1.D.255. The Pyran Nitrile Blood-Brain Barrier Microtubule-mediated Transcytosis (PN-BBB-MTC) Family
The blood–brain barrier (BBB) serves as a vital checkpoint in neuropharmacology, safeguarding the central nervous system (CNS) from potentially harmful substances while also presenting a formidable barrier to therapeutic agents. The CNS is effectively safeguarded by physiological barriers, specifically the BBB and the blood–cerebrospinal fluid barrier. The BBB’s selective permeability is governed by brain microvascular endothelial cells (BMECs), which exhibit a phenotype that is finely tuned to the CNS environment. BBB is impermeable to many molecules, with less than 2% of most drugs reaching the CNS, by creating continuous tight junctions and overexpressing several types of molecular efflux pumps. This results in a barrier that is virtually impenetrable to most molecules, including a vast majority of pharmaceutical compounds (Zhang et al. 2024).
Nanotechnology has led to the emergence of various types of nanomaterials that are being considered as promising carriers. Many approaches including functionalized nanocarriers were widely used to transport drugs and other molecules (such as nucleic acids, proteins, or imaging agents) across the BBB (Tang et al. 2019). The types of nanoparticles (NPs) were categorized as inorganic-based nanocarriers, polymer-based, and biomimetic-based [Tan et al. 2022]. The further application of brain drug delivery is still limited by the large size of NPs, poor targeting efficacy, and difficulties in production.
In the past few decades, numerous therapeutic delivery strategies have been demonstrated to effectively transport drug molecules across the BBB (Tran et al. 2022). Among these strategies, modification of drug molecules has exhibited promising potential. Among the available CNS drugs, small molecules constitute the majority of successful CNS therapeutics owing to their capacity to traverse the BBB via passive or carrier-mediated mechanisms (Dichiara et al. 2024). Hydrophobic molecules with small molecular weight and suitable lipophilicity can penetrate the BBB through simple diffusion. For instance, curcumin-like analogs CRANAD, BODIPY-based small molecules, and cyanine-like DANIR probes all exhibit high BBB permeability. It may be a hydrophobic substance that is not easily administered intravenously. Although among several classes of substances capable of penetrating the BBB, the capillary permeability of small polarity molecules decreased by over 2 orders of magnitude when compared to other organs. Small molecules preserve exclusive advantages in CNS diseases, including ability to balance aqueous and lipid solubility (Nance et al. 2022).
The ligand-modified NPs can respond to receptors and increase BBB permeability better than NPs without modification. Among the various strategies to ferry drugs across the BBB, mesoporous silica NPs (MSNs) have emerged as a versatile platform due to their biocompatibility, tunable pore size, and surface modification capabilities (Chen et al. 2022). When conjugated with our novel compounds, these MSNs are designed to leverage the active transport mechanisms of the BBB. The compounds act as targeting agents that enhance the MSNs’ ability to navigate the complex vascular landscape of the CNS, enabling them to cross the BBB efficiently (Attia et al. 2023).
Zhang et al. 2024 focused on the design and application of 3 red-emissive, 2-photon excitable dicyanyle derivatives (BN, BN1, and BN2) for active CNS targeting. The water-soluble derivative BN1, in particular, demonstrated a rapid internalization with brain BMECs and effective penetration of a 3-dimensional (3D) BBB cell model. This is primarily facilitated by microtubule-mediated active transcytosis, a mechanism that we found to be substantially enhanced by the presence of BN1-functionalized MSNs. These findings are pivotal, as they illustrate a synergistic effect where the MSNs, aided by the BN1 compound, can cross the BBB and deliver therapeutic agents directly to the CNS.
In vivo studies reinforce the potential of this approach, with BN1-functionalized MSNs showing the ability to cross brain capillaries and localize within multiple brain regions. This work not only demonstrates the active transport capabilities of hydrophilic small molecules but also underscores the role of MSNs as a critical vehicle in CNS drug delivery. Zhang et al. 2024 thus provide evidence that a combination of hydrophilic small molecules and MSNs can be effectively used for targeted therapeutic delivery across the BBB