LAUSR

BACKGROUND Ruthenium complexes (RAPTA-C), which are promising anti-metastasis drugs, display enhanced chemotherapeutic efficacy when delivered in a drug delivery system based on polymeric micelles. However, the tedious synthesis process and the difficulty to control the size of the RAPTA-C loaded micelles limited their application in cancer treatment. Using nanocellulose as the reactive scaffold instead of micelles allows access to non-spherical nanoparticles that are readily available, biocompatible, and biodegradable. By grafting polymers with conjugated ruthenium drugs onto nanocellulose, a versatile system can be created where the concentration of drugs can be easily varied. To increase the activity of the macromolecular ruthenium drugs, it is desirable to include a mechanism that allows cleavage of the polymer from the nanocellulose. Thus, boronic ester was used as a linker between polymer and nanocellulose to provide pH--triggered release. METHODS First, nanocellulose was prepared via mechanically assisted TEMPO-mediated oxidation. The carboxylic acid groups on the surface of nanocellulose were then reacted with aminophenylboronic acid to achieve the boronic acid modification. On the other hand, RAPTA-C was conjugated through a substitution reaction to the PEG polymer bearing diol end functionality. By using 2-[[(4-Methylphenyl) sulfonyl] oxy] ethyl 2-propenoate as the leaving group could achieve a convenient drug conjugation. Then, RAPTA-C polymer was attached to nanocellulose through the formation of boronated linkages. RESULTS The successful drug conjugation was determined via NMR, and the polymer attachment to cellulose was confirmed by IR and TGA. It was observed that nanocellulose was successfully modified with synthetic PEG polymer with 0.412% grafting efficiency. Moreover, the as-prepared particles contained a 3.6 times higher concentration (87.2 μΜ) of ruthenium drugs compared to earlier prepared polylactide micelles. CONCLUSION The combination of nanocellulose and the attachment of macromolecular drugs by boronic ester formation represents a promising platform to deliver ruthenium. The system displays improved drug loading efficiency compared to already-reported polymeric micelles. As the designed carrier system is aimed for its use in metastasis cancer treatment, the presence of boronic ester linkage between drug and carrier gives rise to the pH-responsive release of therapeutics. Our formulation offers the opportunity to modify the biocompatible drug carrier nanocellulose with various bioactive polymers quickly and efficiently while allowing release in an acidic tumour environment.