Proteolysis-targeting chimera-doxorubicin conjugate nanoassemblies for dual treatment of EGFR-TKI sensitive and resistant non-small cell lung cancer.

Abstract

Proteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy for targeted protein degradation and drug discovery. However, traditional PROTACs face inherent limitations and may also contribute to induce drug resistance. These challenges have driven the development of innovative strategies to overcome these obstacles. In current study, a PROTAC-DOX conjugates (PDCs) nanoassembly strategy was introduced to enhance tumor-targeting capability and overcome the drawbacks of conventional PROTACs. The designed PDC-S nanoparticles (PDC-S NPs) demonstrated potent anti-tumor activity against drug-resistant strains (IC₅₀ = 4.7 µM) and improved in vivo efficacy (TGI = 76 %) against drug-sensitive strains, while minimizing side effects. Additionally, PDC-S NPs have great potential in tumor immunotherapy. This study provides a novel and promising strategy for the development of PROTAC-Drug Conjugates (PDCs). STATEMENT OF SIGNIFICANCE: We developed a PROTAC-DOX conjugates (PDCs) nanoassembly strategy to address the limitations of traditional PROTACs, such as poor solubility, low targeting specificity, and drug resistance. PDC-S NPs were constructed via self-assembly, which simplified preparation and minimized the toxicity typically associated with carrier-assisted delivery systems. The PDC-S NPs showed improved aqueous solubility and cellular uptake, resulting in efficient EGFR degradation in HCC827 cells. In vivo, PDC-S NPs accumulated at tumor sites via the EPR effect, resulting in enhanced anti-tumor potency with reduced side effects. Furthermore, PDC-S NPs induced immunogenic cell death (ICD) and suppressed PD-L1 and VEGF expression, highlighting great potential in tumor immunotherapy.