scholarly journals Non-Invasive Delivery of Therapeutics into the Brain: The Potential of Aptamers for Targeted Delivery

Biomedicines ◽  
2020 ◽  
Vol 8 (5) ◽  
pp. 120 ◽  
Author(s):  
Bakhtiar Bukari ◽  
Rasika M. Samarasinghe ◽  
Jinjutha Noibanchong ◽  
Sarah L. Shigdar
Keyword(s):  
Brain Tissue ◽  
Targeted Delivery ◽  
Focused Ultrasound ◽  
Circulatory System ◽  
Non Invasive ◽  
Therapeutic Delivery ◽  
Macromolecular Drugs ◽  
Efficient Delivery ◽  
Alternative Delivery ◽  
The Brain

The blood-brain barrier (BBB) is a highly specialised network of blood vessels that effectively separates the brain environment from the circulatory system. While there are benefits, in terms of keeping pathogens from entering the brain, the BBB also complicates treatments of brain pathologies by preventing efficient delivery of macromolecular drugs to diseased brain tissue. Although current non-invasive strategies of therapeutics delivery into the brain, such as focused ultrasound and nanoparticle-mediated delivery have shown various levels of successes, they still come with risks and limitations. This review discusses the current approaches of therapeutic delivery into the brain, with a specific focus on non-invasive methods. It also discusses the potential for aptamers as alternative delivery systems and several reported aptamers with promising preliminary results.

scholarly journals Pulsed Focal ultrasound as a non-invasive method to deliver exosomes in the brain/stroke

2021 ◽  
Author(s):  
Ahmet Alptekin ◽  
Mohammad B Khan ◽  
Roxan Ara ◽  
Mohammad H Rashid ◽  
Fengchong Kong ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Focused Ultrasound ◽  
Biological Fluids ◽  
Brain Structures ◽  
Non Invasive ◽  
Study Results ◽  
Invasive Method ◽  
Pulsed Focused Ultrasound ◽  
Brain Stroke ◽  
The Brain

AbstractExosomes, a component of extracellular vesicles are shown to carry important small RNAs, mRNAs, protein, and bioactive lipid from parent cells and are found in most biological fluids. Investigators have demonstrated the importance of mesenchymal stem cells (MSCs) derived exosomes in repairing stroke lesions. However, exosomes from endothelial progenitor cells (EPCs) have not been tested in any stroke model nor has there been an evaluation of whether these exosomes target/home to areas of pathology. Targeted delivery of IV administered exosomes has been a great challenge and a targeted delivery system is lacking to deliver naïve (unmodified) exosomes from EPCs to the site of interest. Pulsed focused ultrasound (pFUS) is being used for therapeutic and experimental purposes. There has not been any report showing the use of pulsed low-intensity pFUS to deliver exosomes to the site of interest in models of stroke. In this proof of principle study, we have shown different parameters of pFUS to deliver exosomes in the intact and stroke brain with or without IV administration of nanobubbles. The study results showed that administration of nanobubbles is detrimental to the brain structures (micro bleeding and white matter destruction) at peak negative pressure (PNP) of >0.25 MPa, despite enhanced delivery of IV administered exosomes. However, without nanobubbles, pFUS PNP = 1 to 2 MPa enhances the delivery of exosomes in the stroke area without altering the brain structures.

scholarly journals Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mehmet S. Ozdas ◽  
Aagam S. Shah ◽  
Paul M. Johnson ◽  
Nisheet Patel ◽  
Markus Marks ◽  
...  
Keyword(s):  
Focused Ultrasound ◽  
Drug Carriers ◽  
Mri Contrast Agents ◽  
Mri Contrast ◽  
Systemic Injection ◽  
Non Invasive ◽  
Brain Circuits ◽  
Cavitation Detection ◽  
The Brain ◽  
Target Effects

Abstract Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier’s cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry.

scholarly journals Pulsed Focal Ultrasound as a Non-Invasive Method to Deliver Exosomes in the Brain/Stroke

2021 ◽  
Vol 17 (6) ◽  
pp. 1170-1183
Author(s):  
Ahmet Alptekin ◽  
Mohammad B. Khan ◽  
Roxan Ara ◽  
Mohammad H. Rashid ◽  
Fengchong Kong ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Targeted Delivery ◽  
Focused Ultrasound ◽  
Biological Fluids ◽  
Brain Structures ◽  
Endothelial Progenitor ◽  
Study Results ◽  
Pulsed Focused Ultrasound ◽  
The Brain

Exosomes, a component of extracellular vesicles, are shown to carry important small RNAs, mRNAs, protein, and bioactive lipid from parent cells and are found in most biological fluids. Investigators have demonstrated the importance of mesenchymal stem cells derived exosomes in repairing stroke lesions. However, exosomes from endothelial progenitor cells have not been tested in any stroke model, nor has there been an evaluation of whether these exosomes target/home to areas of pathology. Targeted delivery of intravenous administered exosomes has been a great challenge, and a targeted delivery system is lacking to deliver naïve (unmodified) exosomes from endothelial progenitor cells to the site of interest. Pulsed focused ultrasound is being used for therapeutic and experimental purposes. There has not been any report showing the use of low-intensity pulsed focused ultrasound to deliver exosomes to the site of interest in stroke models. In this proof of principle study, we have shown different parameters of pulsed focused ultrasound to deliver exosomes in the intact and stroke brain with or without intravenous administration of nanobubbles. The study results showed that administration of nanobubbles is detrimental to the brain structures (micro bleeding and white matter destruction) at peak negative pressure of >0.25 megapascal, despite enhanced delivery of intravenous administered exosomes. However, without nanobubbles, pulsed focused ultrasound enhances the delivery of exosomes in the stroke area without altering the brain structures.

scholarly journals Focused Ultrasound for Increased Delivery of Intranasal DNA Nanoparticles to Rat Brain

2018 ◽  
Author(s):  
Barbara L. Waszczak ◽  
Nathan McDannold ◽  
Mark J. Cooper
Keyword(s):  
Transgene Expression ◽  
Viral Vectors ◽  
Focused Ultrasound ◽  
Route Of Administration ◽  
Viral Gene ◽  
Dna Nanoparticles ◽  
Non Invasive ◽  
Treatment Conditions ◽  
Cellular Transfection ◽  
The Brain

We will investigate whether focused ultrasound (FUS) can increase delivery to the brain of a non-viral gene vector given by the intranasal route of administration. Aim 1 will examine different FUS treatment conditions to determine if FUS can increase total plasmid DNA nanoparticle (NP) delivery and transgene expression in the sonicated regions, the rat substantia nigra and striatum, two brain areas involved in Parkinson's Disease (PD). Aim 2 will test whether FUS improves tissue penetration and alters cellular transfection patterns in the sonicated regions following intranasal doses of DNA NPs. If successful, FUS may enable agents with poor capabilities of crossing the blood-brain barrier (BBB), e.g. neurotrophic factors, viral and non-viral vectors encoding them, to become disease-altering therapies by a non-invasive route of administration.

scholarly journals Modulated focused ultrasound for treatment of de-myelinating axons in multiple sclerosis lesions – pilot animal studies

2018 ◽  
Author(s):  
Pierre D. Mourad
Keyword(s):  
Multiple Sclerosis ◽  
Mouse Model ◽  
Brain Tissue ◽  
Neurological Disorders ◽  
Animal Studies ◽  
Focused Ultrasound ◽  
Neural Circuits ◽  
Laser Light ◽  
Non Invasive ◽  
Pulsed Focused Ultrasound

Multiple sclerosis is a debilitating disease whose symptoms arise from de-myelination of axons within brain tissue with an attendant loss of central and peripheral function. We among others have shown that transcranial delivery of pulsed focused ultrasound (pFU) can non-destructively activate central neural circuits. Others have shown enhanced myelin remodeling of axons activated by laser light in an optogenetic mouse model. We hypothesize that pFU activation of axons within MS lesions in a rodent model will decrease their de-myelination and increase their re-myelination. If successful, this non-invasive therapy may lead to rapid advancements in the treatment of MS and other de-myelinating neurological disorders.

scholarly journals Sono-optogenetics facilitated by a circulation-delivered rechargeable light source for minimally invasive optogenetics

2019 ◽  
Vol 116 (52) ◽  
pp. 26332-26342 ◽  
Author(s):  
Xiang Wu ◽  
Xingjun Zhu ◽  
Paul Chong ◽  
Junlang Liu ◽  
Louis N. Andre ◽  
...  
Keyword(s):  
Minimally Invasive ◽  
Visible Light ◽  
Optical Fibers ◽  
Focused Ultrasound ◽  
Circulatory System ◽  
Light Sources ◽  
Light Emitters ◽  
Subtype Specificity ◽  
The Brain

Optogenetics, which uses visible light to control the cells genetically modified with light-gated ion channels, is a powerful tool for precise deconstruction of neural circuitry with neuron-subtype specificity. However, due to limited tissue penetration of visible light, invasive craniotomy and intracranial implantation of tethered optical fibers are usually required for in vivo optogenetic modulation. Here we report mechanoluminescent nanoparticles that can act as local light sources in the brain when triggered by brain-penetrant focused ultrasound (FUS) through intact scalp and skull. Mechanoluminescent nanoparticles can be delivered into the blood circulation via i.v. injection, recharged by 400-nm photoexcitation light in superficial blood vessels during circulation, and turned on by FUS to emit 470-nm light repetitively in the intact brain for optogenetic stimulation. Unlike the conventional “outside-in” approaches of optogenetics with fiber implantation, our method provides an “inside-out” approach to deliver nanoscopic light emitters via the intrinsic circulatory system and switch them on and off at any time and location of interest in the brain without extravasation through a minimally invasive ultrasound interface.

INNV-36. NON-INTRUSIVE, NON-INVASIVE AND PATIENT FRIENDLY FOCUSED ULTRASOUND DEVICE AS A DELIVERY VEHICLE FOR CNS TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi113-vi113
Author(s):  
Bhaskar Ramamurthy ◽  
Mallika Keralapura ◽  
John Marshall ◽  
Daniel Need ◽  
Ryan Dittamore ◽  
...  
Keyword(s):  
Focused Ultrasound ◽  
Unmet Need ◽  
Cancer Therapeutics ◽  
Preclinical Study ◽  
Extensive Study ◽  
Large Animal ◽  
Ultrasound Transducers ◽  
Non Invasive ◽  
The Us ◽  
The Brain

Abstract A major impediment to treatment of brain cancers is the inability to transport drugs across the blood-brain barrier (BBB). The development of an effective, targeted, and non-invasive method to penetrate the BBB to deliver cancer therapeutics is an unmet need in the treatment of brain cancers. Large molecular weight chemo- and immuno-therapies such as doxorubicin and others may be potentially effective against brain cancers if such drugs are sufficiently bioavailable in the brain. Focused ultrasound techniques can safely and transiently open the BBB but current techniques require invasive/intrusive or expensive and high-touch procedures and are not optimal for wide adoption. To address this unmet need, we are developing an innovative technique to non-intrusively, non-invasively and transiently open the BBB in a specified location within the brain using guided ultrasound (US). Our device consists of a proprietary US generator that is controlled by a highly portable system that has a small physical footprint, enabling the US generator and system to be placed in confined spaces such as chemotherapy infusion centers. The US generator is cap-shaped device that is placed on a patient’s head that includes multiple sets of ultrasound transducers that are distributed within the cap according to the anatomy of the skull. With our proprietary technique, we calculate the position of the cap in relation to the internal anatomy in a real-time manner and in a non-intrusive and a non-invasive manner. We have recently concluded an extensive study that resulted in algorithms that can accurately guide the US to various targets within the brain across a spectrum of patients. We also have completed a pilot preclinical study on a large animal demonstrating our ability to open the BBB non-invasively and deposit a drug proxy (gadolinium and Evans Blue).

scholarly journals Active Targeting Towards and Inside the Brain based on Nanoparticles: A Review

2020 ◽  
Vol 21 (5) ◽  
pp. 374-383 ◽  
Author(s):  
Morteza Rabiei ◽  
Soheila Kashanian ◽  
Seyedeh S. Samavati ◽  
Shahriar Jamasb ◽  
Steven J.P. McInnes
Keyword(s):  
Brain Tissue ◽  
Targeted Delivery ◽  
Neurological Diseases ◽  
Surgical Techniques ◽  
Research Area ◽  
Ideal Condition ◽  
Capillary Endothelial Cells ◽  
Pass Through ◽  
The Brain ◽  
The Ideal

Background: Treatment of neurological diseases using systemic and non-surgical techniques presents a significant challenge in medicine. This challenge is chiefly associated with the condensation and coherence of the brain tissue. Methods: The coherence structure of the brain is due to the presence of the blood-brain barrier (BBB), which consists of a continuous layer of capillary endothelial cells. The BBB prevents most drugs from entering the brain tissue and is highly selective, permitting only metabolic substances and nutrients to pass through. Results: Although this challenge has caused difficulties for the treatment of neurological diseases, it has opened up a broad research area in the field of drug delivery. Through the utilization of nanoparticles (NPs), nanotechnology can provide the ideal condition for passing through the BBB. Conclusion: NPs with suitable dimensions and optimum hydrophobicity and charge, as well as appropriate functionalization, can accumulate in the brain. Furthermore, NPs can facilitate the targeted delivery of therapeutics into the brain areas involved in Alzheimer’s disease, Parkinson’s disease, stroke, glioma, migraine, and other neurological disorders. This review describes these methods of actively targeting specific areas of the brain.

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