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Drug resistance, accounting for therapeutic failure in the clinic, remains a major challenge to effectively manage cancer. Cyclosporin A (CsA) can reverse multidrug resistance (MDR), especially resistance to epidermal growth factor receptor tyrosine kinase inhibitors. However, the application of both drugs in cancer therapies is hampered by their poor aqueous solubility and low bioavailability due to oral administration. CsA augments the potency of gefitinib (Gef) in both Gef-sensitive and Gef-resistant cell lines. Here, we show that the simultaneous encapsulation of CsA and Gef within polyethylene glycol- block -poly( D, L -lactic acid) (PEG-PLA) produced a stable and systemically injectable nanomedicine, which exhibited a sub-50-nm diameter and spherical structures. Impressively, the co-delivery of therapeutics via single nanoparticles (NPs) outperformed the oral administration of the free drug combination at suppressing tumor growth. Furthermore, in vivo results indicated that CsA formulated in NPs sensitized Gef-resistant cells and Gef-resistant tumors to Gef treatment by inactivating the STAT3/Bcl-2 signaling pathway. Collectively, our nanomedicine approach not only provides an alternative administration route for the drugs of choice but also effectively reverses MDR, facilitating the development of effective therapeutic modalities for cancer.

A nanomedicine approach enables co-delivery of cyclosporin A and gefitinib to potentiate the therapeutic efficacy in drug-resistant lung cancer