To convert Lenvatinib into a polymerizable prodrug monomer, we synthesize a molecule with the same structure, except with an imidazole functionality instead of the original amide unit. We approach this prodrug synthesis by using 6-bromo-4-chloro-7-methoxyquinoline instead of 4chloro-7-methoxyquinoline-6-carboxamide, which is typically used and provides the amide functionality (see Figure ). 6-Bromo-4-chloro-7-methoxyquinoline is reacted with an Nmethylimidazole moiety using Stille coupling, to incorporate the polymerizable imidazole units (see 1 in Figure ). In analogy to the conventional Lenvatinib synthesis, we then couple our pro-moiety functionalized quinoline 1 to the 4-hydroxyphenyl urea building block in a nucleophilic substitution to obtain our prodrug monomer 2 (see Figure ). Interestingly, this compound 2 is still pharmaceutically active; however, with on tenth of the effectiveness compared to the native Lenvatinib drug, as established in a binding assay to its 'vascular endothelial growth factor receptor 2' (VEGFR2) target (see Supporting Information: VEGFR2 Assay). However, this effectiveness of the small prodrug monomer disappears when polymerized into drug-carrying nanoparticles, rendering them a full-fledged prodrug. Previously, we demonstrate that imidazole can take part in a direct arylation C-C cross-coupling polymerization (DAP) with dihalogenated imidazole co-monomers. Our dispersion polymerization implies that all reactants including base, catalyst, stabilizers, and monomers are soluble in the reaction medium. However, the resulting polymer needs to be insoluble in the reaction medium to form the desired nanoparticles. The solvent n-propanol fulfills these requirements on the reaction medium. Potassium tert-butoxide is used as a base and Triton-X45 together with poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA) are employed as stabilizers. The prodrug monomer is added together with the imidazole monomers to the direct arylation dispersion polymerization (DAP), to become incorporated in the polymer backbone, which then phase separates into nanoparticle (see Figure ). The methyl imidazole of the prodrug monomer is polymerizable and should respond to ROS -like the imidazole comonomers -by ring-opening. Cleaving of the ring will degrade the particles and leave behind the amide-and amino acid-like degradation products, as observed previously. We first evaluate the stability of our prodrug monomer 2 under DAP conditions and find that the prodrug monomer remains stable over the period of time of a typical dispersion polymerization (see Supporting Information: Stability of Compound 2 under Polymerization Conditions, Table and Figure ).