Current Challenges and Opportunities in Treating Glioblastoma

Pharmacological Reviews, Journal Year: 2018, Volume and Issue: 70(3), P. 412 - 445

Published: April 18, 2018

Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, has a high mortality rate despite extensive efforts to develop new treatments. GBM exhibits both intra- intertumor heterogeneity, lending resistance eventual tumor recurrence. Large-scale genomic proteomic analysis of tumors uncovered potential drug targets. Effective "druggable" targets must be validated embark on robust medicinal chemistry campaign culminating in discovery clinical candidates. Here, we review recent developments delivery. To identify targets, performed bioinformatics using data from The Cancer Genome Atlas project. We discovered 20 genes, BOC, CLEC4GP1, ELOVL6, EREG, ESR2, FDCSP, FURIN, FUT8-AS1, GZMB, IRX3, LITAF, NDEL1, NKX3-1, PODNL1, PTPRN, QSOX1, SEMA4F, TH, VEGFC, C20orf166AS1 that are overexpressed subpopulation patients correlate with poor survival outcomes. Importantly, nine these genes exhibit higher expression versus low-grade glioma may involved disease progression. In this review, discuss proteins context also conducted computational multi-parameter optimization assess blood-brain barrier (BBB) permeability small molecules trials for treatment. Drug delivery is particularly challenging because BBB hinders molecule transport. Therefore, novel methods, including nanoparticles prodrugs. Given nature complexity targeting central nervous system, effective treatment options major unmet medical need. Identification validation biomarkers associated progression present an exciting opportunity improve devastating disease.

Language: Английский

---

The blood-brain barrier: Physiology and strategies for drug delivery

Advanced Drug Delivery Reviews, Journal Year: 2019, Volume and Issue: 165-166, P. 1 - 14

Published: Nov. 29, 2019

Language: Английский

---

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Proceedings of the National Academy of Sciences, Journal Year: 2016, Volume and Issue: 114(1)

Published: Dec. 19, 2016

MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects opening the BBB by low-intensity pFUS+MB, as evidenced contrast-enhanced MRI, resulted an immediate damage-associated molecular pattern (DAMP) response including elevations heat-shock protein 70, IL-1, IL-18, and TNFα indicative a sterile inflammatory (SIR) parenchyma. Concurrent DAMP presentation, significant proinflammatory, antiinflammatory, trophic factors along neurotrophic neurogenesis were detected; these lasted 24 h. Transcriptomic analysis sonicated brain supported proteomic findings indicated SIR was facilitated through induction NFκB pathway. Histological evaluation demonstrated increased albumin parenchyma cleared h TUNEL

Language: Английский

---

Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies

Nature Reviews Neurology, Journal Year: 2017, Volume and Issue: 14(1), P. 22 - 39

Published: Dec. 15, 2017

Language: Английский

---

Applications of focused ultrasound in the brain: from thermoablation to drug delivery

Nature Reviews Neurology, Journal Year: 2020, Volume and Issue: 17(1), P. 7 - 22

Published: Oct. 26, 2020

Language: Английский

---

Tau-based therapies in neurodegeneration: opportunities and challenges

Nature Reviews Drug Discovery, Journal Year: 2017, Volume and Issue: 16(12), P. 863 - 883

Published: Oct. 6, 2017

Language: Английский

---

Blood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Feb. 3, 2021

Abstract MR-guided focused ultrasound (MRgFUS), in combination with intravenous microbubble administration, has been applied for focal temporary BBB opening patients neurodegenerative disorders and brain tumors. MRgFUS could become a therapeutic tool drug delivery of putative neurorestorative therapies. Treatment Parkinson’s disease dementia (PDD) is an important unmet need. We initiated prospective, single-arm, non-randomized, proof-of-concept, safety feasibility phase I clinical trial (NCT03608553), which still progress. The primary outcomes the study were to demonstrate safety, reversibility disruption PDD, targeting right parieto-occipito-temporal cortex where cortical pathology foremost this state. Changes β-amyloid burden, metabolism after treatments neuropsychological assessments, analyzed as exploratory measurements. Five recruited from October 2018 until May 2019, received two treatment sessions separated by 2–3 weeks. results are set out descriptive manner. Overall, procedure was feasible reversible no serious or radiological side effects. report junction 8/10 5 demonstrated gadolinium enhancement. In all cases procedures uneventful effects encountered associated opening. From pre- post-treatment, mild cognitive improvement observed, major changes detected amyloid fluorodeoxyglucose PET. MRgFUS-BBB PDD thus safe, reversible, can be performed repeatedly. This provides encouragement concept treat PD other disorders.

Language: Английский

---

Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders

Pharmacology & Therapeutics, Journal Year: 2019, Volume and Issue: 204, P. 107402 - 107402

Published: Aug. 27, 2019

Current medication for anxiety disorders is suboptimal in terms of efficiency and tolerability, highlighting the need improved drug treatments. In this review an overview drugs being studied different phases clinical trials their potential treatment fear-, anxiety- trauma-related presented. One strategy followed development refining improving compounds interacting with existing anxiolytic targets, such as serotonergic prototypical GABAergic benzodiazepines. A more innovative approach involves search novel mechanisms action using growing knowledge base concerning relevant neurocircuitries neurobiological underlying pathological fear anxiety. The target systems evaluated include glutamate, endocannabinoid neuropeptide systems, well ion channels targets derived from phytochemicals. Examples promising candidates currently generalised disorder, social panic obsessive compulsive disorder or post-traumatic stress ketamine, riluzole, xenon one common pharmacological modulation glutamatergic neurotransmission, neurosteroid aloradine. Finally, D-cycloserine, MDMA, L-DOPA cannabinoids have shown efficacy enhancing fear-extinction learning humans. They are thus investigated augmentative speeding up long-term effectiveness exposure-based psychotherapy, which could render chronic dispensable many patients. These efforts indicative a rekindled interest renewed optimism discovery field, after decades relative stagnation.

Language: Английский

---

The Mechanosensitive Ion Channel Piezo1 Significantly Mediates In Vitro Ultrasonic Stimulation of Neurons

iScience, Journal Year: 2019, Volume and Issue: 21, P. 448 - 457

Published: Oct. 24, 2019

Ultrasound brain stimulation is a promising modality for probing function and treating disease non-invasively with high spatiotemporal resolution. However, the mechanism underlying its effects remains unclear. Here, we examine role that mouse piezo-type mechanosensitive ion channel component 1 (Piezo1) plays in mediating vitro of ultrasound primary cortical neurons neuronal cell line. We show alone could activate heterologous endogenous Piezo1, initiating calcium influx increased nuclear c-Fos expression but not when pre-treated Piezo1 inhibitor. also found significantly important proteins phospho-CaMKII, phospho-CREB, line, knockdown reduced this effect. Our findings demonstrate activity channels such as stimulated by an contributor to ability stimulate cells vitro.

Language: Английский

---

Nanoparticle Size Effects in Biomedical Applications

ACS Applied Nano Materials, Journal Year: 2021, Volume and Issue: 4(7), P. 6471 - 6496

Published: July 2, 2021

Nanoparticle size plays a central role in determining material properties and performance biomedical applications. A wide variety of functional nanomaterials nano-bioconjugates have been developed for monitoring biochemical activity, controlling biological functions, therapeutic This review focuses on the nanoparticle (typically range 1–100 nm) various applications, origin such effect, optimum requirement best different First, we discuss nanoscale units present life processes along with their role. Next, size-dependent some well-known nanoparticles how those are exploited that used Then, highlight designed specific Finally, attempt to correlate evolutionary selection toward functions.

Language: Английский

---