Nanotherapeutics and the Brain

Joseph, Andrea; Nance, Elizabeth

doi:10.1146/annurev-chembioeng-092220-030853

Cited by 8 publications

(4 citation statements)

References 132 publications

(134 reference statements)

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“…A variety of obstacles for NP-based drug delivery have been elegantly described in several recent reviews (Terstappen et al, 2021;Joseph and Nance, 2022;Nance et al, 2022). Among the most problematic of these include immunogenicity, formation of a protein corona on the NP surface, engulfment of NPs by macrophages in the periphery and microglia in the brain, limited endosomal escape, and toxicity (Saraiva et al, 2016).…”

Section: Overcoming Major Hurdles In Np-based Brain Drug Deliverymentioning

confidence: 99%

“…10.3389/fncel.2023.1226630 10. Future perspectives As described in several recent and comprehensive reviews (Charabati et al, 2020;Joseph and Nance, 2022;Parrasia et al, 2022), many different types of NP formulations have been reported to increase brain drug delivery. Despite these claims, a viable clinical approach has yet to emerge.…”

Section: Direct Translocation Of Cpps Across the Plasma Membranementioning

confidence: 99%

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Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery

Novorolsky

Kasheke

Hakim

et al. 2023

Front. Cell. Neurosci.

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The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca2+) uptake supports NVU function by buffering Ca2+ and stimulating energy production. However, excessive mitochondrial Ca2+ uptake causes toxic mitochondrial Ca2+ overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca2+ uptake and efflux in the brain are mediated by the mitochondrial Ca2+ uniporter complex (MCUcx) and sodium/Ca2+/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCUcx inhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca2+ overloading. These findings suggest that combining MCUcx inhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCUcx inhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCUcx, or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues.

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Section: Overcoming Major Hurdles In Np-based Brain Drug Deliverymentioning

confidence: 99%

Section: Direct Translocation Of Cpps Across the Plasma Membranementioning

confidence: 99%

Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery

Novorolsky

Kasheke

Hakim

et al. 2023

Front. Cell. Neurosci.

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“…Nano-therapeutics: Nanotherapeutics represent a promising area of CNS drug delivery approaches and have revolutionized the concept of drug delivery across brain barriers with some successful exemplars currently in the clinic [216][217][218]. Nanoparticles (NPs)-based platforms of various size ranges and designs can overcome intact or impaired brain barriers and facilitate efficient CNS drug delivery leveraging transport via multiple mechanisms, including paracellular pathway, cell-mediated transport, adsorptive-mediated transcytosis, RMT, CMT or ligand-receptor interactions [219,220].…”

Section: Transport Mechanisms Studies and (Targeted)drug Deliverymentioning

confidence: 99%

In Vitro Models of the Blood–Cerebrospinal Fluid Barrier and Their Applications in the Development and Research of (Neuro)Pharmaceuticals

2022

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The pharmaceutical research sector has been facing the challenge of neurotherapeutics development and its inherited high-risk and high-failure-rate nature for decades. This hurdle is partly attributable to the presence of brain barriers, considered both as obstacles and opportunities for the entry of drug substances. The blood–cerebrospinal fluid (CSF) barrier (BCSFB), an under-studied brain barrier site compared to the blood–brain barrier (BBB), can be considered a potential therapeutic target to improve the delivery of CNS therapeutics and provide brain protection measures. Therefore, leveraging robust and authentic in vitro models of the BCSFB can diminish the time and effort spent on unproductive or redundant development activities by a preliminary assessment of the desired physiochemical behavior of an agent toward this barrier. To this end, the current review summarizes the efforts and progresses made to this research area with a notable focus on the attribution of these models and applied techniques to the pharmaceutical sector and the development of neuropharmacological therapeutics and diagnostics. A survey of available in vitro models, with their advantages and limitations and cell lines in hand will be provided, followed by highlighting the potential applications of such models in the (neuro)therapeutics discovery and development pipelines.

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“…Our findings demonstrate that these PLE materials not only mimic the rheological properties of soft tissues but also generate biologically relevant transport. As such, we expect that PLEs can be used as in vitro models of biological tissues to identify physical mechanisms underlying the performance of targeted drug delivery vectors7,8,102 and nanotherapeutics [103][104][105]. Specifically, PLE materials can provide a well-controlled synthetic environment in which we can assess the role of interparticle interactions, transient binding, particle shape, and composition of interstitial fluid on the ability of nanoparticles, liposomes, and other species to penetrate and accumulate within soft tissues.…”

mentioning

confidence: 99%

Nanoparticle transport in biomimetic polymer‐linked emulsions

Keane,

Constantine,

Mellor

et al. 2023

AIChE Journal

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The ability of nanoparticles to penetrate and transport through soft tissues is essential to delivering therapeutics to treat diseases or signaling agents for advanced imaging and sensing. Nanoparticle transport in biological systems, however, is challenging to predict and control due to the physicochemical complexity of tissues and biological fluids. Here, we demonstrate that nanoparticles suspended in a novel class of soft matter—polymer‐linked emulsions (PLEs)—exhibit characteristics essential for mimicking transport in biological systems, including subdiffusive dynamics, non‐Gaussian displacement distributions, and decoupling of dynamics from material viscoelasticity. Using multiple particle tracking, we identify the physical mechanisms underlying this behavior, which we attribute to a coupling of nanoparticle dynamics to fluctuations in the local network of polymer‐linked droplets. Our findings demonstrate the potential of PLEs to serve as fully synthetic mimics of biological transport.

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Nanotherapeutics and the Brain

Cited by 8 publications

References 132 publications

Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery

Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery

In Vitro Models of the Blood–Cerebrospinal Fluid Barrier and Their Applications in the Development and Research of (Neuro)Pharmaceuticals

Nanoparticle transport in biomimetic polymer‐linked emulsions

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