Erlotinib-functionalized dextran derivatives enable self-assembly of redox-responsive paclitaxel dimers for lung Cancer treatment after intratracheal delivery.

The intratracheal route enables an enhanced drug accumulation within the lungs together with reduced systemic exposure, making it a promising approach for treating epidermal growth factor receptor (EGFR)-overexpressed non-small cell lung cancer (NSCLC). In this study, dextran-PEG-erlotinib co-polymers (DPE), novel amphiphilic conjugates with outstanding therapeutic activities against EGFR-overexpressed NSCLC and stabilizing effects were synthesized and facilitated self-assembly of redox-sensitive paclitaxel dimers. The obtained nanoassemblies (DPE dimer NPs) exhibited high drug loading efficiency, satisfactory stability and optimal redox responsive paclitaxel release profile comparable with control nanoassemblies (TPGS dimer NPs), where paclitaxel dimers were assembled in the presence of TPGS, a therapeutically inert stabilizer. The DPE dimer NPs evidenced an enhanced cellular uptake efficiency and cytotoxicity in EGFR-overexpressed HCC827 cells as compared to TPGS dimer NPs. These also demonstrated superior tumor penetration ability and inhibition potential in HCC827 3D tumor spheroid. Compared to TPGS dimer NPs and Taxol® intravenous injection, the DPE dimer NPs illustrated an improved anticancer effect with reduced systemic toxicity and excellent biocompatibility after intratracheal administration to the HCC827 metastatic lung cancer mouse model. These results revealed a great potential of DPE as a stabilizer to synergistically improve the therapeutic efficacy of paclitaxel dimers against EGFR-overexpressed NSCLC after intratracheal administration.