Nanoassembled t -Boc-Amino Acid Conjugate of Sulfapyridine for Potentiated Rheumatoid Arthritis Management

Sulfapyridine (SP), a second-line therapeutic agent for rheumatoid arthritis (RA), exhibits limited clinical utility due to its suboptimal physicochemical characteristics and high systemic toxicity. To overcome these limitations, a rational prodrug design strategy was employed, involving the conjugation of SP to tert -butoxycarbonyl (Boc)-protected natural amino acids, i.e., glycine, alanine, leucine, and proline via enzyme- and pH-sensitive amide linkages. The synthesized t -Boc-protected amino acid prodrugs were structurally characterized, and their susceptibility to hydrolysis/bioconversion to release the parent drug was evaluated in different milieus such as buffers, enzymes, human plasma, and synovial fluid. To further address pharmacokinetic challenges and enhance drug retention in arthritic joints, self-assembled nanoparticles were fabricated by using a kinetic trapping approach. Among the synthesized prodrugs, the SP-leucine (SP-Leu) conjugate exhibited the most favorable self-assembly characteristics, forming nanostructures with an average particle size of 181.2 nm, a polydispersity index of 0.28, and a zeta potential of −31.76 mV, indicating good colloidal stability. A single intra-articular administration of SP-Leu nanoparticles to adjuvant-induced arthritic rats mitigated inflammatory arthritis remarkably, thereby demonstrating prolonged retention at the inflamed site, sustained therapeutic efficacy, and reduced dosing frequency. Collectively, these findings highlight amino-acid-conjugated prodrug nanoassemblies as a promising platform to improve the therapeutic index of SP and provide a safer, more effective treatment modality for RA.