Rational Design of Targeted Gold Nanoclusters with High Affinity to Integrin αvβ3 for Combination Cancer Therapy

The unique attributes of targeted nano-drug delivery systems (TNDDSs) over conventional cancer therapies in suppressing off-target effects make them one of the most promising options for cancer treatment. There is evidence that the density of surface-conjugated ligands is a crucial factor in achieving the desired therapeutic efficacy of TNDDSs, but this is hardly manageable in conventional nanomaterials. In this context, ligand-protected gold nanoclusters (AuNCs) are excellent candidates for developing new TNDDSs with a unique control on their surface functionalities, thus helping to achieve enhanced delivery performance. Here, we study the interactions and binding free energies between ten different functionalized Au₁₄₄(SR)₆₀ (SR = thiolate ligand) nanoclusters and integrin αvβ3 using molecular dynamics simulations and the umbrella sampling method to obtain the optimal formulations. The AuNCs were functionalized with anticancer drugs (5-fluorouracil or signaling pathways inhibitors, such as capivasertib, linifanib, tanespimycin, and taselisib) and integrin-targeting peptides (RGD4C or QS13), and we identified the optimal mixed ligand layer to enhance their binding affinity to the cancer cell receptor. The results showed that changing the proportions of the same type of ligands on the surface of AuNCs led to differences of up to 38 kcal/mol in computed binding free energies. RGD4C as the targeting peptide resulted in greater affinity for αvβ3, and in most formulations studied, a higher amount of drug than peptide was needed. Polar and charged residues, such as Ser123, Asp150, Tyr178, Arg214, and Asp251 were found to play a significant role in AuNC binding. Our simulations also revealed that Mn²⁺ cations are crucial for stabilizing the αvβ3-AuNC complex. These findings demonstrate the potential of carefully designing the surface composition of TNDDSs to optimize their target affinity and specificity.