Page 75 - AN-4-2

Advanced Neurology Brain bioavailability of targeted protein degraders

of many non-polar ethylene groups and high HBDs. DMSO. In mice, even a low dose of 3 mg/kg of Tween
3
Alternatively, incorporating nitrogen-containing triazole 80/polysorbate-80 can transiently disrupt the BBB, allowing
rings in the linker can improve aqueous solubility due to formulated drugs to cross. An infusion of the non-ionic
159
the electron-donating nitrogen group, which enhances its surfactant Tween 80 helped kyotorphin, an oligopeptide
ability to form hydrogen bonds. On the contrary, rigidified that typically does not penetrate the BBB, to cross and
piperidine and piperazine linkers have demonstrated induce analgesia. Anionic surfactants, such as sodium
160
improved aqueous solubility and permeability due to their lauryl sulfate (also known as sodium dodecyl sulfate, SDS),
constrained conformations while maintaining reasonable are typically included in microquantities in formulations
plasma, chemical, and metabolic stability. targeting CNS indications. Short-term BBB disruption
can be triggered by SDS doses as low as 1.0 g/kg. TPDs
Efforts to increase a TPD’s plasma half-life, such as
linker rigidification and the enhancement of lipophilic can therefore be dissolved in solvents such as ethanol or
DMSO and co-formulated with SDS PEG hydroxystearate,
properties, can amplify its interaction with BBB endothelial which transiently destabilizes membranes and temporarily
cell membranes. However, these modifications may also disrupts the BBB to facilitate brain penetration.
increase its interaction with other endothelial cells in the
body and lead to binding with blood cellular components’ One commonly used formulation excipient,
membranes. Consequently, while CNS exposure may β-cyclodextrin, has been reported to inhibit the
improve, undesirable tissue distribution of the TPD could caveolae-mediated pathway and prevent macromolecular
161
also increase in multiple organs/compartments, potentially substance endocytosis/extravasation through the BBB.
leading to off-target toxicity. However, another study suggests that 2-hydroxypropyl-β-
cyclodextrin may enter endothelial cells. 162
If structural tailoring enhances CNS exposure, it must
be demonstrated beyond a reasonable doubt that decreased Diuretic mannitol has been shown to induce osmotic
hepatic metabolism resulting in reduced plasma clearance shrinking of endothelial cells and disrupt the BBB
and increased systemic presence is not the underlying architecture when infused at a 2M solution through the
163
cause. To establish this, the amount of administered dose carotid arteries. In addition, selective agonists that
(AD) that actually reaches the brain can be compared induce adenosine receptor signaling transiently enhance
across different approaches (% AD/g of brain). BBB permeability, facilitating the entry of otherwise
impermeable macromolecules into the CNS. 164
Generally, drug action in the brain is primarily driven
by the amount of drug uptake, which is measured as % The inhalant anesthetic isoflurane has been reported
AD/g of brain tissue. This depends equally on the plasma to disrupt the membrane lipid nanodomains and trigger
area under the curve and the BBB permeability-surface caveolar transport in brain endothelial cells, thus
area product: augmenting cisplatin delivery to the brain for treating
glaucoma. This disruption is reversible, with the BBB
% AD/g = (BBB-surface area product) × (Plasma area regaining tightness after the cessation of anesthesia.
165
under the curve) Therefore, it should be crucial to evaluate whether the
While the % AD/g of a TPD indicates its ability to observed CNS bioavailability is due to the solvent/
cross the BBB, it is also influenced by TPD’s plasma excipient, high doses of the anesthetic agent, or inherent
concentration. 3 drug properties.
19. Formulation excipients and inhalant 20. The way forward
anesthetic selection for increasing target A high dose of CNS-targeted investigational molecule
protein degraders’ BBB permeability can breach the neurotoxicity threshold, disrupt the
BBB, and exhibit brain bioavailability. It is therefore
Administering TPDs in a vehicle that transiently opens imperative to distinguish between the BBB disruption-
the BBB and facilitates their delivery into the brain triggered penetration and permeability-driven pathways
parenchyma is a plausible strategy for crossing the BBB, by employing the EB dye brain staining approach. Using
particularly in pre-clinical settings. Solvent-mediated the EB dye method, the parenteral dose of optimized CNS-
disruption of the BBB can result from doses of solvents, targeted lead candidates can also be titrated (or kept as low
such as ethanol or dimethyl sulfoxide (DMSO) at levels as possible) to identify the optimal dose for assessing BBB
ranging from 1 – 4 g/kg. 157,158
permeability upon parenteral administration. Further, it
For instance, administering just 50 µl of 50% would be interesting to determine whether XL01126, when
DMSO to a 20 g mouse equates to a dose of 1.25 g/kg of administered at doses as high as 30 mg/kg intraperitoneally

Volume 4 Issue 2 (2025) 69 doi: 10.36922/an.5140