Accelerated Discovery of Zn(II) Therapeutic Coordination Polymers (TCPs) for Controlled Drug Release

Abstract

Therapeutic Coordination Polymers (TCPs) are a distinct class of nonporous drug-release materials in which tunable release kinetics arise from degradation of metal-ligand coordination bonds. Here, we report a high-throughput (HT) screening workflow that significantly accelerates TCP discovery by enabling parallel evaluation of 192 reaction conditions across four nonsteroidal anti-inflammatory drugs (NSAIDs: Diclofenac, Ibuprofen, Indomethacin, Naproxen) and six bis-imidazole or methyl-imidazole linkers (biim-4, biim-5, biim-6, biim-8, biim-4m, biim-6m). This approach yielded 15 crystalline zinc-based materials, including 13 TCPs and 2 metallocycles, with 12 representing previously unreported structures. The workflow offers a generalizable platform to expand the accessible chemical space for TCP formation and to broaden the range of compatible drug candidates. Among the linkers investigated, biim-4m emerged as particularly effective, forming TCPs with all four NSAIDs (ZnDiclo4m, ZnIbu4m, ZnIndo4m, ZnNap4m). These materials exhibited sustained drug-release kinetics in simulated body fluids, with intrinsic dissolution rates several orders of magnitude slower than those of their corresponding sodium salt forms. To evaluate the influence of the polymeric framework, a discrete Zn(II)-diclofenac-methylimidazole complex was synthesized to model a monomeric coordination unit. Dissolution studies showed significantly faster release from the monomeric complex compared to its polymeric counterpart, underscoring the functional advantage of the extended TCP architecture. Cell viability assays demonstrated biim-4m-derived TCPs were well tolerated below 50 µM relative to the native drugs. Overall, this work presents a scalable and versatile strategy for TCP discovery, highlights the structural features that contribute to sustained drug release, and supports the development of coordination polymer-based therapeutics with tunable performance.