Drug delivery to the central nervous system

Nance, Elizabeth; Pun, Suzie H.; Saigal, Rajiv; Sellers, Drew L.

doi:10.1038/s41578-021-00394-w

Cited by 136 publications

(106 citation statements)

References 217 publications

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“…Several strategies targeting efflux transporters, angiogenesis factors, and other factors threatening the integrity of the BBB have been explored to improve the delivery of drugs into the brain [ 32 ]. Other degenerative CNS disorders such as AD, PD cause BBB dysfunction with simultaneous increase in gliosis, neurovascular dysfunction, neuroinflammation and progressive loss of nerve function [ 33 ]. Chronic psychiatric disorders including schizophrenia also compromise neurovascular health [ 33 ].…”

Section: Challenges In Cns Drug Deliverymentioning

confidence: 99%

A Comprehensive Review of Cross-Linked Gels as Vehicles for Drug Delivery to Treat Central Nervous System Disorders

Mashabela

Maboa

Miya

et al. 2022

Gels

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Gels are attractive candidates for drug delivery because they are easily producible while offering sustained and/or controlled drug release through various mechanisms by releasing the therapeutic agent at the site of action or absorption. Gels can be classified based on various characteristics including the nature of solvents used during preparation and the method of cross-linking. The development of novel gel systems for local or systemic drug delivery in a sustained, controlled, and targetable manner has been at the epitome of recent advances in drug delivery systems. Cross-linked gels can be modified by altering their polymer composition and content for pharmaceutical and biomedical applications. These modifications have resulted in the development of stimuli-responsive and functionalized dosage forms that offer many advantages for effective dosing of drugs for Central Nervous System (CNS) conditions. In this review, the literature concerning recent advances in cross-linked gels for drug delivery to the CNS are explored. Injectable and non-injectable formulations intended for the treatment of diseases of the CNS together with the impact of recent advances in cross-linked gels on studies involving CNS drug delivery are discussed.

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Section: Challenges In Cns Drug Deliverymentioning

confidence: 99%

A Comprehensive Review of Cross-Linked Gels as Vehicles for Drug Delivery to Treat Central Nervous System Disorders

Mashabela

Maboa

Miya

et al. 2022

Gels

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“…Subsequently, small molecules can then be tested in several animal models to establish evidence of CNS entry and general and brain-specific PK/PD. Inefficient drug delivery to the CNS is a major challenge for treating ADRD, as well as glioma, stroke, and traumatic brain injury [ 79 ]. Some small, hydrophobic drugs can cross the BBB.…”

Section: Discovery and Validation Of Small Molecules Targeting Ncrnasmentioning

confidence: 99%

“…For example, risdiplam is taken orally and crosses the BBB to increase functional SMN proteins in the CNS [ 80 ]. However, if oral administration does not lead to sufficient levels of small molecules in the CNS, other routes of delivery can be considered, including intravenous infusion, intranasal delivery, intrathecal delivery to the cerebrospinal fluid, intraventricular infusion, and focused ultrasound to transiently disrupt the BBB [ 79 ]. For the selected delivery route, maximally tolerated dose, target engagement, and efficacy at the molecular, cellular, and behavioral levels can be established.…”

Section: Discovery and Validation Of Small Molecules Targeting Ncrnasmentioning

confidence: 99%

Small Molecule Drugs Targeting Non-Coding RNAs as Treatments for Alzheimer’s Disease and Related Dementias

Nguyen

Chau

Krichevsky

2021

Genes

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Despite the enormous burden of Alzheimer’s disease and related dementias (ADRD) on patients, caregivers, and society, only a few treatments with limited efficacy are currently available. While drug development conventionally focuses on disease-associated proteins, RNA has recently been shown to be druggable for therapeutic purposes as well. Approximately 70% of the human genome is transcribed into non-protein-coding RNAs (ncRNAs) such as microRNAs, long ncRNAs, and circular RNAs, which can adopt diverse structures and cellular functions. Many ncRNAs are specifically enriched in the central nervous system, and their dysregulation is implicated in ADRD pathogenesis, making them attractive therapeutic targets. In this review, we first detail why targeting ncRNAs with small molecules is a promising therapeutic strategy for ADRD. We then outline the process from discovery to validation of small molecules targeting ncRNAs in preclinical studies, with special emphasis on primary high-throughput screens for identifying lead compounds. Screening strategies for specific ncRNAs will also be included as examples. Key challenges—including selecting appropriate ncRNA targets, lack of specificity of small molecules, and general low success rate of neurological drugs and how they may be overcome—will be discussed throughout the review.

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“…Blood-brain barrier (BBB) highly protects the central nervous system (CNS) ( Nance et al, 2022 ), preventing 98% of small molecules and 100% of large molecules from entering the brain ( Sánchez-Navarro et al, 2017 ). It is the main obstacle for drug delivery into the brain ( Banks, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

BBPpredict: A Web Service for Identifying Blood-Brain Barrier Penetrating Peptides

Chen

Zhang

et al. 2022

Front. Genet.

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Blood-brain barrier (BBB) is a major barrier to drug delivery into the brain in the treatment of central nervous system (CNS) diseases. Blood-brain barrier penetrating peptides (BBPs), a class of peptides that can cross BBB through various mechanisms without damaging BBB, are effective drug candidates for CNS diseases. However, identification of BBPs by experimental methods is time-consuming and laborious. To discover more BBPs as drugs for CNS disease, it is urgent to develop computational methods that can quickly and accurately identify BBPs and non-BBPs. In the present study, we created a training dataset that consists of 326 BBPs derived from previous databases and published manuscripts and 326 non-BBPs collected from UniProt, to construct a BBP predictor based on sequence information. We also constructed an independent testing dataset with 99 BBPs and 99 non-BBPs. Multiple machine learning methods were compared based on the training dataset via a nested cross-validation. The final BBP predictor was constructed based on the training dataset and the results showed that random forest (RF) method outperformed other classification algorithms on the training and independent testing dataset. Compared with previous BBP prediction tools, the RF-based predictor, named BBPpredict, performs considerably better than state-of-the-art BBP predictors. BBPpredict is expected to contribute to the discovery of novel BBPs, or at least can be a useful complement to the existing methods in this area. BBPpredict is freely available at http://i.uestc.edu.cn/BBPpredict/cgi-bin/BBPpredict.pl.

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Drug delivery to the central nervous system

Cited by 136 publications

References 217 publications

A Comprehensive Review of Cross-Linked Gels as Vehicles for Drug Delivery to Treat Central Nervous System Disorders

A Comprehensive Review of Cross-Linked Gels as Vehicles for Drug Delivery to Treat Central Nervous System Disorders

Small Molecule Drugs Targeting Non-Coding RNAs as Treatments for Alzheimer’s Disease and Related Dementias

BBPpredict: A Web Service for Identifying Blood-Brain Barrier Penetrating Peptides

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