Molecular Targets and Nanoparticulate Systems Designed for the Improved Therapeutic Intervention in Glioblastoma Multiforme

Abstract

Glioblastoma multiforme (GBM) is the most aggressive and fatal CNS related tumors, which is responsible for about 4% of cancer-related deaths. Current GBM therapy includes surgery, radiation, and chemotherapy. The effective chemotherapy of GBM is compromised by two barriers, i. e., the blood-brain barrier (BBB) and the blood tumor barrier (BTB). Therefore, novel therapeutic approaches are needed. Nanoparticles are one of the highly efficient drug delivery systems for a variety of chemotherapeutics that have gained massive attention from the last three decades. Perfectly designed nanoparticles have the ability to cross BBB and BTB and precisely deliver the chemotherapeutics to GBM tissue/cells. Nanoparticles can encapsulate both hydrophilic and lipophilic drugs, genes, proteins, and peptides, increase the stability of drugs by protecting them from degradation, improve plasma half-life, reduce adverse effects and control the release of drugs/genes at the desired site. This review focussed on the different signaling pathways altered in GBM cells to understand the rationale behind selecting new therapeutic targets, challenges in the drug delivery to the GBM, various transport routes in brain delivery, and recent advances in targeted delivery of different drug and gene loaded various lipidic, polymeric and inorganic nanoparticles in the effective management of GBM.

Key words

drug delivery - pharmaceutics - cancer - anticancer drugs

Publication History

Received: 13 September 2020

Accepted: 19 October 2020

Article published online:
09 November 2020

• References

• 1 Fakhoury M. Drug delivery approaches for the treatment of glioblastoma multiforme. Artif Cells Nanomed Biotechnol 2016; 44: 1365-1373
• 2 https://www.wcrf.org/dietandcancer/cancer-trends/worldwide-cancer-data
• 3 Zhou J, Atsina KB, Himes BT. et al. Novel delivery strategies for glioblastoma. Cancer J 2012; 18: 89-99
• 4 Arjona D, Rey JA, Taylor SM. Early genetic changes involved in low-grade astrocytic tumor development. Curr Mol Med 2006; 6: 645-650
• 5 Parsons DW, Jones S, Zhang X. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321: 1807-1812
• 6 Jhanwar-Uniyal M, Labagnara M, Friedman M. et al. Glioblastoma: Molecular pathways, stem cells and therapeutic targets. Cancers (Basel) 2015; 7: 538-555
• 7 Ahmad J, Akhter S, Rizwanullah M. et al. Nanotechnology based theranostic approaches in alzheimer’s disease management: Current status and future perspective. Curr Alzheimer Res 2017; 14: 1164-1181
• 8 Barkat MA, Harshita. Rizwanullah M. et al. Therapeutic nanoemulsion: Concept to delivery. Curr Pharm Des 2020; 26: 1145-1166
• 9 Ahmad J, Rizwanullah M, Amin S. et al. Nanostructured lipid carriers (NLCs): Nose-to-brain delivery and theranostic application. Curr Drug Metab 2020; 21: 1-8
• 10 Nam L, Coll C, Erthal LC. et al. Drug delivery nanosystems for the localized treatment of glioblastoma multiforme. Materials 2018; 11: 779
• 11 Raucher D, Dragojevic S, Ryu J. Macromolecular drug carriers for targeted glioblastoma therapy: Preclinical studies, challenges, and future perspectives. Front Oncol 2018; 8: 624 doi:10.3389/fonc.2018.00624
• 12 Ozturk-Atar K, Eroglue H, Calis S. Novel advances in targeted drug delivery. J Drug Target 2018; 26: 633-642
• 13 Kang C, Sun Y, Zhu Y. et al. Delivery of nanoparticles for treatment of brain tumor. Curr Drug Metab 2016; 17: 745-754
• 14 Kaisar MA, Sajja RK, Prasad S. et al. New experimental models of the blood-brain barrier for CNS drug discovery. Expert Opin Drug Discov 2017; 12: 89-103
• 15 Patel M, Souto EB, Singh KK. Advances in brain drug targeting and delivery: Limitations and challenges of solid lipid nanoparticles. Expert Opin Drug Deliv 2013; 10: 889-905
• 16 Gao H. Progress and perspectives on targeting nanoparticles for brain drug delivery. Acta Pharm Sin B 2016; 6: 268-286
• 17 Wang X, Yu X, Vaughan W. et al. Novel drug-delivery approaches to the blood-brain barrier. Neurosci Bull 2015; 31: 257-264
• 18 Ronaldson PT, Davis TP. Targeting transporters: Promoting blood-brain barrier repair in response to oxidative stress injury. Brain Res 2015; 1623: 39-52
• 19 Oller-Salvia B, Sanchez-Navarro M, Giraltab E. et al. Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery. Chem Soc Rev 2016; 45: 4690-4707
• 20 Gutkin A, Cohen ZR, Peer D. Harnessing nanomedicine for therapeutic intervention in glioblastoma. Expert Opin Drug Deliv 2016; 13: 1573-1582
• 21 Grabrucker AM, Ruozi B, Belletti D. et al. Nanoparticle transport across the blood brain barrier. Tissue Barriers 2016; 4: e1153568
• 22 Banks WA. From blood–brain barrier to blood–brain interface: New opportunities for CNS drug delivery. Nat Rev Drug Discov 2016; 15: 275-292
• 23 Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab 2012; 32: 1959-1972
• 24 Lichota J, Skjørringe T, Thomsen LB. et al. Macromolecular drug transport into the brain using targeted therapy. J Neurochem 2010; 113: 1-13
• 25 Sagare AP, Deane R, Zlokovic BV. Low-density lipoprotein receptor-related protein 1: A physiological Aβ homeostatic mechanism with multiple therapeutic opportunities. Pharmacol Ther 2012; 136: 94-105
• 26 Yu YJ, Zhang Y, Kenrick M. et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med 2011; 3: 84ra44
• 27 Miura Y, Takenaka T, Toh K. Cyclic RGD-linked polymeric micelles for targeted delivery of platinum anticancer drugs to glioblastoma through the blood-brain tumor barrier. ACS Nano 2013; 7: 8583-8592
• 28 Demeule M, Currie JC, Bertrand Y. et al. Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2. J Neurochem 2008; 106: 1534-1544
• 29 ClinicalTrials.gov identifier: NCT01480583
• 30 Rao KS, Reddy MK, Horning JL. et al. TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs. Biomaterials 2008; 29: 4429-4438
• 31 Gao H, Zhang S, Cao S. et al. Angiopep-2 and activatable cell-penetrating peptide dual-functionalized nanoparticles for systemic glioma-targeting delivery. Mol Pharm 2014; 11: 2755-2763
• 32 Cancer Genome Atlas Research Network, Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455: 1061-1068
• 33 Pearson JRD, Regad T. Targeting cellular pathways in glioblastoma multiforme. Signal Transduct Target Ther 2017; 2: e17040
• 34 Khan MA, Jain VK, Rizwanullah M. et al. PI3K/AKT/mTOR pathway inhibitors in triple-negative breast cancer: A review on drug discovery and future challenges. Drug Discov Today 2019; 24: 2181-2191
• 35 Regad T, Targeting RTK. signaling pathways in cancer. Cancers (Basel) 2015; 7: 1758-1784
• 36 Joensuu H, Puputti M, Sihto H. et al. Amplification of genes encoding KIT, PDGFRα and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme. J Pathol 2005; 207: 224-231
• 37 Akhter MH, Madhav NVS, Ahmad J. Epidermal growth factor based active targeting: A paradigm shift towards advance tumor therapy. Artif Cells Nanomed Biotechnol 2018; 46: 1188-1198
• 38 Polivka J, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther 2014; 142: 164-175
• 39 Carracedo A, Pandolfi PP. The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene 2008; 27: 5527-5541
• 40 Prasad G, Sottero T, Yang X. et al. Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. Neuro Oncol 2011; 13: 384-392
• 41 Masri J, Bernath A, Martin J. et al. mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res 2007; 67: 11712-11720
• 42 He G, Siddik ZH, Huang Z. et al. Induction of p21 by p53 following DNA damage inhibits both Cdk4 and Cdk2 activities. Oncogene 2005; 24: 2929-2943
• 43 Michaud K, Solomon DA, Oermann E. et al. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res 2010; 70: 3228-3238
• 44 Han J, Alvarez-Breckenridge CA, Wang QE. et al. β signaling and its targeting for glioma treatment. Am J Cancer Res 2015; 5: 945-955
• 45 Lamouille S, Derynck R. Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol 2007; 178: 437-451
• 46 Rooke HM, Crosier KE. The smad proteins and TGF beta signaling: uncovering a pathway critical in cancer. Pathology 2001; 33: 73-84
• 47 Petterson SA, Dahlrot RH, Hermansen SK. et al. High levels of c-Met is associated with poor prognosis in glioblastoma. J Neurooncol 2015; 122: 517-527
• 48 Cruickshanks N, Zhang Y, Yuan F. et al. Role and therapeutic targeting of the HGF/MET pathway in glioblastoma. Cancers (Basel) 2017; 9: e87
• 49 Brennan CW, Verhaak RG, McKenna A. et al. The somatic genomic landscape of glioblastoma. Cell 2013; 155: 462-477
• 50 Sayal KK, Higgins GS, Hammond EM. Uncovering the influence of the FGFR1 pathway on glioblastoma radiosensitivity. Ann Transl Med 2016; 4: e538
• 51 Gouazé-Andersson V, Delmas C, Taurand M. et al. FGFR1 induces glioblastoma radioresistance through the PLCγ/Hif1α pathway. Cancer Res 2016; 76: 3036-3044
• 52 Maris C, D’Haene N, Trépant AL. et al. IGF-IR: a new prognostic biomarker for human glioblastoma. British J Cancer 2015; 113: 729-737
• 53 Leclerc C, Haeich J, Aulestia FJ. et al. Calcium signaling orchestrates glioblastoma development: Facts and conjunctures. Biochim Biophys Acta 2016; 1863: 1447-1459
• 54 Zhang Y, Cruickshanks N, Yuan F. et al. Targetable T-type calcium channels drive glioblastoma. Cancer Res 2017; 77: 3479-3490
• 55 Fajardo AM, Piazza GA, Tinsley HN. The role of cyclic nucleotide signaling pathways in cancer: targets for prevention and treatment. Cancers 2014; 6: 436-458
• 56 Fiscus RR. Involvement of cyclic GMP and protein kinase G in the regulation of apoptosis and survival in neural cells. Neurosignals 2002; 11: 175-190
• 57 Mahtab A, Rizwanullah M, Pandey S. et al. Quality by design driven development and optimization of Teriflunomide loaded nanoliposomes for treatment of rheumatoid arthritis: An in vitro and in vivo assessments. J Drug Deliv Sci Tech 2019; 51: 383-396
• 58 Gilani SJ, Jahangir MA, Rizwanullah M. et al. Nano-based therapy for treatment of skin cancer. Recent Pat Antiinfect Drug Discov 2018; 13: 151-163
• 59 Deshpande PP, Biswas S, Torchilin VP. Current trends in the use of liposomes for tumor targeting. Nanomedicine 2013; 8: 1509-1528
• 60 Chen C, Duan Z, Yuan Y. et al. Peptide-22 and Cyclic RGD functionalized liposomes for glioma targeting drug delivery overcoming BBB and BBTB. ACS Appl Mater Interfaces 2017; 9: 5864-5873
• 61 Liu C, Liu XN, Wang GL. et al. A dual-mediated liposomal drug delivery system targeting the brain: Rational construction, integrity evaluation across the blood-brain barrier, and the transporting mechanism to glioma cells. Int J Nanomedicine 2017; 12: 2407-2425
• 62 Lakkadwala S, Dos Santos Rodrigues B, Sun C. et al. Dual functionalized liposomes for efficient co-delivery of anticancer chemotherapeutics for the treatment of glioblastoma. J Control Release 2019; 307: 247-260
• 63 Rizwanullah M, Amin S, Ahmad J. Improved pharmacokinetics and antihyperlipidemic efficacy of rosuvastatin-loaded nanostructured lipid carriers. J Drug Target 2017; 25: 58-74
• 64 Varghese NM, Venkatachalam S, Saxena SK. Nanocarriers for brain specific delivery of antiretro viral drugs: Challenges and achievements. J Drug Target 2018; 26: 195-207
• 65 Neves AR, Queiroz JF, Weksler B. et al. Solid lipid nanoparticles as a vehicle for brain-targeted drug delivery: Two new strategies of functionalization with apolipoprotein E. Nanotechology 2015; 26: 495103
• 66 Garanti T, Alhnan MA, Wan KW. RGD-decorated solid lipid nanoparticles enhanced tumor targeting, penetration and anticancer effect of asiatic acid. Nanomedicine (Lond) 2020; 15: 1567-1583
• 67 Rahiminejad A, Dinarvand R, Johari B. et al. Preparation and investigation of indirubin-loaded SLN nanoparticles and their anticancer effects on human glioblastoma U87MG cells. Cell Biol Int 2019; 43: 2-11
• 68 Soni K, Rizwanullah M, Kohli K. Development and optimization of sulforaphane-loaded nanostructured lipid carriers by the Box-Behnken design for improved oral efficacy against cancer: in vitro, ex vivo and in vivo assessments. Artif Cells Nanomed Biotechnol 2018; 46: 15-31
• 69 Harshita Barkat MA, Rizwanullah M. Paclitaxel-loaded nanolipidic carriers with improved oral bioavailability and anticancer activity against human liver carcinoma. AAPS PharmSciTech 2019; 20: e87
• 70 Rizwanullah M, Ahmad J, Amin S. Nanostructured lipid carriers: A novel platform for chemotherapeutics. Curr Drug Deliv 2016; 13: 4-26
• 71 Song S, Mao G, Du J. et al. Novel RGD containing, temozolomide-loading nanostructured lipid carriers for glioblastoma multiforme chemotherapy. Drug Deliv 2016; 23: 1404-1408
• 72 Zhang J, Xiao X, Zhu J. et al. Lactoferrin- and RGD-comodified, temozolomide and vincristine-coloaded nanostructured lipid carriers for gliomatosis cerebri combination therapy. Int J Nanomedicine 2018; 13: 3039-3051
• 73 Chen Y, Pan L, Jiang M. et al. Nanostructured lipid carriers enhance the bioavailability and brain cancer inhibitory efficacy of curcumin both in vitro and in vivo. Drug Deliv 2016; 23: 1383-1392
• 74 Rizwanullah M, Amin S, Mir SR. et al. Phytochemical based nanomedicines against cancer: Current status and future prospects. J Drug Target 2018; 26: 731-752
• 75 Akhter MH, Rizwanullah M, Ahmad J. et al. Nanocarriers in advanced drug targeting: Setting novel paradigm in cancer therapeutics. Artif Cells Nanomed Biotechnol 2018; 46: 873-884
• 76 Shahab MS, Rizwanullah M, Alshehri S. et al. Optimization to development of chitosan decorated polycaprolactone nanoparticles for improved ocular delivery of dorzolamide: In vitro, ex vivo and toxicity assessments. Int J Biol Macromol 2020; 163: 2392-2404
• 77 Rizwanullah M, Alam M. Harshita et al. Polymer-lipid hybrid nanoparticles: A next-generation nanocarrier for targeted treatment of solid tumors. Curr Pharm Des 2020; 26: 1206-1215
• 78 Khan FA, Rizwanullah M, Perwez A. et al. Polymeric Nanomedicines in Treatment of Breast Cancer: Review of Contemporary Research. Frontiers in Anti-Cancer Drug Discovery. 2020; 11: 36-66
• 79 Ramalho MJ, Sevin E, Gosselet F. et al. Pereira, Receptor-mediated PLGA nanoparticles for glioblastoma multiforme treatment. Int J Pharm 2018; 545: 84-92
• 80 Li H, Tong Y, Bai L. et al. Lactoferrin functionalized PEG-PLGA nanoparticles of shikonin for brain targeting therapy of glioma. Int J Biol Macromol 2018; 107: 204-211
• 81 de Oliveira RR, Nascimento TL, Salomão MA. et al. Increased nose-to-brain delivery of melatonin mediated by polycaprolactone nanoparticles for the treatment of glioblastoma. Pharm Res 2019; 36: e131
• 82 Morshed RA, Cheng Y, Auffinger B. et al. The potential of polymeric micelles in the context of glioblastoma therapy. Front Pharmacol 2013; 4: e157
• 83 Haider N, Fatima S, Taha M. et al. Nanomedicines in diagnosis and treatment of cancer: An update. Curr Pharm Des 2020; 26: 1216-1231
• 84 Quader S, Liu X, Chen Y. et al. cRGD peptide-installed epirubicin-loaded polymeric micelles for effective targeted therapy against brain tumors. J Control Release 2017; 258: 56-66
• 85 Li AJ, Zheng HY, Liu GD. et al. Efficient delivery of docetaxel for the treatment of brain tumors by cyclic RGD-tagged polymeric micelles. Mol Med Rep 2015; 11: 3078-3086
• 86 Huang Y, Liu W, Gao F. et al. c(RGDyK)-decorated Pluronic micelles for enhanced doxorubicin and paclitaxel delivery to brain glioma. Int J Nanomedicine 2016; 11: 1629-1641
• 87 Kannan RM, Nance E, Kannan S. et al. Emerging concepts in dendrimer-based nanomedicine: from design principles to clinical applications. J Intern Med 2014; 276: 579-617
• 88 Akhter MH, Ahsan MJ, Rahman M, Anwar S, Rizwanullah M. et al. Advancement in nanotheranostics for effective skin cancer therapy: State of the art. Curr Nanomed 2020; 10: 90-104
• 89 Swami R, Singh I, Kulhari H. et al. P-hydroxy benzoic acid conjugated dendrimer nanotherapeutics as potential carriers for targeted drug delivery to brain: An in vitro and in vivo evaluation. J Nanoparticle Res 2015; 17: e265
• 90 Sharma AK, Gupta L, Sahu H. et al. Chitosan engineered PAMAM dendrimers as nanoconstructs for the enhanced anticancer potential and improved in vivo brain pharmacokinetics of temozolomide. Pharm Res 2018; 35: e9
• 91 Gajbhiye V, Jain NK. The treatment of glioblastoma xenografts by surfactant conjugated dendritic nanoconjugates. Biomaterials 2011; 32: 6213-6225
• 92 Pinel S, Thomas N, Boura C. et al. Approaches to physical stimulation of metallic nanoparticles for glioblastoma treatment. Adv Drug Deliv Rev 2019; 138: 344-357
• 93 Kong L, Qiu J, Sun W. et al. Multifunctional PEI-entrapped gold nanoparticles enable efficient delivery of therapeutic siRNA into glioblastoma cells. Biomater Sci 2017; 5: 258-266
• 94 Kouri FM, Hurley LA, Daniel WL. et al. miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. Genes Dev 2015; 29: 732-745
• 95 Zhao L, Li Y, Zhu J. et al. Chlorotoxin peptide-functionalized polyethylenimine-entrapped gold nanoparticles for glioma SPECT/CT imaging and radionuclide therapy. J Nanobiotechnology 2019; 17: e30
• 96 Wankhede M, Bouras A, Kaluzova M. et al. Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy. Expert Rev Clin Pharmacol 2012; 5: 173-186
• 97 Mahmoudi K, Bouras A, Bozec D. et al. Magnetic hyperthermia therapy for the treatment of glioblastoma: A review of the therapy’s history, efficacy and application in humans. Int J Hyperthermia 2018; 34: 1316-1328
• 98 Lu Q, Dai X, Zhang P. et al. Fe3O4@Au composite magnetic nanoparticles modified with cetuximab for targeted magneto-photothermal therapy of glioma cells. Int J Nanomedicine 2018; 13: 2491-2505
• 99 Shevtsov M, Nikolaev B, Marchenko Y. et al. Targeting experimental orthotopic glioblastoma with chitosan-based superparamagnetic iron oxide nanoparticles (CS-DX-SPIONs). Int J Nanomedicine 2018; 13: 1471-1482
• 100 Akilo OD, Choonara YE, Strydom AM. et al. An in vitro evaluation of a carmustine-loaded Nano-co-Plex for potential magnetic-targeted intranasal delivery to the brain. Int J Pharm 2016; 500: 196-209
• 101 Kafa H, Wang JTW, Al-Jamal KT. Current perspective of carbon nanotubes application in neurology. Int Rev Neurobiol 2016; 130: 229-263
• 102 Guo Q, Shen XT, Li YY. et al. Carbon nanotubes-based drug delivery to cancer and brain. J Huazhong Univ Sci Technol Med Sci 2017; 37: 635-641
• 103 Lu YJ, Wei KC, Ma CCM. et al. Dual targeted delivery of doxorubicin to cancer cells using folate-conjugated magnetic multi-walled carbon nanotubes. Colloids Surf B Biointerfaces 2012; 89: 1-9
• 104 Romano-Feinholz S, Salazar-Ramiro A, Muñoz-Sandoval E. et al. Cytotoxicity induced by carbon nanotubes in experimental malignant glioma. Int J Nanomedicine 2017; 12: 6005-6026
• 105 Pottoo FH, Javed MN, Rahman JU. et al. Targeted delivery of miRNA based therapeuticals in the clinical management of Glioblastoma Multiforme. Semin Cancer Biol 2020;
• 106 Mangraviti A, Tzeng SY, Kozielski KL. et al. Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo. ACS Nano 2015; 9: 1236-1249
• 107 Liu Y, Zou Y, Feng C. et al. Charge conversional biomimetic nanocomplexes as a multifunctional platform for boosting orthotopic Glioblastoma RNAi therapy. Nano Lett 2020; 20: 1637-1646
• 108 Janiszewska J, Posadas I, Játiva P. et al. Second generation amphiphilic poly-lysine dendrons inhibit glioblastoma cell proliferation without toxicity for neurons or astrocytes. PLoS One 2016; 11: e0165704
• 109 Hayward SL, Wilson CL, Kidambi S. Hyaluronic acid-conjugated liposome nanoparticles for targeted delivery to CD44 overexpressing glioblastoma cells. Oncotarget 2016; 7: 34158-34171
• 110 Yang J, Zhang Q, Liu Y. et al. Nanoparticle-based co-delivery of siRNA and paclitaxel for dual-targeting of glioblastoma. Nanomedicine(Lond) 2020; 15: 1391-1409