Tyrosine Kinase Inhibitors for Glioblastoma Multiforme: Challenges and Opportunities for Drug Delivery
Abstract
:1. Introduction
2. Pathophysiology of GBM and Role of TKs
2.1. Pathophysiology of GBM
2.1.1. p53 and PTEN Pathway
2.1.2. Isocitrate Dehydrogenase (IDH) Pathway
2.1.3. Retinoblastoma (RB) Pathway
2.1.4. Histone H3 Pathway
2.1.5. Interleukins (ILs) Pathway
2.2. Role of TKs in Pathophysiology of GBM
3. Preclinical GBM Models
4. Tyrosine Kinase Inhibitors (TKIs)
5. Clinical Trials of TKIs in Treatment of GBM and Disappointing Outcomes
6. Pediatric High-Grade Gliomas (pHGGS)
7. Strategies to Achieve Targeted Delivery of TKIs
7.1. Altering BBB Permeability
7.1.1. Chemical Disruption
7.1.2. Focused Ultrasound
7.1.3. Inhibition of Efflux Transporters
7.1.4. Chemical Modification of Molecules
7.1.5. Intra-Arterial Drug Delivery
7.2. Bypassing BBB via Alternate Routes
7.2.1. Direct Injection
7.2.2. Implantable Polymeric Systems
7.2.3. Convection Enhanced Delivery (CED)
7.2.4. Intranasal Delivery
7.3. BBB Crossing via Nanotechnology
7.3.1. Liposomes
7.3.2. Polymeric Nanoparticles
7.3.3. Polymeric Micelles
7.3.4. Albumin Nanoparticles
7.3.5. Inorganic Nanocarriers
7.3.6. Other Nanocarriers
Formulation | Drug/Targeting Ligand | Particle size | Cell line/Model Used | Outcomes/References |
---|---|---|---|---|
Actively targeted nanoparticles | ||||
Ultra-small fluorescent core–shell silica NPs | Dasatinib; cyclic-arginine-glycine-aspartic acid peptide | 6–7 nm | TS543 neurosphere cultures Genetically engineered mouse model of glioblastoma |
|
Polymeric NPs based on PLGA-b-PEG-COOH | Dactolisib; Gint4.T aptamer | - | U87MG GBM cells Nude mice bearing intracranial U87MG tumor xenografts |
|
PEG-b-poly(ε-caprolactone-co-dithiolane trimethylene carbonate)-mefenamate micelles | Sorafenib; Apo-lipoprotein E peptide | 24 nm | U-87 MG cells U-87 MG-Luc tumor-bearing mice |
|
PEGylated bilirubin NPs | Cediranib and paclitaxel; D-T7 peptide | Cediranib NPs: 71.5 nm Paclitaxel NPs: 77.2 nm | C6 cell line C6 glioma bearing mice |
|
Liposomes composed of DOTAP, DOPE, Cholesterol and DSPE-PEG2000 | Doxorubicin and Erlotinib; Transferrin, cell penetrating peptide (PFVYLI) | 161.90 ± 4.60 nm | U87, bEnd.3 and glial cell lines |
|
Passively targeted nanoparticles | ||||
Lipid nanocapsules | Sorafenib | 54 ± 1 nm | U87MG cell line Orthotopic U87MG glioblastoma model |
|
Poly(styrene-co-maleic acid) micelles | Crizotinib and Dasatinib | Crizotinib micelles: 121 nm Dasatinib micelles: 89.14 nm | Various cell lines; U87 and NZG1003 3D spheroids; Female C57BL/6 mice, inoculated with GL261 GBM tumor mass SC |
|
Human serum albumin nanoparticles | Ibrutinib and Hydroxychloroquine | 160.1 ± 0.7 nm | C6-luc cells Orthotopic glioma xenograft developed by intracranial transplantation of C6-luc cells in mice |
|
8. Conclusions and Perspectives
Funding
Data Availability Statement
Conflicts of Interest
References
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Drug (Dosing) | Clinical Indication and Target of TKI | Clinical Trial | Outcomes of Trial (References) |
---|---|---|---|
Imatinib (600 mg/day) | Chronic myeloid leukemia, gastrointestinal tumor Bcr-Abl, KIT, PDGFR | Phase II trial for primary inoperable or incompletely resected and recurrent GBM |
|
Imatinib mesylate (oral dose of 600 mg/day) in combination with hydroxyurea (oral dose of 500 mg twice daily) vs. hydroxyurea alone (500 mg 3 times daily) | - | Phase III study in patients with temozolomide resistant progressive glioblastoma |
|
Gefitinib (initial oral dose of 500 mg/day, escalated to 750 mg and then 1000 mg in case patient received enzyme-inducing drugs or dexamethasone) | Non-small cell lung cancer EGFR | Phase II trial for GBM at first recurrence |
|
Cediranib (oral dose of 30 mg/day) and gefitinib (oral dose of 500 mg/day) vs. cediranib and placebo | - | Phase II trial for recurrent or progressive GBM |
|
Dovitinib (oral dose of 500 mg/day for 5 days, 2 days off weekly on a 28-day cycle) | FGFR, VEGFR, PDGFR | Phase II trial for relapsed or progressive GBM |
|
Sunitinib (oral dose of 37.5 mg/day to start, escalation to 50 mg/day or reduction to 25 or 12.5 mg/day depending on the toxicities) | Gastrointestinal tumor, renal cell carcinoma, pancreatic neuroendocrine tumor KIT, PDGFR, VEGFR1-2, FLT3 | Phase II trial for first recurrence of primary GBM |
|
Nintedanib (oral dose of 200 mg twice a day) | PDGFR, FGFR, VEGFR | Phase II trial for recurrent high-grade gliomas |
|
Cabozantinib (Starting oral dose of 140 mg/day considered to be high and then reduced to 100 mg/day) | Progressive metastatic medullary thyroid cancer, renal cell carcinoma, hepatocellular carcinoma previously treated with sorafenib VEGFR1-2, Met, ROS1, RET, AXL, NTRK, KIT | Phase II trial for recurrent or refractory GBM naïve to prior antiangiogenic therapy |
|
Cediranib (Initial treatment with 45 mg/day, followed by stepwise dose reduction in patients with dose-limiting toxicities) | VEGFR1-3, KIT, PDGFR | Phase II trial for recurrent GBM |
|
Erlotinib (oral dose of 150 mg/day for patients not on drugs that increase CYP3A4 activity and 300 mg/day for patients on drugs that increase CYP3A4 activity, followed by dose escalation) | Non-small cell lung cancer EGFR | Phase II trial for first relapse GBM |
|
Pazopanib (oral dose of 800 mg/day) | Renal cell carcinoma, soft tissue sarcoma VEGFR, PDGFR, KIT | Phase II trial for recurrent GBM |
|
Cediranib (oral dose of 30 mg/day) monotherapy and cediranib (oral dose of 20 mg/day) combination with lomustine (oral dose of 110 mg/m2 once every 6 weeks) versus lomustine alone | VEGFR1-3, KIT, PDGFR | Phase III trial for recurrent GBM |
|
Dacomitinib (oral dose of 45 mg/day) | Non-small cell lung cancer EGFR, HER2 | Phase II trial for recurrent GBM and EGFR amplification with or without variant III (EGFRvIII) deletion |
|
Afatinib (initiated at 20 mg/day and escalated to 40 and 50 mg/day) with or without temozolomide (75 mg/m2 for 21 days every 28-day cycle) vs. temozolomide monotherapy | Non-small cell lung cancer, squamous cell carcinoma of lung EGFR, HER2 | Phase I/II trial for recurrent GBM |
|
Bevacizumab (5 mg/kg intravenously every 2 weeks) alone and in combination with sorafenib (200 mg twice a day for 1–5 days a week then modified to 200 mg/day because of toxicities) | Renal cell carcinoma, hepatocellular carcinoma, differentiated thyroid cancer VEGFR1-3, TIE2, PDGFR, FGFR, BRAF, CRAF, KIT, FLT-3 | Phase II trial for recurrent GBM |
|
Axitinib (treatment initiated at oral dose of 5 mg twice daily and adjusted according to toxicity) or bevacizumab or lomustine | Renal cell carcinoma VEGFR1-3, PDGFR, KIT, FLT-3 | Phase II trial for recurrent GBM |
|
Axitinib (started at oral dose of 5 mg twice daily)Avelumab (10 mg/kg intravenously over 60 min every 2 weeks) | - | Phase II trial for recurrent GBM |
|
Radiation plus temozolomide with or without vandetanib (100 mg/day 5–7 days prior to radiation) | Unresectable or metastatic medullary thyroid cancer EGFR, VEGFR2-3, RET | Phase II trial for newly diagnosed GBM |
|
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Share and Cite
Brar, H.K.; Jose, J.; Wu, Z.; Sharma, M. Tyrosine Kinase Inhibitors for Glioblastoma Multiforme: Challenges and Opportunities for Drug Delivery. Pharmaceutics 2023, 15, 59. https://doi.org/10.3390/pharmaceutics15010059
Brar HK, Jose J, Wu Z, Sharma M. Tyrosine Kinase Inhibitors for Glioblastoma Multiforme: Challenges and Opportunities for Drug Delivery. Pharmaceutics. 2023; 15(1):59. https://doi.org/10.3390/pharmaceutics15010059
Chicago/Turabian StyleBrar, Harpinder K., Jiney Jose, Zimei Wu, and Manisha Sharma. 2023. "Tyrosine Kinase Inhibitors for Glioblastoma Multiforme: Challenges and Opportunities for Drug Delivery" Pharmaceutics 15, no. 1: 59. https://doi.org/10.3390/pharmaceutics15010059
APA StyleBrar, H. K., Jose, J., Wu, Z., & Sharma, M. (2023). Tyrosine Kinase Inhibitors for Glioblastoma Multiforme: Challenges and Opportunities for Drug Delivery. Pharmaceutics, 15(1), 59. https://doi.org/10.3390/pharmaceutics15010059