G, Silber JR, et al. siRNA nanoparticle suppresses drug-resistant gene and prolongs survival in an orthotopic glioblastoma xenograft mouse model. Adv Funct Mater. 2021; 31: 2007166.
Lee SY. Temozolomide resistance in glioblastoma multiforme. Genes Dis. 2016; 3: 198-210.
Kohsaka S, Wang L, Yachi K, Mahabir R, Narita T, Itoh T, et al. STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulating MGMT expression. Mol Cancer Ther. 2012; 11: 1289-99.
Rehman FU, Liu Y, Yang Q, Yang H, Liu R, Zhang D, et al. Heme oxygenase-1 targeting exosomes for temozolomide resistant glioblastoma synergistic therapy. J Control Release. 2022; 345: 696-708.
Luo H, Chen Z, Wang S, Zhang R, Qiu W, Zhao L, et al. c-MycmiR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma. Brain. 2015; 138: 3654-72.
Masui K, Tanaka K, Akhavan D, Babic I, Gini B, Matsutani T, et al. mTOR complex 2 controls glycolytic metabolism in glioblastoma through Fox O acetylation and upregulation of c-Myc. Cell Metab. 2013; 18: 726-39.
Ma Y, Zhang J, Rui Y, Rolle J, Xu T, Qian Z, et al. Depletion of glioma stem cells by synergistic inhibition of mTOR and c-Myc with a biological camouflaged cascade brain-targeting nanosystem. Biomaterials. 2021; 268: 120564.
Cui D, Xu Q, Wang K, Che X. Gli1 is a potential target for alleviating multidrug resistance of gliomas. J Neurol Sci. 2010; 288: 156-66.
Melamed JR, Ioele SA, Hannum AJ, Ullman VM, Day ES. Polyethylenimine-spherical nucleic acid nanoparticles against Gli1reduce the chemoresistance and stemness of glioblastoma cells. Mol Pharm. 2018; 15: 5135-45.
Bertucci A, Prasetyanto EA, Septiadi D, Manicardi A, Brognara E, Gambari R, et al. Combined delivery of temozolomide and anti-miR221 PNA using mesoporous silica nanoparticles induces apoptosis in resistant glioma cells. Small. 2015; 11: 5687-95.
Wang L, Pan T, Wang Y, Yu J, Qu P, Chen Y, et al. Effect of nanoparticles of DOX and miR-125b on DNA damage repair in glioma U251 cells and underlying mechanisms. Molecules. 2022; 27: 6201.
Yang Q, Zhou Y, Chen J, Huang N, Wang Z, Cheng Y. Gene therapy for drug-resistant glioblastoma via lipid-polymer hybrid nanoparticles combined with focused ultrasound. Int JNanomedicine. 2021; 16: 185-99.
Xue Y, Gao Y, Meng F, Luo L. Recent progress of nanotechnologybased theranostic systems in cancer treatments. Cancer Biol Med. 2021; 18: 336-51.
Liu Y, Bao Q, Chen Z, Yao L, Ci Z, Wei X, et al. Circumventing drug resistance pathways with a nanoparticle-based photodynamic method. Nano Lett. 2021; 21: 9115-23.
Li R, Chen Z, Dai Z, Yu Y. Nanotechnology assisted photo-and sonodynamic therapy for overcoming drug resistance. Cancer Biol Med. 2021; 18: 388-400.
Zhang D, Tian S, Liu Y, Zheng M, Yang X, Zou Y, et al. Near infrared-activatable biomimetic nanogels enabling deep tumor drug penetration inhibit orthotopic glioblastoma. Nat Commun. 2022; 13: 6835.
Pellosi DS, Paula LB, de Melo MT, Tedesco AC. Targeted and synergic glioblastoma treatment: multifunctional nanoparticles delivering verteporfin as adjuvant therapy for temozolomide chemotherapy. Mol Pharm. 2019; 16: 1009-24.
Zhang B, Xue R, Sun C. Rational design of ROS-responsive nanocarriers for targeted X-ray-induced photodynamic therapy and cascaded chemotherapy of intracranial glioblastoma. Nanoscale. 2022; 14: 5054-67.
Yu Y, Wang A, Wang S, Sun Y, Chu L, Zhou L, et al. Efficacy of temozolomide-conjugated gold nanoparticle photothermal therapy of drug-resistant glioblastoma and its mechanism study. Mol Pharm. 2022; 19: 1219-29.
Zeng X, Wang Q, Tan X, Jia L, Li Y, Hu M, et al. Mild thermotherapy and hyperbaric oxygen enhance sensitivity of TMZ/PSi nanoparticles via decreasing the stemness in glioma. J Nanobiotechnology. 2019; 17: 47.
Zhang C, Wu J, Liu W, Zheng X, Zhang W, Lee CS, et al. Hypocrellin-based multifunctional phototheranostic agent for NIR-triggered targeted chemo/photodynamic/photothermal synergistic therapy against glioblastoma. ACS Appl Bio Mater. 2020; 3: 3817-26.
Liu D, Cheng Y, Qiao S, Liu M, Ji Q, Zhang BL, et al. Nanocodelivery of temozolomide and siPD-L1 to reprogram the drugresistant and immunosuppressive microenvironment in orthotopic glioblastoma. ACS Nano. 2022; 16: 7409-27.
Meng L, Wang C, Lu Y, Sheng G, Yang L, Wu Z, et al. Targeted regulation of blood-brain barrier for enhanced therapeutic efficiency of hypoxia-modifier nanoparticles and immune checkpoint blockade antibodies for glioblastoma. ACS Appl Mater Interfaces. 2021; 13: 11657-71.
Tan J, Duan X, Zhang F, Ban X, Mao J, Cao M, et al. Theranostic nanomedicine for synergistic chemodynamic therapy and chemotherapy of orthotopic glioma. Adv Sci(Weinh). 2020; 7: 2003036.
Lee IC, Lo TL, Young TH, Li YC, Chen NG, Chen CH, et al. Differentiation of neural stem/progenitor cells using low-intensity ultrasound. Ultrasound Med Biol. 2014; 40: 2195-206.
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