Targeting delivery in Parkinson's disease

Newland, Ben; Dunnett, Stephen B.; Dowd, Eilís

doi:10.1016/j.drudis.2016.06.003

Cited by 15 publications

(12 citation statements)

References 64 publications

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“…This approach could form a welcome supplement to other promising disease-modifying strategies including cell replacement therapies 40 by possibly slowing either neurotoxic microglial effects or propagation of synucleinopathy to grafted tissue. While our animal studies demonstrated acute efficacy with intranigral stereotactic drug administration, systemic administration may be more desirable, as there is greater ease of repeat administration and less risk of infection and less need for costly, technically demanding surgical procedures 41 . Future studies may focus on incorporation of chemical modifications to our AMs, such as quaternary ammonium groups 42 , that may facilitate crossing of the blood-brain barrier, while hopefully retaining microglia-and scavenger receptor-targeting ability.…”

Section: Discussionmentioning

confidence: 89%

Polymer brain-nanotherapeutics for multipronged inhibition of microglial α-synuclein aggregation, activation, and neurotoxicity

et al. 2016

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Neuroinflammation, a common neuropathologic feature of neurodegenerative disorders including Parkinson disease (PD), is frequently exacerbated by microglial activation. The extracellular protein α-synuclein (ASYN), whose aggregation is characteristic of PD, remains a key therapeutic target, but the control of synuclein trafficking and aggregation within microglia has been challenging. First, we established that microglial internalization of monomeric ASYN was mediated by scavenger receptors (SR), CD36 and SRA1, and was rapidly accompanied by the formation of ASYN oligomers. Next, we designed a nanotechnology approach to regulate SR-mediated intracellular ASYN trafficking within microglia. We synthesized mucic acid-derivatized sugar-based amphiphilic molecules (AM) with optimal stereochemistry, rigidity, and charge for enhanced dual binding affinity to SRs and fabricated serum-stable nanoparticles via flash nanoprecipitation comprising hydrophobe cores and amphiphile shells. Treatment of microglia with AM nanoparticles decreased monomeric ASYN internalization and intracellular ASYN oligomer formation. We then engineered composite deactivating NPs with dual character, namely shell-based SR-binding amphiphiles, and core-based antioxidant poly (ferrulic acid), to investigate concerted inhibition of oxidative activation. In ASYN-challenged microglia treated with NPs, we observed decreased ASYN-mediated acute microglial activation and diminished microglial neurotoxicity caused by exposure to aggregated ASYN. When the composite NPs were administered in vivo within the substantia nigra of fibrillar ASYN-challenged wild type mice, there was marked attenuation of activated microglia. Overall, SR-targeting AM nanotechnology represents a novel paradigm in alleviating microglial activation in the context of synucleinopathies like PD and other neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 89%

Polymer brain-nanotherapeutics for multipronged inhibition of microglial α-synuclein aggregation, activation, and neurotoxicity

et al. 2016

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“…Systems thinking can be applied to design nanoparticles for specific neurological diseases. For example, in PD the therapeutic goal is often to save dying dopaminergic neurons in the presence of BBB impairment, oxidative stress, and microglial cell activation . Nanoparticles can more easily cross an impaired BBB to access the brain parenchyma.…”

Section: Synthesizing Nanomaterials Properties and Pathophysiology Halmentioning

confidence: 99%

“…For example, in PD the therapeutic goal is often to save dying dopaminergic neurons in the presence of BBB impairment, oxidative stress, and microglial cell activation. 214 Nanoparticles can more easily cross an impaired BBB to access the brain parenchyma. However, nanoparticles are likely to be scavenged out of the brain parenchyma by phagocytic activated microglia.…”

Section: Synthesizing Nanomaterials Properties and Pathophysiology Halmentioning

confidence: 99%

Systems‐level thinking for nanoparticle‐mediated therapeutic delivery to neurological diseases

Curtis

Zhang

Liao

et al. 2016

WIREs Nanomed Nanobiotechnol

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Neurological diseases account for 13% of the global burden of disease. As a result, treating these diseases costs $750 billion a year. Nanotechnology, which consists of small (~1-100 nm) but highly tailorable platforms, can provide significant opportunities for improving therapeutic delivery to the brain. Nanoparticles can increase drug solubility, overcome the blood-brain and brain penetration barriers, and provide timed release of a drug at a site of interest. Many researchers have successfully used nanotechnology to overcome individual barriers to therapeutic delivery to the brain, yet no platform has translated into a standard of care for any neurological disease. The challenge in translating nanotechnology platforms into clinical use for patients with neurological disease necessitates a new approach to: (1) collect information from the fields associated with understanding and treating brain diseases and (2) apply that information using scalable technologies in a clinically-relevant way. This approach requires systems-level thinking to integrate an understanding of biological barriers to therapeutic intervention in the brain with the engineering of nanoparticle material properties to overcome those barriers. To demonstrate how a systems perspective can tackle the challenge of treating neurological diseases using nanotechnology, this review will first present physiological barriers to drug delivery in the brain and common neurological disease hallmarks that influence these barriers. We will then analyze the design of nanotechnology platforms in preclinical in vivo efficacy studies for treatment of neurological disease, and map concepts for the interaction of nanoparticle physicochemical properties and pathophysiological hallmarks in the brain. WIREs Nanomed Nanobiotechnol 2017, 9:e1422. doi: 10.1002/wnan.1422 For further resources related to this article, please visit the WIREs website.

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“…29 This ability to compress and expand is useful for applications where biomaterial-assisted delivery of cells or therapeutics through a small cannula size is required (i.e., stereotactic injection into the central nervous system). 35 We tested the ability of microcarriers to be injected through a 30 gauge needle or a glass capillary (internal diameters of 160 and 140 µm respectively). ESI Fig.…”

Section: Design and Characteristics Of Cryogelsmentioning

confidence: 99%

Heparin-based, injectable microcarriers for controlled delivery of interleukin-13 to the brain

et al. 2020

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Targeting delivery in Parkinson's disease

Cited by 15 publications

References 64 publications

Polymer brain-nanotherapeutics for multipronged inhibition of microglial α-synuclein aggregation, activation, and neurotoxicity

Polymer brain-nanotherapeutics for multipronged inhibition of microglial α-synuclein aggregation, activation, and neurotoxicity

Systems‐level thinking for nanoparticle‐mediated therapeutic delivery to neurological diseases

Heparin-based, injectable microcarriers for controlled delivery of interleukin-13 to the brain

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