Drug Delivery Challenges in Brain Disorders across the Blood–Brain Barrier: Novel Methods and Future Considerations for Improved Therapy

Achar, Aneesha; Myers, Rosemary; Ghosh, Chaitali

doi:10.3390/biomedicines9121834

Cited by 68 publications

(43 citation statements)

References 196 publications

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“…Transporters at the BBB play a vital role in regulating the entry of molecules from the blood to the brain, but some, such as e ux pumps, challenge the delivery of drugs into the brain (27). In addition, in brain disorders such as AD, transporter activity is altered, potentially contributing to disease progression (73,74); however the full extent of AD-related changes in BBB transporters in human are not known.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the BBB and its transporters form a major impediment for researchers developing drugs that target the brain for the treatment of CNS disorders, such as AD (26). Moreover, dysfunction of the BBB associated with AD likely further hinders drug delivery due to the altered physiological conditions of the BBB and the brain (27), which can lead to altered drug metabolism.…”

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confidence: 99%

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Alzheimer’s disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound

Chaves

Wasielewska

Cuní-López

et al. 2023

Preprint

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Background The blood-brain barrier (BBB) has a major role in maintaining homeostasis of the brain. The primary function of the BBB is regulating the entry of molecules from the blood to the brain while protecting the brain from potentially harmful endogenous and exogenous substances. Transporters expressed in brain endothelial cells (BECs) mediate the uptake or efflux of compounds to and from the brain and they can also challenge the delivery of drugs into the brain for the treatment of brain disorders including Alzheimer’s disease (AD). AD is the most common form of dementia, however, currently there is limited understanding of the role of BBB transporters in AD-related BBB dysfunction. Methods We investigated differences in BBB transporter expression and activity in brain endothelial-like cells (iBECs) differentiated from induced pluripotent stem cells (iPSCs) obtained from people carrying the familial AD Presenilin 1 (PSEN1) mutation (PSEN1 exon 9 deletion; AD-iBECs), healthy controls (Ctrl-iBECs), and isogenic PSEN1 exon 9-corrected lines (PSEN1COR-iBECs). We first characterized the expression levels of 12 BBB transporters in AD-, Ctrl-, and isogenic iBECs to identify any AD specific differences. We then exposed the cells to focused ultrasound, in the absence (FUSonly) or presence of microbubbles (FUS+MB), to examine whether the expression or activity of key transporters can be modulated by therapeutic ultrasound, a novel technique allowing for transient BBB opening. Results Our results identified differences in the expression of BBB transporters between AD-iBECs and control iBECs, suggesting disease-specific effects on transporter expression. Additionally, our results demonstrated FUSonly and FUS+MB have the potential to modulate efflux transporter activity. Interestingly, AD-iBECs demonstrated significantly reduced PGP-mediated Aβ accumulation following FUS+MB, an effect not seen in Ctrl-iBECs, suggesting disease-related differences. Conclusions Our findings demonstrate that PSEN1 mutant AD-iBECs possess phenotypical differences compared to PSEN1 corrected and unrelated control iBECs in BBB transporter expression and function. Additionally, we show that FUSonly and FUS+MB can modulate the BBB transporter expression and functional activity in iBECs, having potential implications on drug penetration and amyloid clearance. These findings highlight the differential responses of patient cells to FUS treatment, with patient-derived models likely providing an important tool for modelling of therapeutic effects of FUS.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Alzheimer’s disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound

Chaves

Wasielewska

Cuní-López

et al. 2023

Preprint

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“…One of the major limitations of treating brain tumors is the difficulty of delivering drugs to the brain. The brain is surrounded by the blood–brain barrier (BBB), a selective barrier formed by endothelial cells in the cerebral microvessels, which regulates nutrient and ion transport and protects the brain from neurotoxic molecules to maintain brain homeostasis [ 34 ]. Unfortunately, most drugs cannot cross the BBB via physiological pathways due to the extreme selectivity of the barrier, which constitutes the greatest obstacle to systemic treatment for most central nervous system (CNS) diseases.…”

Section: Strategies To Improve Permeability Of Nanocarrier Through the Blood-brain Barriermentioning

confidence: 99%

Nanomedicine in Clinical Photodynamic Therapy for the Treatment of Brain Tumors

Kim

Lee

2022

Biomedicines

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The current treatment for malignant brain tumors includes surgical resection, radiotherapy, and chemotherapy. Nevertheless, the survival rate for patients with glioblastoma multiforme (GBM) with a high grade of malignancy is less than one year. From a clinical point of view, effective treatment of GBM is limited by several challenges. First, the anatomical complexity of the brain influences the extent of resection because a fine balance must be struck between maximal removal of malignant tissue and minimal surgical risk. Second, the central nervous system has a distinct microenvironment that is protected by the blood–brain barrier, restricting systemically delivered drugs from accessing the brain. Additionally, GBM is characterized by high intra-tumor and inter-tumor heterogeneity at cellular and histological levels. This peculiarity of GBM-constituent tissues induces different responses to therapeutic agents, leading to failure of targeted therapies. Unlike surgical resection and radiotherapy, photodynamic therapy (PDT) can treat micro-invasive areas while protecting sensitive brain regions. PDT involves photoactivation of photosensitizers (PSs) that are selectively incorporated into tumor cells. Photo-irradiation activates the PS by transfer of energy, resulting in production of reactive oxygen species to induce cell death. Clinical outcomes of PDT-treated GBM can be advanced in terms of nanomedicine. This review discusses clinical PDT applications of nanomedicine for the treatment of GBM.

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“…Similarly, pharmaceutical applications in brain health are not without obstacles. These include drugs for brain cancer, neurodegenerative diseases, stroke and epilepsy [ 141 ]. Many therapeutics struggle with the restrictive structure of the BBB and attempts are currently being made to functionalise them as nanostructures to overcome poor permeability.…”

Section: Bioavailability and Delivery Of Microalgae Extracts To The T...mentioning

confidence: 99%

Potential Psychoactive Effects of Microalgal Bioactive Compounds for the Case of Sleep and Mood Regulation: Opportunities and Challenges

2022

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Sleep deficiency is now considered an emerging global epidemic associated with many serious health problems, and a major cause of financial and social burdens. Sleep and mental health are closely connected, further exacerbating the negative impact of sleep deficiency on overall health and well-being. A major drawback of conventional treatments is the wide range of undesirable side-effects typically associated with benzodiazepines and antidepressants, which can be more debilitating than the initial disorder. It is therefore valuable to explore the efficiency of other remedies for complementarity and synergism with existing conventional treatments, leading to possible reduction in undesirable side-effects. This review explores the relevance of microalgae bioactives as a sustainable source of valuable phytochemicals that can contribute positively to mood and sleep disorders. Microalgae species producing these compounds are also catalogued, thus creating a useful reference of the state of the art for further exploration of this proposed approach. While we highlight possibilities awaiting investigation, we also identify the associated issues, including minimum dose for therapeutic effect, bioavailability, possible interactions with conventional treatments and the ability to cross the blood brain barrier. We conclude that physical and biological functionalization of microalgae bioactives can have potential in overcoming some of these challenges.

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Drug Delivery Challenges in Brain Disorders across the Blood–Brain Barrier: Novel Methods and Future Considerations for Improved Therapy

Cited by 68 publications

References 196 publications

Alzheimer’s disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound

Alzheimer’s disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound

Nanomedicine in Clinical Photodynamic Therapy for the Treatment of Brain Tumors

Potential Psychoactive Effects of Microalgal Bioactive Compounds for the Case of Sleep and Mood Regulation: Opportunities and Challenges

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