A Virus‐Mimicking Nucleic Acid Nanogel Reprograms Microglia and Macrophages for Glioblastoma Therapy

Advanced Materials, Journal Year: 2021, Volume and Issue: 33(9)

Published: Jan. 27, 2021

Immunotherapy is recognized as one of the most promising approaches to treat cancers. However, its effect in glioblastoma (GBM) treatment insufficient, which can part be attributed immunosuppressive tumor microenvironment (TME). Microglia and macrophages are main immune infiltrating cells TME GBM. Unfortunately, instead initiating anti-tumor response, GBM-infiltrating microglia switch a tumor-promoting phenotype (M2), support growth, angiogenesis, immunosuppression by release cytokines. In this work, virus-mimicking membrane-coated nucleic acid nanogel Vir-Gel embedded with therapeutic miRNA developed, reprogram from pro-invasive M2 an M1 phenotype. By mimicking virus infection process, significantly enhances targetability cell uptake efficiency miR155-bearing nanogel. vivo evaluations demonstrate that apparently prolongs circulation lifetime miR155 endows it active tumor-targeting capability excellent inhibition efficacy. Owing noninvasive feature effective delivery capability, provides general convenient platform successfully wide range diseases.

Language: Английский

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Brain Co‐Delivery of Temozolomide and Cisplatin for Combinatorial Glioblastoma Chemotherapy

Advanced Materials, Journal Year: 2022, Volume and Issue: 34(33)

Published: June 23, 2022

Glioblastoma (GBM) is an intractable malignancy with high recurrence and mortality. Combinatorial therapy based on temozolomide (TMZ) cisplatin (CDDP) shows promising potential for GBM in clinical trials. However, significant challenges include limited blood-brain-barrier (BBB) penetration, poor targeting of tissue/cells, systemic side effects, which hinder its efficacy therapy. To surmount these challenges, new GBM-cell membrane camouflaged pH-sensitive biomimetic nanoparticles (MNPs) inspired by the fact that cancer cells readily pass BBB localize homologous cells, are developed. This study's results show MNPs can efficiently co-load TMZ CDDP, transport across to specifically target GBM. Incorporation polymer then allows controlled release drug cargos at sites combination Mice bearing orthotopic U87MG or drug-resistant U251R tumor treated MNPs@TMZ+CDDP a potent anti-GBM effect, greatly extending survival time relative mice receiving single-drug loaded nanoparticles. No obvious effects apparent histological analyses blood routine studies. Considering results, nanoparticle formulation overcomes multiple currently limiting combined CDDP appears be strategy future combinatorial chemotherapy.

Language: Английский

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Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: March 3, 2021

Chimeric antigen receptor (CAR) T cell therapy has emerged as one of the major breakthroughs in cancer immunotherapy last decade. Outstanding results hematological malignancies and encouraging pre-clinical anti-tumor activity against a wide range solid tumors have made CAR cells most promising fields for therapies. is currently being investigated including glioblastoma (GBM), tumor which survival only modestly improved over past decades. targeting EGFRvIII, Her2, or IL-13Rα2 been tested GBM, but first clinical trials shown modest results, potentially due to GBM heterogeneity presence an immunosuppressive microenvironment. Until now, use autologous manufacture products norm, this approach several disadvantages regarding production time, cost, manufacturing delay dependence on functional fitness patient cells, often reduced by disease previous Universal “off-the-shelf,” allogeneic, alternative that can overcome these issues, allow multiple modifications combinations target antigens avoid escape. Advances genome editing tools, especially via CRISPR/Cas9, might overcoming two main limitations allogeneic product, i.e., graft-vs.-host host allorejection. Here, we will discuss how could multivalent approaches alteration microenvironment, allowing development next generation therapies treatment patients with GBM.

Language: Английский

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Nanomedicine for brain cancer

Advanced Drug Delivery Reviews, Journal Year: 2022, Volume and Issue: 182, P. 114115 - 114115

Published: Jan. 22, 2022

Language: Английский

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Brain co‐delivery of first‐line chemotherapy drug and epigenetic bromodomain inhibitor for multidimensional enhanced synergistic glioblastoma therapy

Exploration, Journal Year: 2022, Volume and Issue: 2(4)

Published: April 19, 2022

Glioblastoma (GBM) is a central nervous system tumor with poor prognosis due to the rapid development of resistance mono chemotherapy and brain targeted delivery. Chemoimmunotherapy (CIT) combines drugs activators innate immunity that hold great promise for GBM synergistic therapy. Herein, we chose temozolomide, TMZ, epigenetic bromodomain inhibitor, OTX015, further co-encapsulated them within our well-established erythrocyte membrane camouflaged nanoparticle yield ApoE peptide decorated biomimetic nanomedicine (ABNM@TMZ/OTX). Our nanoplatform successfully addressed limitations in brain-targeted drug co-delivery, simultaneously achieved multidimensional enhanced CIT. In mice bearing orthotopic GL261 GBM, treatment ABNM@TMZ/OTX resulted marked inhibition greatly extended survival time little side effects. The pronounced efficacy can be ascribed three key factors: (i) improved nanoparticle-mediated targeting delivery therapeutic agents by blood circulation blood-brain barrier penetration; (ii) inhibited cellular DNA repair TMZ sensitivity cells; (iii) anti-tumor immune responses inducing immunogenic cell death inhibiting PD-1/PD-L1 conjugation leading expression CD4

Language: Английский

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Cancer cell-mitochondria hybrid membrane coated Gboxin loaded nanomedicines for glioblastoma treatment

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 28, 2023

Abstract Glioblastoma (GBM) remains the most lethal malignant tumours. Gboxin, an oxidative phosphorylation inhibitor, specifically restrains GBM growth by inhibiting activity of F 0 1 ATPase complex V. However, its anti-GBM effect is seriously limited poor blood circulation, brain barrier (BBB) and non-specific tissue/cell uptake, leading to insufficient Gboxin accumulation at sites, which limits further clinical application. Here we present a biomimetic nanomedicine (HM-NPs@G) coating cancer cell-mitochondria hybrid membrane (HM) on surface Gboxin-loaded nanoparticles. An additional design element uses reactive oxygen species responsive polymer facilitate at-site release. The HM camouflaging endows HM-NPs@G with unique features including good biocompatibility, improved pharmacokinetic profile, efficient BBB permeability homotypic dual tumour cell mitochondria targeting. results suggest that achieve circulation (4.90 h versus 0.47 free Gboxin) (7.73% ID/g 1.06% shown Gboxin). Effective inhibition in orthotopic U87MG patient derived X01 stem xenografts female mice extended survival time negligible side effects are also noted. We believe represents promising treatment for tumours potential.

Language: Английский

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Signaling pathways in brain tumors and therapeutic interventions

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Jan. 4, 2023

Abstract Brain tumors, although rare, contribute to distinct mortality and morbidity at all ages. Although there are few therapeutic options for brain enhanced biological understanding unexampled innovations in targeted therapies immunotherapies have considerably improved patients’ prognoses. Nonetheless, the reduced response rates unavoidable drug resistance of currently available treatment approaches become a barrier further improvement tumor (glioma, meningioma, CNS germ cell lymphoma) treatment. Previous literature data revealed that several different signaling pathways dysregulated tumor. Importantly, better targeting influences malignant behavior cells might open way development novel therapies. Thus, is an urgent need more comprehensive pathogenesis these which result greater progress approaches. This paper began with brief description epidemiology, incidence, risk factors, as well survival tumors. Next, major underlying tumors’ current therapies, including clinical trials, immunotherapies, system been systemically reviewed discussed. Finally, future perspective challenges strategies were emphasized.

Language: Английский

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Efficient delivery of Temozolomide using ultrasmall large-pore silica nanoparticles for glioblastoma

Journal of Controlled Release, Journal Year: 2023, Volume and Issue: 357, P. 161 - 174

Published: March 30, 2023

The prognosis of brain cancers such as glioblastoma remains poor despite numerous advancements in the field neuro-oncology. presence blood barrier (BBB) along with highly invasive and aggressive nature presents a difficult challenge for developing effective therapies. Temozolomide (TMZ) is first line agent used clinic it has been useful increasing patient survival rates. However, TMZ suffers from issues related to its pharmacokinetics, short plasma half-life (2 h), subjected P-gp efflux, limited extravasation (∼20%). It postulated that reducing efflux tissue exposure could prove treating preventing tumour recurrence. Herein, ultra-small, large pore silica nanoparticles (USLP) have loaded TMZ, surface PEGlyated reduce decorated cascade targeting protein lactoferrin efficient uptake across BBB into glioblastoma. Our results demonstrate USLP improves permeability vitro evidenced using transwell model which mimics endothelial tight junctions permeation being enhanced PEGylated particles. Data also suggests formulations can significantly ratio TMZ. In apoptosis studies on cell lines U87 GL261 were conducted showed an improvement induced compared pure Finally, proof-of-concept preclinical mouse study demonstrated when given intravenously at 50 mg/kg, particles accumulation within few hours without any obvious pathophysiological changes vital organs assessed via histology. Overall, data our innovative delivery system permeating potential improve efficacy therapy.

Language: Английский

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Strategies to Improve Drug Delivery Across the Blood–Brain Barrier for Glioblastoma

Current Neurology and Neuroscience Reports, Journal Year: 2024, Volume and Issue: 24(5), P. 123 - 139

Published: April 5, 2024

Abstract Purpose of Review Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth effective new New approaches drug delivery and clinical trial design are needed. Recent Findings We discuss how blood–brain barrier tumor microenvironment pose challenges for development therapies glioblastoma. Next, we treatments that aim overcome these barriers, including novel designs such as nanoparticles antibody–drug conjugates, methods delivery, convection-enhanced intra-arterial enhance penetration, disruption by focused ultrasound laser interstitial thermal therapy. Lastly, address future opportunities, positing combination therapy best strategy treatment, neoadjuvant window-of-opportunity simultaneously therapeutic effectiveness with interrogation on-treatment biologic endpoints, adaptive platform basket trials imperative design. Summary GBM treatment should account blood-brain immunosuppression improving combining treatments, integrating designs.

Language: Английский

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Glioblastoma and brain connectivity: the need for a paradigm shift

The Lancet Neurology, Journal Year: 2024, Volume and Issue: 23(7), P. 740 - 748

Published: June 13, 2024

Language: Английский

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