A Self-Assembled Affibody-Drug Conjugate Nanoagent for EGFR-Targeted Synergistic Codelivery of Exatecan and an MDM2 Inhibitory Peptide.

Regulation of the tumor suppressor p53 is a promising approach for cancer treatment; however, a single regulatory method often shows limited efficacy. Here, we develop an affibody-drug conjugate nanoagent (ADCN) for the targeted codelivery of topoisomerase I inhibitor DX8591 and p53-MDM2 inhibitor PMI to upregulate p53 levels in cancer cells. The tripartite conjugate ZEGFR:1907-PMI-DX8591 self-assembled into nanoparticles with an average diameter of 74.4 nm, resulting in improved pharmacokinetic profiles and enhanced tumor-targeting ability. After efficient EGFR-mediated cellular uptake, the ZEGFR:1907-PMI-DX8591 ADCN released DX8591 and PMI intracellularly, leading to synergistic p53 activation by inducing p53 production and blocking its degradation. In EGFR-positive non-small cell lung tumor models, the ADCN showed excellent tumor accumulation and achieved 81.7% tumor growth inhibition, which was 1.5-fold and 1.2-fold higher than those of the ZEGFR:1907-PMI and ZEGFR:1907-DX8591 monotherapies, respectively. This affibody-based delivery system provides a promising strategy for synergistic cancer therapy.