Page 17 - JCTR-11-2

Journal of Clinical and
Translational Research US-mediated drug delivery

Present pharmacological treatments do not address the treated mice were notably improved compared to antibody
underlying causes of the disease (curative) but instead treatment alone. 61,85
alleviate the symptoms (palliative) by acting primarily on Preclinical studies have shown the potential of
acetylcholinesterase and N-methyl-D-aspartate (NMDA) MB-assisted US for delivering therapeutics in AD.
receptors. Numerous experimental molecules, including For instance, MB-assisted US using a lab-made device
those targeting Aβ or tau accumulation, are under (1 MHz, 10 Hz PRF, 0.7 MPa, 10 ms pulse duration, DC
investigation for AD. 81,82 However, the results of recent 10%, for 6 s) with lab-made lipid-shelled MBs effectively
clinical trials have been less promising than pre-clinical delivered the 2N tau isoform-specific single chain antibody
findings, with many therapeutics failing to reach their fragment (RN2N) across the forebrain of P301L human tau
brain targets. This is due not only to their physicochemical transgenic pR5 mice. 91,92 This approach improved the i.c.
and pharmacological properties but also to the presence bioavailability of RN2N compared to the RN2N treatment
of biological barriers. To overcome these challenges, alone, resulting in reduced anxiety-like behavior. Similarly,
specialized US protocols have been designed and validated a novel tau-specific monoclonal antibody (RNF5) was
in pre-clinical and clinical studies to facilitate the delivery delivered by MB-assisted US to the forebrain of the
of therapeutics using MB/ND-assisted US.
K369I tau transgenic K3 mouse model. Although i.c.
93
5.2. Pre-clinical phase bioavailability was improved with the US, no behavioral
improvement was observed in these mice. In addition, Liu
Several pre-clinical studies have demonstrated the et al. evaluated the delivery of quercetin, an antioxidant
84
feasibility, safety, and efficacy of MB-assisted US for and anti-inflammatory molecule, using MB-assisted US.
reversible BBB opening in various transgenic murine Quercetin was loaded onto lab-made MBs, which were
models of AD, including APP/PS1dE9, 63,83-86 PDAPP, intravenously injected, followed by exposure of the parietal
83
TgCRND8, 87-89 5xFAD, 61,90 pR5, 91,92 and K3. For instance, cortex in APP/PS1 mice to US waves (1 MPa for 5 min)
93
Choi et al. investigated BBB opening in three transgenic using a lab-made US device. MB-assisted US facilitated
63
APP/PS1 mice and three wild-type mice using an BBB opening, quercetin release, and its i.c. accumulation.
acoustically mediated US approach. After an i.v. injection Quercetin treatment significantly reduced neuronal
of SonoVue (25 µL), the left hippocampus was exposed apoptosis, neuroinflammation, calcium homeostasis
®
to US waves (1.525 MHz, 20% duty cycle (DC), 20 ms variation, and oxidative stress, ultimately enhancing learning
pulse duration, 0.6 MPa) for 1 min using a lab-made and memory capacities in AD mice.
MRgFUS device. DCE-MRI revealed that MB-assisted
62
MRgFUS successfully induced reversible BBB opening in Furthermore, Gouveia et al. explored ND-assisted US
the hippocampus of both wild-type and AD mice without (lab-made US device; 2 MPa, 10 ms bursts, 1 Hz, for 180 s)
causing any tissue damage. Similarly, Burgess et al. to deliver the anesthetic pentobarbital into the amygdala
87
validated these findings in TgCRND8 transgenic mice. of TgCRND8 transgenic mice to achieve neuromodulation
®
Collectively, these studies underscore that MB-assisted US (Table 4). The NDs were composed of Definity MB shells
can safely and reversibly open the BBB in mouse models and loaded with pentobarbital. ND vaporization did not
of AD. disrupt the BBB, but the released lipophilic pentobarbital
crossed the BBB, localizing the therapeutic effect to
In addition, MB-assisted MRgFUS has facilitated the the target area. Pentobarbital-loaded NDs significantly
delivery of various therapeutics in AD mouse models, improved agitation and aggressive behavior in AD mice
including full-size antibodies and antibody fragments compared to unloaded NDs. However, only behavioral
targeting Aβ, 61,83,85,86,88-90 or tau, 91-93 as well as antioxidant tests were conducted. Further studies assessing the brain
and anti-inflammatory molecules. Regardless of the drug bioavailability with or without ND-assisted US are
84
US protocol or the MBs used, MB-assisted MRgFUS needed.
significantly increased the i.c. the concentration of anti-Aβ
antibodies (e.g., BAM-10, IVIg, Aducanumab, anti-pGlu3 Collectively, these findings underscore the promise of
Aβ, anti-Aβ 1–40 ,) in the hippocampus of AD mice compared MB/ND-assisted MRgFUS as an innovative modality for
to antibody treatment alone. 61,83,85,86,88-90 These antibodies delivering therapeutics to treat AD.
bound to Aβ plaques, activated phagocytic microglia,
and increased the number of astrocytes associated with 5.3. Clinical phase
Aβ plaques, 61,85,86 leading to a significant reduction in Aβ Recent clinical investigations have explored the feasibility,
plaque load in the hippocampus. 61,85,88,89 Furthermore, this safety, and efficacy of acoustically mediated BBB opening
therapeutic strategy significantly enhanced hippocampal and therapeutic delivery in AD patients. Three clinical trials
neurogenesis. 61,85,88,89 As a result, cognitive functions in demonstrated the feasibility, reproducibility, safety, and

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