Abstract
Resistance to chemotherapy is a key factor affecting Non-small cell lung cancer spinal metastasis (NSCLC-SM) treatment efficiency. In this study, Osteopontin (OPN), an intracellular and a secreted glycoprotein, showed overexpression in NSCLC-SM. Further studies demonstrated that OPN promoted chemoresistance by activating mTORC2/AKT/NF-κB/MDR1 signaling via interaction with integrin αvβ3. Subsequently, it was confirmed that a specific inhibitor of OPN/αvβ3, the pentapeptide Gly-Arg-Gly-Asp-Ser (TFA), targeted NSCLC-SM and promoted chemosensitivity by competitively blocking the OPN/αvβ3 interaction and by inhibiting the downstream signaling. Therefore, a TFA-modified and cisplatin (DDP)-loaded hollow MnO2 structure (H-MnO2/DDP(Cy)-TFA nanocapsules) was fabricated in the present study. The H-MnO2/DDP(Cy)-TFA targeted OPN, exhibited responses to the tumor microenvironment, and demonstrated high drug loading and controlled release. In a NSCLC-SM mouse model, H-MnO2/DDP(Cy)-TFA enhanced chemosensitivity and suppressed tumor progression via combination effect of targeted inhibition of OPN and controlled release of DDP. Collectively, the present study elucidated the mechanism underlying OPN-mediated NSCLC chemoresistance and a nano-drug delivery platform was developed as a new therapeutic strategy for precisely targeting NSCLC-SM and for enhancing chemosensitivity.
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