Synthesis of a Diapocynin Prodrug for Its Prolonged Release from Zwitterionic Biodegradable Nanoparticles

Today, neurodegenerative diseases are affecting more and more individuals. A typical therapeutic target to treat the progression of the symptoms related to these diseases is the proinflammatory microglia. Diapocynin, the dimeric version of apocynin, is often the drug of choice. However, suitable carriers for its controlled delivery are currently lacking in the clinics. In fact, its high hydrophilicity hampers the development of a formulation enabling its sustained release in a biological environment. In this work, the possibility of modifying diapocynin is explored in order to synthesize a prodrug that can be chemically incorporated into biodegradable zwitterionic polymer nanoparticles (NPs). These NPs are synthesized via combination of ring opening polymerization and reversible addition–fragmentation chain transfer (RAFT) polymerization, allowing the incorporation of the desired number of diapocynin units into the carrier and thus to set the drug dosage a priori. The chemical binding of diapocynin avoids its premature release compared to its physical loading inside similar nanovectors. With this strategy, sustained diapocynin release can be achieved for more than 9 days, thus paving the way to a therapy with low number of repeated administrations. Diapocynin is demonstrated efficiently for the treatment of neurodegenerative diseases. However, a strategy for its prolonged release is lacking. Here, a diapocynin cross‐linker is synthesized and chemically incorporated in biodegradable polymer nanoparticles. The hydrolysis of the ester bonds allows the release of diapocynin for up to 9 days, outperforming the release devices based on the physical encapsulation of the drug.