Abstract

Efficient delivery of hydrophobic drugs remains a significant challenge, often hindered by poor distribution within aqueous bloodstreams. Current medical literature shows that over 40% of all drugs in clinical use are hydrophobic, and 90% or more of newly developed drugs are described as Class II (high permeability, low solubility), or Class IV (low permeability, low solubility). Carbon dots (CDs) offer a promising solution as drug delivery vehicles due to their aqueous dispersibility, generally low cytotoxicity and ease of surface functionalization. Traditional conjugation methods widely rely on covalent bonds such as amide bonds, which are robust but difficult to cleave, hindering drug release. Furthermore, their formation often requires expensive and hazardous coupling agents such as 1-Ethyl-3-(3-dimethylaminoporpyl)carbodiimide. Herein and to the best of our knowledge, we report for the first time, the solid-state mechanochemical formation of imine bonds to conjugate a hydrophobic model drug to the surfaces of CDs. Initial efforts focused on solution-based conjugation before transitioning to mechanochemistry, which was ultimately successful. 1H-NMR analysis confirmed successful formation of imine bond linkages through the conversion of an aldehyde into an imine functional group without the need for a solvent, or any additional reagents. Additionally, release of the model drug was achieved reaching a plateau after 24 hours. A preliminary resazurin cytotoxicity assay demonstrated the low cytotoxicity of the CDs before and after altering the surfaces with imine bonds. Our findings highlight a straightforward and sustainable method for CD functionalization, paving the way for alternative covalent linkages and greener conjugation strategies.