Chiral-Induced Selective Sensing and Transport of Irinotecan by P-Glycoprotein-Inspired Nanochannel Sensors

Understanding how chirality influences and controls the transmembrane transport and efflux of irinotecan in P-glycoprotein (P-gp) is crucial for elucidating its chemotherapy resistance mechanism. Herein, we developed P-glycoprotein-inspired nanochannels by decorating the chiral active receptors ( D- / L- Asp enantiomers) of P-gp on the inner surface of artificial cone-shaped nanochannels and dynamically and statically analyzed the chiral-mediated selective recognition, adsorption, transport, and release behaviors of irinotecan in biomimetic nanochannels. Interesting results showed that irinotecan preferentially aggregated and adsorbed in the L -Asp-modified channel, resulting in sensitive sensing and fast transport with a flux of 0.033 nmol cm −2 min −1 . The chiral-selective current-responsive ratio of the L- Asp channel/ D- Asp channel for irinotecan reached up to 3.5, and the chiral-selective transport coefficient α ( L- Asp/ D- Asp channel) was determined to be 2.5, achieving chiral-induced selective recognition and transport of irinotecan in biomimetic nanochannels, representing that chirality acts as a gating switch. Furthermore, the L- Asp channel exhibited sensitivity and specificity for irinotecan with a wide detection range (10 −7 to 10 −4 M), a low detection limit (0.026 μM), and good cycling stability. Chemical spectroscopic titrations and theoretical simulations illustrate that the chirality-gated switch for irinotecan transport is modulated by the affinity differences arising from multiple hydrogen-bond interactions between D- / L- Asp receptors immobilized on the nanochannels and irinotecan. These findings provide a new approach to simulate and understand the transport and efflux mechanisms of irinotecan regulated by P-gp chirality. Additionally, they offer valuable insights for the design of chiral biosensors and microfluidic devices.