Focused ultrasound-induced blood-brain barrier opening for non-viral, non-invasive, and targeted gene delivery

Lin, Chung-Yin; Hsieh, Han-Yi; Pitt, William G.; Huang, Chiung-Yin; Tseng, I-Fan; Yeh, Chih‐Kuang; Wei, Kuo-Chen; Liu, Hao-Li

doi:10.1016/j.jconrel.2015.06.010

Cited by 79 publications

(53 citation statements)

References 30 publications

(40 reference statements)

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“…~100 nm diameter) non-viral liposomal-based gene vectors [66]. Although transfection efficiency was not reported, luciferase co-localized with neurons and astrocytes [37].…”

Section: Resultsmentioning

confidence: 99%

Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound

Mead

Mastorakos

Suk

et al. 2016

Journal of Controlled Release

131

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Gene therapy holds promise for the treatment of many pathologies of the central nervous system (CNS), including brain tumors and neurodegenerative diseases. However, the delivery of systemically administered gene carriers to the CNS is hindered by both the blood-brain barrier (BBB) and the nanoporous and electrostatically charged brain extracelluar matrix (ECM), which acts as a steric and adhesive barrier. We have previously shown that these physiological barriers may be overcome by, respectively, opening the BBB with MR image-guided focused ultrasound (FUS) and microbubbles and using highly compact “brain penetrating” nanoparticles (BPN) coated with a dense polyethylene glycol corona that prevents adhesion to ECM components. Here, we tested whether this combined approach could be utilized to deliver systemically administered DNA-bearing BPN (DNA-BPN) across the BBB and mediate localized, robust, and sustained transgene expression in the rat brain. Systemically administered DNA-BPN delivered through the BBB with FUS led to dose-dependent transgene expression only in the FUS-treated region that was evident as early as 24 h post administration and lasted for at least 28 days. In the FUS-treated region ~42% of all cells, including neurons and astrocytes, were transfected, while less than 6% were transfected in the contralateral non-FUS treated hemisphere. Importantly, this was achieved without any sign of toxicity or astrocyte activation. We conclude that the image-guided delivery of DNA-BPN with FUS and microbubbles constitutes a safe and non-invasive strategy for targeted gene therapy to the brain.

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“…~100 nm diameter) non-viral liposomal-based gene vectors [66]. Although transfection efficiency was not reported, luciferase co-localized with neurons and astrocytes [37].…”

Section: Resultsmentioning

confidence: 99%

Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound

Mead

Mastorakos

Suk

et al. 2016

Journal of Controlled Release

131

View full text Add to dashboard Cite

show abstract

“…O’Reilly et al investigated the time taken for the BBB to close and the opening volume on the time scale of closure after focused US exposure; no significant differences were detected on MRI between large- and small-volume sonications, suggesting that safe BBB opening can be achieved by US combined with microbubbles 79. Lin et al demonstrated that the BBB can be successfully opened by US-triggered microbubble destruction and thus the delivery of exogenous substances can be significantly improved, although the specific mechanisms are still unclear 80. So far, the following statements can be made: the ARF pushes microbubbles toward the vascular wall and promotes an impact on vascular cells that induces a loose intercellular gap; and microbubbles inside the vasculature can produce microstreams and shock waves, thus compromising the stability of the vascular wall.…”

Section: Immunotherapy Assisted By Ummdmentioning

confidence: 99%

Ultrasound-mediated microbubble destruction: a new method in cancer immunotherapy

Zhang

Jia

et al. 2018

OTT

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Immunotherapy provides a new treatment option for cancer. However, it may be therapeutically insufficient if only using the self-immune system alone to attack the tumor without any aiding methods. To overcome this drawback and improve the efficiency of therapy, new treatment methods are emerging. In recent years, ultrasound-mediated microbubble destruction (UMMD) has shown great potential in cancer immunotherapy. Using the combination of ultrasound and targeted microbubbles, molecules such as antigens or genes encoding antigens can be efficiently and specifically delivered into the tumor tissue. This review focuses on the recent progress in the application of UMMD in cancer immunotherapy.

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“…In this manner, microbubble and DNA complexes were used to markedly enhance the expression of brain-derived neurotrophic factor and enhanced green fluorescence protein in murine brains (Huang et al, 2012a,b). Microbubbles can also be co-administered with liposomal gene carriers to specifically open a region of the BBB by focused US, which uses an acoustic lens to center the US at a specific point (Lin et al, 2015). Co-administration of microbubbles with dense PEG-coated nanoparticles was able to open the BBB and transfect a variety of brain cells for at least 28 days with systemic administration (Nance et al, 2014; Mead et al, 2016).…”

Section: Systemic Deliverymentioning

confidence: 99%

Non-Viral Nucleic Acid Delivery Strategies to the Central Nervous System

Tan

Sellers

Pham

et al. 2016

Front. Mol. Neurosci.

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With an increased prevalence and understanding of central nervous system (CNS) injuries and neurological disorders, nucleic acid therapies are gaining promise as a way to regenerate lost neurons or halt disease progression. While more viral vectors have been used clinically as tools for gene delivery, non-viral vectors are gaining interest due to lower safety concerns and the ability to deliver all types of nucleic acids. Nevertheless, there are still a number of barriers to nucleic acid delivery. In this focused review, we explore the in vivo challenges hindering non-viral nucleic acid delivery to the CNS and the strategies and vehicles used to overcome them. Advantages and disadvantages of different routes of administration including: systemic injection, cerebrospinal fluid injection, intraparenchymal injection and peripheral administration are discussed. Non-viral vehicles and treatment strategies that have overcome delivery barriers and demonstrated in vivo gene transfer to the CNS are presented. These approaches can be used as guidelines in developing synthetic gene delivery vectors for CNS applications and will ultimately bring non-viral vectors closer to clinical application.

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Focused ultrasound-induced blood-brain barrier opening for non-viral, non-invasive, and targeted gene delivery

Cited by 79 publications

References 30 publications

Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound

Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound

Ultrasound-mediated microbubble destruction: a new method in cancer immunotherapy

Non-Viral Nucleic Acid Delivery Strategies to the Central Nervous System

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