Development of novel nanoliposomes co-loaded with ROR1 inhibitor and Ce6 for the treatment of EGFR-TKIs resistant NSCLC by synergistic targeted inhibitor therapy and photodynamic therapy.

Currently, developing effective treatments for epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) resistant non-small cell lung cancer (NSCLC) is one of the main research focuses in the field. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the receptor tyrosine kinase family, whose knockdown could effectively inhibit the growth of EGFR-TKIs resistant NSCLC. Targeted inhibitor therapy and photodynamic therapy (PDT) combination is a promising strategy for reducing drug resistance and side effects. 12d, a novel small molecule ROR1 inhibitor we synthesized previously, exhibited promising antitumor activity both in vitro and in vivo. However, its poor water solubility significantly compromised therapeutic efficacy and bioavailability. Here, to improve the solubility of 12d and to take advantage of the PDT benefits of the photosensitizer Ce6, we constructed a light-activatable liposomal co-delivery system (12d/Ce6-LP) for the treatment of EGFR-TKIs resistant NSCLC. In vitro assays demonstrated that 12d/Ce6-LP significantly enhanced cellular uptake, provoked G2/M cell cycle arrest, promoted apoptosis, and impeded the ROR1, protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) signaling pathways through a synergistic treatment with targeted inhibitor therapy and PDT. Furthermore, 12d/Ce6-LP revealed potent tumor growth inhibition in EGFR-TKIs resistant NSCLC xenograft models, prolonged systemic circulation, and excellent biodistribution. In summary, 12d/Ce6-LP represented a novel nanotherapeutic strategy of the EGFR-TKIs resistant NSCLC through a synergistic mechanism of "targeted inhibitor therapy and photodynamic" offering a promising paradigm for the treatment of drug-resistant malignancies.