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

Narsinh, Kazim H.; Perez, Edgar; Haddad, Alexander F.; Young, Jacob S.; Savastano, Luis; Villanueva-Meyer, Javier E.; Winkler, Ethan; de Groot, John

doi:10.1007/s11910-024-01338-x

Cited by 4 publications

(2 citation statements)

References 127 publications

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“…Focused ultrasound pulses of varying durations have been recently used to transport liposomes to the brain in a non-invasive manner [35][36][37]. AFU-assisted nanoplexes have great potential to transport a large variety of therapeutic agents, including hydrophilic and hydrophobic drugs, siRNA, antisense oligonucleotides (ASOs), but not bigger plasmid DNA because they can fragment under ultrasound treatment [38].…”

Section: Discussionmentioning

confidence: 99%

Development of Focused Ultrasound-Assisted Nanoplexes for RNA Delivery

Ranjan,

Bosch,

Lukkari

et al. 2024

Nanomaterials

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RNA-based therapeutics, including siRNA, have obtained recognition in recent years due to their potential to treat various chronic and rare diseases. However, there are still limitations to lipid-based drug delivery systems in the clinical use of RNA therapeutics due to the need for optimization in the design and the preparation process. In this study, we propose adaptive focused ultrasound (AFU) as a drug loading technique to protect RNA from degradation by encapsulating small RNA in nanoliposomes, which we term nanoplexes. The AFU method is non-invasive and isothermal, as nanoplexes are produced without direct contact with any external materials while maintaining precise temperature control according to the desired settings. The controllability of sample treatments can be effectively modulated, allowing for a wide range of ultrasound intensities to be applied. Importantly, the absence of co-solvents in the process eliminates the need for additional substances, thereby minimizing the potential for cross-contaminations. Since AFU is a non-invasive method, the entire process can be conducted under sterile conditions. A minimal volume (300 μL) is required for this process, and the treatment is speedy (10 min in this study). Our in vitro experiments with silencer CD44 siRNA, which performs as a model therapeutic drug in different mammalian cell lines, showed encouraging results (knockdown > 80%). To quantify gene silencing efficacy, we employed quantitative polymerase chain reaction (qPCR). Additionally, cryo-electron microscopy (cryo-EM) and atomic force microscopy (AFM) techniques were employed to capture images of nanoplexes. These images revealed the presence of individual nanoparticles measuring approximately 100–200 nm in contrast with the random distribution of clustered complexes observed in ultrasound-untreated samples of liposome nanoparticles and siRNA. AFU holds great potential as a standardized liposome processing and loading method because its process is fast, sterile, and does not require additional solvents.

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Section: Discussionmentioning

confidence: 99%

Development of Focused Ultrasound-Assisted Nanoplexes for RNA Delivery

Ranjan,

Bosch,

Lukkari

et al. 2024

Nanomaterials

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“…One limitation to the in vivo efficacy of BET bromodomain inhibitors is poor brain penetration ( Supplemental Table 2 ). To increase drug concentrations in the brain, we would further investigate new drug delivery systems such as disrupting the BBB using focused ultrasound ( 46 , 47 ) or bypassing the BBB using convection-enhanced delivery ( 48 ) and intranasal delivery ( 49 ). Nevertheless, our findings support the possible use of BET bromodomain inhibitor to increase the radiation-mediated antitumor effect for the treatment of DMG.…”

Section: Discussionmentioning

confidence: 99%

BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma

Watanabe,

Clutter,

Gullette

et al. 2024

Journal of Clinical Investigation

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Diffuse midline glioma (DMG) H3K27-altered is one of the devastating childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation anti-tumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo-and extra-terminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA-seq and CUT & RUN showed that BET bromodomain inhibitors regulate the expression of DNA repair genes mediated by H3K27 acetylation at enhancers. BET bromodomain inhibitors enhanced DMG radiation-response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitors as radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment of DMG.

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Lipid Nanoparticles for Brain Tumor Theranostics: Challenges and Status

Kaur,

Gautam,

Nanda

et al. 2024

Bioconjugate Chem.

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Lipid nanoparticles have been recognized as a powerful weapon for delivering various imaging and therapeutic agents to the localized solid tumors, especially brain tumors individually or in combination. Promisingly, lipid-based nanosystems have been considered as safe delivery systems which are even approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). One recent spotlight of lipid nanoparticles as COVID-19 mRNA vaccines where lipid nanoparticles play an important role in effectively protecting and delivering mRNA to the desired cells. As of now, successive progress in lipid-based nanocarriers, viz., nanoliposomes, solid lipid nanoparticles, ionizable lipid nanostructures, etc., with better biochemical and biophysical stabilities, has been noticed and reported. Moreover, lipid nanostructures have been considered as versatile therapeutics platforms for a variety of diseases due to their biocompatibility, ability to protect and deliver therapeutics to the localized site, and better reproducibility and reliability. However, lipid nanoparticles still face morphological and biochemical changes upon their in vivo administration. These changes alter the specific biological and pathological response of lipid nanoparticles during their personalized brain tumor theranostics. Second, lipid nanomedicine still faces major challenges of zero premature leakage of loaded cargo, long-term colloidal stability, and off targeting. Herein, various lipidbased nanomedicines for brain tumor imaging and therapeutics "theranostics" have been reviewed and summarized considering major aspects of preclinical and clinical studies. On the other hand, engineering and biological challenges of lipid theranostics systems with relevant advantages and guidelines for clinical practice for different brain tumors have also been discussed. This review provides in-depth knowledge of lipid nanoparticle-based theranostics agents for brain tumor imaging and therapeutics.

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

Cited by 4 publications

References 127 publications

Development of Focused Ultrasound-Assisted Nanoplexes for RNA Delivery

Development of Focused Ultrasound-Assisted Nanoplexes for RNA Delivery

BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma

Lipid Nanoparticles for Brain Tumor Theranostics: Challenges and Status

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