Convection-enhanced drug delivery for glioblastoma: a review

D’Amico, Randy S.; Aghi, Manish K.; Vogelbaum, Michael A.; Bruce, Jeffrey N.

doi:10.1007/s11060-020-03408-9

Cited by 82 publications

(71 citation statements)

References 64 publications

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“…Lack of BBB penetration has been an obstacle for many potential therapies for GBM. Direct intra-tumoral therapies via convection-enhanced delivery are currently being tested but have yet to show a survival benefit and have added risk of invasive surgery [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

A Novel Blood-Brain Barrier-Permeable Chemotherapeutic Agent for the Treatment of Glioblastoma

Ozawa

Rodriguez

Zhao

et al. 2021

Cureus

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IntroductionThe standard treatment for glioblastoma (GBM) patients is surgical tumor resection, followed by radiation and chemotherapy with temozolomide (TMZ). Unfortunately, 60% of newly diagnosed GBM patients express high levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) and are TMZresistant, and all patients eventually become refractory to treatment. The blood-brain barrier (BBB) is an obstacle to the delivery of chemotherapeutic agents to GBM, and BBB-permeable agents that are efficacious in TMZ-resistant and refractory patients are needed. The large amino acid transporter 1 (LAT1) is expressed on the BBB and in GBM and is detected at much lower levels in normal brain tissue. A LAT1-selective therapeutic would potentially target brain tumors while avoiding uptake by healthy tissue. MethodsWe report a novel chemical entity (QBS10072S) that combines a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate and tested it against GBM models in vitro and in vivo. For in vitro studies, DNA damage was assessed with a gamma H2A.X antibody and cell viability was assessed by WST-1 assay and/or CellTiter-Glo assay. For in vivo studies, QBS10072S (with or without radiation) was tested in orthotopic glioblastoma xenograft models, using overall survival and tumor size (as measured by bioluminescence), as endpoints. ResultsQBS10072S is 50-fold more selective for LAT1 vs. LAT2 in transport assays and demonstrates significant growth suppression in vitro of LAT1-expressing GBM cell lines. Unlike TMZ, QBS10072S is cytotoxic to cells with both high and low levels of MGMT expression. In orthotopic GBM xenografts, QBS10072S treatment significantly delayed tumorigenesis and prolonged animal survival compared to the vehicle without adverse effects. ConclusionQBS10072S is a novel BBB-permeable chemotherapeutic agent with the potential to treat TMZ-resistant and recurrent GBM as monotherapy or in combination with radiation treatment.

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Section: Discussionmentioning

confidence: 99%

A Novel Blood-Brain Barrier-Permeable Chemotherapeutic Agent for the Treatment of Glioblastoma

Ozawa

Rodriguez

Zhao

et al. 2021

Cureus

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“…These microcatheters are connected to mechanical pumps to provide a continuous, positive-pressure micro-infusion of desired agents through target tissues allowing directed distribution along with large brain volumes and minimizing systemic side effects. While the long-term efficacy of the agents delivered and studied to date remains challenging to evaluate, CED is a promising technique for treating intracranial tumors [77][78][79]. CED bypasses the challenge posed by the BBB.…”

Section: Device-based and Physicochemical Disruption Of The Bbbmentioning

confidence: 99%

Transportation of Single-Domain Antibodies through the Blood–Brain Barrier

Ruiz-López

Schuhmacher

2021

Biomolecules

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Single-domain antibodies derive from the heavy-chain-only antibodies of Camelidae (camel, dromedary, llama, alpaca, vicuñas, and guananos; i.e., nanobodies) and cartilaginous fishes (i.e., VNARs). Their small size, antigen specificity, plasticity, and potential to recognize unique conformational epitopes represent a diagnostic and therapeutic opportunity for many central nervous system (CNS) pathologies. However, the blood–brain barrier (BBB) poses a challenge for their delivery into the brain parenchyma. Nevertheless, numerous neurological diseases and brain pathologies, including cancer, result in BBB leakiness favoring single-domain antibodies uptake into the CNS. Some single-domain antibodies have been reported to naturally cross the BBB. In addition, different strategies and methods to deliver both nanobodies and VNARs into the brain parenchyma can be exploited when the BBB is intact. These include device-based and physicochemical disruption of the BBB, receptor and adsorptive-mediated transcytosis, somatic gene transfer, and the use of carriers/shuttles such as cell-penetrating peptides, liposomes, extracellular vesicles, and nanoparticles. Approaches based on single-domain antibodies are reaching the clinic for other diseases. Several tailoring methods can be followed to favor the transport of nanobodies and VNARs to the CNS, avoiding the limitations imposed by the BBB to fulfill their therapeutic, diagnostic, and theragnostic promises for the benefit of patients suffering from CNS pathologies.

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“…As an example, D PMI-a 16 , a D-peptide inhibitor of the p53-MDM2 interaction, encapsulated in liposomes decorated via a poly(ethylene glycol) spacer with a cyclic RGD peptide was effective in GB models (97,103). Convection-enhanced delivery is also an option to improve delivery of targeted drugs to GB, applying local drug delivery that bypasses the BBB, while limiting associated systemic toxicities (233).…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy

et al. 2021

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Inhibition of the MDM2/X-p53 interaction is recognized as a potential anti-cancer strategy, including the treatment of glioblastoma (GB). In response to cellular stressors, such as DNA damage, the tumor suppression protein p53 is activated and responds by mediating cellular damage through DNA repair, cell cycle arrest and apoptosis. Hence, p53 activation plays a central role in cell survival and the effectiveness of cancer therapies. Alterations and reduced activity of p53 occur in 25-30% of primary GB tumors, but this number increases drastically to 60-70% in secondary GB. As a result, reactivating p53 is suggested as a treatment strategy, either by using targeted molecules to convert the mutant p53 back to its wild type form or by using MDM2 and MDMX (also known as MDM4) inhibitors. MDM2 down regulates p53 activity via ubiquitin-dependent degradation and is amplified or overexpressed in 14% of GB cases. Thus, suppression of MDM2 offers an opportunity for urgently needed new therapeutic interventions for GB. Numerous small molecule MDM2 inhibitors are currently undergoing clinical evaluation, either as monotherapy or in combination with chemotherapy and/or other targeted agents. In addition, considering the major role of both p53 and MDM2 in the downstream signaling response to radiation-induced DNA damage, the combination of MDM2 inhibitors with radiation may offer a valuable therapeutic radiosensitizing approach for GB therapy. This review covers the role of MDM2/X in cancer and more specifically in GB, followed by the rationale for the potential radiosensitizing effect of MDM2 inhibition. Finally, the current status of MDM2/X inhibition and p53 activation for the treatment of GB is given.

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Convection-enhanced drug delivery for glioblastoma: a review

Cited by 82 publications

References 64 publications

A Novel Blood-Brain Barrier-Permeable Chemotherapeutic Agent for the Treatment of Glioblastoma

A Novel Blood-Brain Barrier-Permeable Chemotherapeutic Agent for the Treatment of Glioblastoma

Transportation of Single-Domain Antibodies through the Blood–Brain Barrier

MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy

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