Pathways for Drug Delivery to the Central Nervous System

On, Ngoc; Yathindranath, Vinith; Sun, Zhizhi; Miller, Donald W.

doi:10.1002/9781118833322.ch16

Cited by 4 publications

(5 citation statements)

References 157 publications

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“…Hence, for any brain tumor therapeutics, it is vital to plan suitable design and delivery strategies at the early stages of development. Enhanced drug delivery to the brain has been achieved by three broad methods: (1) bypassing the BBB entirely by direct administration into the brain, (2) modifying the therapeutic molecule to enhance stability and permeability through passive diffusion or carrier and receptor-mediated routes, and (3) transiently disrupting the tight junction complexes for enhanced paracellular entry [ 53 ]. Intracerebroventricular and intracerebral administration (with or without convection-enhanced diffusion) involving direct administration of drugs to the brain has been examined, as has local brain drug delivery approaches using surgical implants made of biodegradable materials (e.g., hydrogel, Gliadel) [ 54 , 55 , 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Spermidine/Spermine N1-Acetyltransferase 1 (SAT1)—A Potential Gene Target for Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid Nanoparticle to Deliver siRNA

Yathindranath

Safa

Sajesh

et al. 2022

Cancers

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Spermidine/spermine N1-acetyltransferase 1 (SAT1) responsible for cell polyamine catabolism is overexpressed in glioblastoma multiforme (GB). Its role in tumor survival and promoting resistance towards radiation therapy has made it an interesting target for therapy. In this study, we prepared a lipid nanoparticle-based siRNA delivery system (LNP-siSAT1) to selectively knockdown (KD) SAT1 enzyme in a human glioblastoma cell line. The LNP-siSAT1 containing ionizable DODAP lipid was prepared following a microfluidics mixing method and the resulting nanoparticles had a hydrodynamic size of around 80 nm and a neutral surface charge. The LNP-siSAT1 effectively knocked down the SAT1 expression in U251, LN229, and 42MGBA GB cells, and other brain-relevant endothelial (hCMEC/D3), astrocyte (HA) and macrophage (ANA-1) cells at the mRNA and protein levels. SAT1 KD in U251 cells resulted in a 40% loss in cell viability. Furthermore, SAT1 KD in U251, LN229 and 42MGBA cells sensitized them towards radiation and chemotherapy treatments. In contrast, despite similar SAT1 KD in other brain-relevant cells no significant effect on cytotoxic response, either alone or in combination, was observed. A major roadblock for brain therapeutics is their ability to cross the highly restrictive blood–brain barrier (BBB) presented by the brain microcapillary endothelial cells. Here, we used the BBB circumventing approach to enhance the delivery of LNP-siSAT1 across a BBB cell culture model. A cadherin binding peptide (ADTC5) was used to transiently open the BBB tight junctions to promote paracellular diffusion of LNP-siSAT1. These results suggest LNP-siSAT1 may provide a safe and effective method for reducing SAT1 and sensitizing GB cells to radiation and chemotherapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Spermidine/Spermine N1-Acetyltransferase 1 (SAT1)—A Potential Gene Target for Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid Nanoparticle to Deliver siRNA

Yathindranath

Safa

Sajesh

et al. 2022

Cancers

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“…The BBB plays an essential role in maintaining homeostasis within the CNS environment and is equipped with a wide array of both influx and efflux transport proteins that regulate concentration ion gradients, the delivery of macromolecules to meet the energy needs of the brain, and prevents the entry of numerous, potentially harmful substances from entering the CNS environment. [21][22][23] Evaluation of currently available literature has demonstrated varying levels of CNS penetration of tyrosine kinase inhibitors (TKIs) with activity against RET (Table 1). [24][25][26][27][28][29][30][31] The CNS penetration of selpercatinib has been demonstrated in both in vitro and in vivo mouse tumor models and multiple patient case reports.…”

Section: Pharmacokinetics and Pharmacodynamics Of Selpercatinib And B...mentioning

confidence: 99%

Response to Selpercatinib in a Patient With Recurrent Glioblastoma and RET Amplification

Czech

Chen

Morgan

et al. 2022

Journal of the National Comprehensive Cancer Network

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Glioblastoma (GBM) is a malignant central nervous system neoplasm that remains largely incurable. Limited treatment options currently exist after disease progression on standard-of-care first-line therapy. However, repurposing the use of approved therapies in patients with potentially targetable genomic alterations continues to be an emerging area of interest. This report presents the first description of a patient with isocitrate dehydrogenase wild-type GBM with an underlying RET amplification who demonstrated a near-complete response while receiving therapy with the RET inhibitor selpercatinib. The case highlights the excellent blood-brain barrier penetration of selpercatinib, as well as its potential role in the management of RET-amplified GBM. Larger biomarker-enriched studies are needed to confirm the results of this case report. Given the rare incidence of RET alterations in GBM, findings from this report can help guide and support optimal treatment strategies for patients with RET-altered GBM.

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“…LAT1 has a lower transport capacity in comparison to GLUT1 [ 53 ]. Despite this, LAT1 is one of the most studied CMT for drug uptake into the brain [ 26 ].…”

Section: Drugs Unable To Permeate In the Brain From The Bloodstream Can Be Transformed Into Prodrugs Able To Be Transported By Influx Tramentioning

confidence: 99%

Targeting Systems to the Brain Obtained by Merging Prodrugs, Nanoparticles, and Nasal Administration

2021

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About 40 years ago the lipidization of hydrophilic drugs was proposed to induce their brain targeting by transforming them into lipophilic prodrugs. Unfortunately, lipidization often transforms a hydrophilic neuroactive agent into an active efflux transporter (AET) substrate, with consequent rejection from the brain after permeation across the blood brain barrier (BBB). Currently, the prodrug approach has greatly evolved in comparison to lipidization. This review describes the evolution of the prodrug approach for brain targeting considering the design of prodrugs as active influx substrates or molecules able to inhibit or elude AETs. Moreover, the prodrug approach appears strategic in optimization of the encapsulation of neuroactive drugs in nanoparticulate systems that can be designed to induce their receptor-mediated transport (RMT) across the BBB by appropriate decorations on their surface. Nasal administration is described as a valuable alternative to obtain the brain targeting of drugs, evidencing that the prodrug approach can allow the optimization of micro or nanoparticulate nasal formulations of neuroactive agents in order to obtain this goal. Furthermore, nasal administration is also proposed for prodrugs characterized by peripheral instability but potentially able to induce their targeting inside cells of the brain.

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Pathways for Drug Delivery to the Central Nervous System

Cited by 4 publications

References 157 publications

Spermidine/Spermine N1-Acetyltransferase 1 (SAT1)—A Potential Gene Target for Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid Nanoparticle to Deliver siRNA

Spermidine/Spermine N1-Acetyltransferase 1 (SAT1)—A Potential Gene Target for Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid Nanoparticle to Deliver siRNA

Response to Selpercatinib in a Patient With Recurrent Glioblastoma and RET Amplification

Targeting Systems to the Brain Obtained by Merging Prodrugs, Nanoparticles, and Nasal Administration

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