Page 9 - JCTR-11-2

Journal of Clinical and
Translational Research US-mediated drug delivery

further contributes to the exclusion of these therapeutics diseases [MeSH terms]) AND (‘English’[language]). The
by transporting them out of the brain tissue and back into search terms for the ClinicalTrials.gov database were:
the bloodstream. 6 ‘blood–brain barrier opening’ AND ‘drug delivery’ AND
The integrity and various functions of the BBB are ‘ultrasound’ AND ‘microbubbles OR nanodroplets’ AND
often compromised in many brain diseases, for example, ‘neurodegenerative diseases’. The inclusion and exclusion
due to neuroinflammation. Such BBB disruptions are criteria are summarized in Table 1. The results of our
7-9
the consequences of disease progression. The increase in database analysis are presented in Figure 2.
BBB permeability observed in Alzheimer’s and PDs is 3. Acoustically mediated drug delivery
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positively correlated with improved i.c. bioavailability of using microbubbles and NDs
therapeutic molecules, although it still fails to reach an
efficient therapeutic dose. The intra-individual and inter- The great interest in acoustically mediated drug delivery
individual heterogeneity of these BBB disruptions might using MBs and NDs for the treatment of brain disorders,
explain this observation. In this context, the design and particularly neurodegenerative diseases, is clearly reflected
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validation of targeted drug delivery systems are needed in the increasing number of publications in this field, as
to increase the i.c. dose of therapeutic molecules while shown in the histogram chart in Figure 3. This US modality
minimizing off-target effects. induces transient, efficient, and safe permeabilization of
the BBB, thereby enhancing the extravasation and the i.c.
For several decades, the scientific community has been 22-25
developing safe and efficient methods for i.c. delivery of bioavailability of therapeutics (Figure 4). . The resulting
increase in the i.c. dose of therapeutics improves their
therapeutic molecules. These methods can be classified therapeutic efficacy while minimizing their off-target
into two categories: (1) the invasive methods, which effects on healthy tissues. Hynynen et al. 26,27 were the first
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require surgical interventions to insert i.c. implants or to report BBB disruption in a rabbit model without causing
microchips or to perform intraventricular and intrathecal neuronal damage.
infusions; (2) the non-invasive methods, which rely on
either biochemical agents (e.g., mannitol, vasoactive As described below, MBs and NDs can also act as
agents, etc.) or physical agents (e.g., electric field, sonoresponsive drug carriers, releasing their payload
magnetic field, etc.) to transiently disrupt the BBB, or specifically in the target tissue under US action. Furthermore,
on genetic/chemical modifications (e.g., fusion proteins, these sonoresponsive particles can be functionalized
cell-penetrating peptides, etc.) of therapeutics or the use with targeting agents to bind membrane biomarkers that
of biopharmaceutical vectors (e.g., nanoparticles, Trojan are overexpressed on target cells (e.g., endothelial and
horses, viral vectors, etc.) to deliver molecules through the cerebral cells, etc.), thereby improving the specificity of
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BBB’s native transport pathways. 13-16 Among these drug therapeutic delivery. This US modality is non-invasive,
delivery methods, acoustically mediated drug delivery easy to apply, and cost-effective, making it a viable method
using microbubbles (MBs) or nanodroplets (NDs) is a for i.c. delivery of a wide range of therapeutics, including
promising modality for the non-invasive and targeted chemotherapeutics, monoclonal antibodies, nucleic acids,
delivery of therapeutic molecules into brain tissues. 17-21 viral vectors, stem cells, and immune cells. The technique
is typically guided by magnetic resonance imaging (MRI)
In this review, we will first discuss the different and monitored using passive cavitation detection devices
approaches using MBs and NDs in combination with (PCD). Therapeutic delivery can be triggered on demand
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ultrasound (US). We will then review pre-clinical and and precisely controlled spatially and temporally by US
clinical studies employing this strategy for the treatment focusing and directed propagation. In this section, we
of neurodegenerative diseases, including its efficacy, safety, will describe MBs and NDs, including their composition,
limitations, and future prospects.
2. Methods Table 1. Inclusion and exclusion criteria used to select studies
The electronic databases PubMed and ClinicalTrials.gov Inclusion criteria Exclusion criteria
®
were screened using pre-defined search dates (January 1995 In vivo In silico, In vitro
– July 2024) and terms related to i.c. drug delivery using Original article Review papers, comments, and letters
microbubbles/NDs-assisted US for brain diseases. The Efficacity, bioavailability, safety Neuropsychiatric disorders,
BBB opening and drug delivery Neurooncological diseases
search terms for the PubMed database were: (BBB opening Neurodegenerative diseases Drug delivery with US only
®
[MeSH terms]) AND (drug delivery [MeSH terms]) MB/ND-assisted US Other languages
AND (US [MeSH terms]) AND (microbubbles [MeSH English
terms] OR NDs [MeSH terms]) AND (neurodegenerative Abbreviations: MB: Microbubble; ND: Nanodroplet; US: Ultrasound.

Volume 11 Issue 2 (2025) 3 doi: 10.36922/jctr.24.00061