Understanding Drug Delivery to the Brain Using Liposome-Based Strategies: Studies that Provide Mechanistic Insights Are Essential

Juhairiyah, Firda; Lange, Elizabeth C. M. de

doi:10.1208/s12248-021-00648-z

Cited by 66 publications

(46 citation statements)

References 125 publications

(167 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, the AUC brain /AUC plasma ratio for free Givinostat was 0.372, higher than liposomal formulations ratios (0.020 for LIP-GIV and 0.014 for LIP/m-GIV). As Givinostat is a hydrophobic small molecule (~400 Da), it is able to cross the BBB by simple diffusion, unlike liposome formulations, which cross the BBB through endo/transcytosis [ 38 ]. In accordance with the results obtained for Vincristine entrapped in liposomes [ 37 ], we showed that the incorporation of Givinostat in liposomes should improve the therapeutic index by increasing the duration of drug exposure to the target tissue.…”

Section: Resultsmentioning

confidence: 99%

Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics

Taiarol

Bigogno²,

Sesana

et al. 2022

Cancers

View full text Add to dashboard Cite

Glioblastoma is the most common and aggressive brain tumor, associated with poor prognosis and survival, representing a challenging medical issue for neurooncologists. Dysregulation of histone-modifying enzymes (HDACs) is commonly identified in many tumors and has been linked to cancer proliferation, changes in metabolism, and drug resistance. These findings led to the development of HDAC inhibitors, which are limited by their narrow therapeutic index. In this work, we provide the proof of concept for a delivery system that can improve the in vivo half-life and increase the brain delivery of Givinostat, a pan-HDAC inhibitor. Here, 150-nm-sized liposomes composed of cholesterol and sphingomyelin with or without surface decoration with mApoE peptide, inhibited human glioblastoma cell growth in 2D and 3D models by inducing a time- and dose-dependent reduction in cell viability, reduction in the receptors involved in cholesterol metabolism (from −25% to −75% of protein levels), and reduction in HDAC activity (−25% within 30 min). In addition, liposome-Givinostat formulations showed a 2.5-fold increase in the drug half-life in the bloodstream and a 6-fold increase in the amount of drug entering the brain in healthy mice, without any signs of overt toxicity. These features make liposomes loaded with Givinostat valuable as potential candidates for glioblastoma therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics

Taiarol

Bigogno²,

Sesana

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…Whereas providing interesting data, such studies have room for improvement to provide sufficient mechanistic insight. 78 A number of animal studies using microdialysis for time-course information on unbound drug in plasma and brain provide such mechanistic information. [78][79][80][81][82][83][84] Overall, these studies show that brain distribution of a drug administered as liposomal formulation depends on both drug properties and liposomal formulation characteristics (Table 2).…”

Section: Figure 2 (Continued)mentioning

confidence: 99%

“…Only the unbound drugs that reach the brainECF and/or brainICF (red dashed circles) are available for target site binding in these physiological compartments to induce their pharmacological effect. 78 Patients with human traumatic brain injury were studied regarding morphine brain delivery, by comparing the brain injury site and the "better" brain site using microdialysis. 40 K p,uu,brain was 0.64 in the "better" human brain tissue indicating active BBB efflux of morphine, and was substantially changed to 1.0 at the injury site, indicating lack of efflux function due to the traumatic injury.…”

Section: What Happens With Small Molecules?mentioning

confidence: 99%

“…78 A number of animal studies using microdialysis for time-course information on unbound drug in plasma and brain provide such mechanistic information. [78][79][80][81][82][83][84] Overall, these studies show that brain distribution of a drug administered as liposomal formulation depends on both drug properties and liposomal formulation characteristics (Table 2). It may indeed enhance BBB drug delivery for drugs that have limited BBB transport, such as methotrexate and DAMGO, but may also counteract active uptake, as is the case for diphenhydramine (Table 2) and quetiapine, where the latter used lipid core nanocapsules.…”

Section: Figure 2 (Continued)mentioning

confidence: 99%

“…The unbound drug can exchange between brainECF and CSF, and between brainECF and brainICF;[5] The liposome may enter brainICF and can release the drug in the brainICF. Only the unbound drugs that reach the brainECF and/or brainICF (red dashed circles) are available for target site binding in these physiological compartments to induce their pharmacological effect 78. BBB, blood-brain barrier; BCSFB, blood-cerebrospinal fluid barrier; CSF, cerebrospinal fluid; ECF, extracellular fluid; PK, pharmacokinetic.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Understanding the Blood‐Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics

Lange

Udenaes

2022

Clin Pharma and Therapeutics

Self Cite

View full text Add to dashboard Cite

This review addresses questions on how to accomplish successful central nervous system (CNS) drug delivery (i.e., having the right concentration at the right CNS site, at the right time), by understanding the rate and extent of blood‐brain barrier (BBB) transport and intra‐CNS distribution in relation to CNS target site(s) exposure. To this end, we need to obtain and integrate quantitative and connected data on BBB using the Combinatory Mapping Approach that includes in vivo and ex vivo animal measurements, and the physiologically based comprehensive LEICNSPK3.0 mathematical model that can translate from animals to humans. For small molecules, slow diffusional BBB transport and active influx and efflux BBB transport determine the differences between plasma and CNS pharmacokinetics. Obviously, active efflux is important for limiting CNS drug delivery. Furthermore, liposomal formulations of small molecules may to a certain extent circumvent active influx and efflux at the BBB. Interestingly, for CNS pathologies, despite all reported disease associated BBB and CNS functional changes in animals and humans, integrative studies typically show a lack of changes on CNS drug delivery for the small molecules. In contrast, the understanding of the complex vesicle‐based BBB transport modes that are important for CNS delivery of large molecules is in progress, and their BBB transport seems to be significantly affected by CNS diseases. In conclusion, today, CNS drug delivery of small drugs can be well assessed and understood by integrative approaches, although there is still quite a long way to go to understand CNS drug delivery of large molecules.

show abstract

Lipid Nanoparticles: Versatile Drug Delivery Vehicles for Traversing the Blood Brain Barrier to Treat Brain Cancer

Cai,

Drummond,

Zhai

et al. 2024

Adv Funct Materials

View full text Add to dashboard Cite

The blood‐brain barrier (BBB) poses a significant challenge in delivering therapeutic agents for brain diseases due to its high selectivity against foreign substances. This limitation greatly hampers the effectiveness of conventional chemotherapeutic drugs in treating brain cancers. In response, lipid‐based nanoparticles (LNPs) have emerged as a promising approach, offering opportunities for targeted drug delivery by conjugating targeting ligands onto their surface. This review provides a comprehensive overview of recent advancements in utilizing LNPs to traverse the BBB for enhanced transport of bioactive compounds into the brain, specifically for cancer treatments. Beginning with an exploration of the biological structure and functions of the BBB and the blood‐brain tumor barrier (BBTB), the review highlights the advantages presented by LNPs. Subsequently, it delves into strategies for surface modification of nanoparticles to enhance BBB targeting and improve efficacy in brain cancer treatment. Finally, the review offers insights into future prospects for designing the next generation of LNPs. The review presented herein aims to contribute to the ongoing efforts in overcoming the challenges associated with BBB penetration, ultimately advancing therapeutic strategies for brain cancer and other neurological disorders.

show abstract

Understanding Drug Delivery to the Brain Using Liposome-Based Strategies: Studies that Provide Mechanistic Insights Are Essential

Cited by 66 publications

References 125 publications

Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics

Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics

Understanding the Blood‐Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics

Lipid Nanoparticles: Versatile Drug Delivery Vehicles for Traversing the Blood Brain Barrier to Treat Brain Cancer

Contact Info

Product

Resources

About