Nanoassemblies of Self-Immolative Boronate-Bridged Retinoic Acid Dimeric Prodrug as a Clot-Targeted Self-Deliverable Antithrombotic Nanomedicine

Abstract

All trans-retinoic acid (atRA) has potent antiinflammatory and antiplatelet activity, but its clinical translation as an antithrombotic drug has been hampered by its low therapeutic efficacy. Here, we describe a facile and elegant strategy that converts atRA into systemically injectable antithrombotic nanoparticles. The strategy involves the dimerization of two atRA molecules using a self-immolative boronate linker that is cleaved specifically by hydrogen peroxide (H 2 O 2 ) to release anti-inflammatory hydroxybenzyl alcohol (HBA), followed by dimerization-induced self-assembly to generate colloidally stable nanoparticles. The boronated atRA dimeric prodrug (BRDP) could form injectable nanoparticles in the presence of fucoidan that serves as an emulsifier and a targeting ligand to P-selectin overexpressed on the damaged endothelium. In response to H 2 O 2 , fucoidan-decorated BRDP (f-BRDP) nanoassemblies dissociate to release both atRA and HBA, while scavenging H 2 O 2 . In a mouse model of ferric chloride (FeCl 3 )-induced carotid arterial thrombosis, f-BRDP nanoassemblies target the thrombosed vessel and significantly inhibit thrombus formation. The results demonstrate that dimerization of atRA molecules via a boronate linker enables the formation of stable nanoassemblies with several benefits: high drug loading, drug self-delivery, on-demand multiple antithrombotic actions, and simple fabrication of nanoparticles. Overall, this strategy provides a promising expedient and practical route for the development of translational self-deliverable antithrombotic nanomedicine.

Boronate Ester Hydrogels for Biomedical Applications: Challenges and Opportunities

“…Upon exposure to ROS and following deboronation, a PBA ester-linked molecule is converted to a phenol ester-linked molecule that can then rearrange and free the molecule of interest. Initially developed for peroxide detection, the so-called self-immolative boronic acid linker has been used for the delivery of an antithrombotic drug (i.e., all-trans retinoic acid) from nanoparticles in response to ROS . It holds great potential for the design of ROS-responsive drug delivery systems based on BE hydrogels.…”

Marine biomaterials in biomedical nano/micro-systems

“…In addition, fucoidan has been reported to inhibit intracellular inflammatory cascades and slow down inflammatory tissue damage by inhibiting the activation of the NF-κB, MAPK, and Akt signal pathways. This also offers potential synergistic therapeutic effects while facilitating the active targeting of fucoidan-based nanomaterials [ 160 , 161 ]. Fucoidan-based and fucoidan-coated nanomaterials were designed based on the specificity of fucoidan ligands to P-selectin receptors in order to target endogenous and stimulus-induced overexpressed P-selectin [ 162 – 165 ].…”

The effect of lengths of branched-chain fatty alcohols on the efficacy and safety of docetaxel-prodrug nanoassemblies

“…Carrier-free nanoassemblie technology is expected to reduce chemotherapy toxicity through targeted delivery and avoid the safety risks caused by the use of carrier materials 17 . Carrier-free nanoassemblie usually includes pure drug nanoassemblies, prodrug nanoassemblies, and so on 18 , 19 , 20 , 21 , 22 , 23 , 24 . Pure drug nanoassemblies refer to the self-assembly of only drugs, which is characterized by good safety without the use of carriers.…”