Intrathecal drug delivery in the era of nanomedicine

Fowler, Martha J; Cotter, Jennifer D; Knight, B.; Sevick‐Muraca, Eva M.; Sandberg, David I.; Sirianni, Rachael W.

doi:10.1016/j.addr.2020.02.006

Cited by 101 publications

(77 citation statements)

References 214 publications

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“…Use of Etop-MNPs would improve upon this situation because they could be used to focally increase drug delivery, even to areas that represent "blind alleys" with respect to CSF access (16). Iron oxide particles have been administered intrathecally in animals (44)(45)(46)(47). Nanostructures have been proposed for enhancing intrathecal drug delivery (16,(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Etoposide-Bound Magnetic Nanoparticles Designed for Remote Targeting of Cancer Cells Disseminated Within Cerebrospinal Fluid Pathways

et al. 2020

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Magnetic nanoparticles (MNPs) have potential for enhancing drug delivery in selected cancer patients, including those which have cells that have disseminated within cerebrospinal fluid (CSF) pathways. Here, we present data related to the creation and in vitro use of new two-part MNPs consisting of magnetic gold-iron alloy cores which have streptavidin binding sites, and are coated with biotinylated etoposide. Etoposide was chosen due to its previous use in the CSF and ease of biotinylation. Etoposide magnetic nanoparticles (“Etop-MNPs”) were characterized by several different methods, and moved at a distance by surface-walking of MNP clusters, which occurs in response to a rotating permanent magnet. Human cell lines including D283 (medulloblastoma), U138 (glioblastoma), and H2122 (lung adenocarcinoma) were treated with direct application of Etop-MNPs (and control particles), and after remote particle movement. Cell viability was determined by MTT assay and trypan blue exclusion. Results indicated that the biotinylated etoposide was successfully bound to the base MNPs, with the hybrid particle attaining a maximum velocity of 0.13 ± 0.018 cm/sec. Etop-MNPs killed cancer cells in a dose-dependent fashion, with 50 ± 6.8% cell killing of D283 cells (for example) with 24 h of treatment after remote targeting. U138 and H2122 cells were found to be even more susceptible to the killing effect of Etop-MNPs than D283 cells. These findings indicate that the novel Etop-MNPs have a cytotoxic effect, and can be moved relatively rapidly at physiologic distances, using a rotating magnet. While further testing is needed, intrathecal administration of Etop-MNPs holds promise for magnetically-enhanced eradication of cancer cells distributed within CSF pathways, particularly if given early in the course of the disease.

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Section: Discussionmentioning

confidence: 99%

Etoposide-Bound Magnetic Nanoparticles Designed for Remote Targeting of Cancer Cells Disseminated Within Cerebrospinal Fluid Pathways

et al. 2020

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“…Lastly, one important point of discussion arises for the delivery of therapeutic molecules to central nervous system (CNS) since the blood-brain barrier (BBB) and blood spinal cord barrier (BSCB) represents a bottleneck in the development of new therapies to treat CNS diseases. Indeed, in the last decade a great deal of effort has been dedicated to the achievement of an efficient and effective drug delivery to CNS focusing on the types of administration as well as on the design and modification of the potential therapeutic molecules (Krizbai et al, 2016;Kumar et al, 2017;Alexander et al, 2019;Fowler et al, 2020). A promising approach to circumvent the BBB and the BSCB is the delivery of therapeutic molecules directly to CNS through intrathecal injection (IT).…”

Section: Non-coding Rna Diagnostics and Therapeuticsmentioning

confidence: 99%

Non-coding RNAs in Nervous System Development and Disease

Salvatori¹,

Biscarini²,

Morlando³

2020

Front. Cell Dev. Biol.

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The rapid advance of RNA sequencing technologies contributed to a deep understanding of transcriptome composition and has allowed the discovery of a large number of non-coding RNAs (ncRNAs). The ability of these RNA molecules to be engaged in intricate and dynamic interactions with proteins and nucleic acids led to a great expansion of gene expression regulation mechanisms. By this matter, ncRNAs contribute to the increase in regulatory complexity that becomes highly specific between tissues and cell types. Among the ncRNAs, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are especially abundant in nervous system and have been shown to be implicated in its development, plasticity and aging as well as in neurological disorders. This review provides an overview of how these two diverse classes of ncRNAs control cellular processes during nervous system development, physiology, and disease conditions with particular emphasis on neurodegenerative disorders. The use of ncRNAs as biomarkers, tools, or targets for therapeutic intervention in neurodegeneration are also discussed.

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“…It is clear, therefore, how CED could achieve regional disease control but fail at covering other distant areas. Nonetheless, it holds the potential for controlling brainstem pathology and, if coupled with other innovative approaches, such as craniospinal radiation or intrathecal delivery of chemotherapeutics, could change, at least in part, the dire prognosis [ 98 ]. The use of CED to effectively deliver chemotherapeutic agents (chemosurgery) would thus become one of the weapons in the arsenal against DIPG.…”

Section: The Paradox Of Using Ced For Dipgmentioning

confidence: 99%

Convection Enhanced Delivery for Diffuse Intrinsic Pontine Glioma: Review of a Single Institution Experience

Tosi

Souweidane

2020

Pharmaceutics

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Diffuse intrinsic pontine gliomas (DIPGs) are a pontine subtype of diffuse midline gliomas (DMGs), primary central nervous system (CNS) tumors of childhood that carry a terrible prognosis. Because of the highly infiltrative growth pattern and the anatomical position, cytoreductive surgery is not an option. An initial response to radiation therapy is invariably followed by recurrence; mortality occurs approximately 11 months after diagnosis. The development of novel therapeutics with great preclinical promise has been hindered by the tightly regulated blood–brain barrier (BBB), which segregates the tumor comportment from the systemic circulation. One possible solution to this obstacle is the use of convection enhanced delivery (CED), a local delivery strategy that bypasses the BBB by direct infusion into the tumor through a small caliber cannula. We have recently shown CED to be safe in children with DIPG (NCT01502917). In this review, we discuss our experience with CED, its advantages, and technical advancements that are occurring in the field. We also highlight hurdles that will likely need to be overcome in demonstrating clinical benefit with this therapeutic strategy.

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Intrathecal drug delivery in the era of nanomedicine

Cited by 101 publications

References 214 publications

Etoposide-Bound Magnetic Nanoparticles Designed for Remote Targeting of Cancer Cells Disseminated Within Cerebrospinal Fluid Pathways

Etoposide-Bound Magnetic Nanoparticles Designed for Remote Targeting of Cancer Cells Disseminated Within Cerebrospinal Fluid Pathways

Non-coding RNAs in Nervous System Development and Disease

Convection Enhanced Delivery for Diffuse Intrinsic Pontine Glioma: Review of a Single Institution Experience

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