A nanotherapeutic strategy to overcome chemoresistance to irinotecan/7-ethyl-10-hydroxy-camptothecin in colorectal cancer

Clinical development of 7-ethyl-10‑hydroxy-camptothecin (SN38), the active metabolite of irinotecan (CPT-11), is hindered by its insolubility and poor stability. Another obstacle is that tumors could become resistant to SN38/CPT-11 through multiple mechanisms involving breast cancer resistance protein (BCRP). Herein one of the most potent and selective BCRP inhibitors, Ko143, is encapsulated into a recently constructed prodrug PEG-S-S-SN38 displaying a high and fixed drug loading, multiple intratumoral stimuli (oxidative stress, GSH and esterase)-responsive drug release and significant in vitro and in vivo superiorities over CPT-11. The obtained “combo” for simultaneous delivery of SN38 and Ko143, named as [email protected] , has a high SN38 loading efficacy (14.85 wt.%) and a good Ko143 encapsulation efficacy (3.79%). Through generating panels of human colorectal cancer models expressing altered levels of BCRP via lentiviral transfection and CRISPR-Cas9, characteristics of different drug formulations are carefully evaluated. Impressively, [email protected] nanoparticles effectively reverse chemoresistance to CPT-11 (resistance index dropping from ∼274.00–456.00 to ∼1.70–4.68) and PEG-S-S-SN38 (resistance index dropping from ∼5.83–14.00 to ∼1.70–4.68) in three BCRP-overexpressing cancer cell lines. More importantly, reversal of BCRP-mediated chemoresistance to CPT-11 ( P values lower than 0.001–0.0001) and PEG-S-S-SN38 ( P values lower than 0.01–0.001) by [email protected] nanoparticles are further confirmed with two panels of colorectal cancer xenograft models in vivo . As the first nano-formulation of Ko143 and the first systemic co-delivery vehicle of SN38/CPT-11 and a BCRP inhibitor, [email protected] provides a new approach for resolving the bottlenecks for clinical translation of SN38 and numerous “chemosensitizers” like Ko143, and exhibits promising applicability in precision cancer medicine. Statement of significance To resolve the bottlenecks in clinical application of anticancer agents SN38/CPT-11 and the most potent breast cancer resistant protein (BCRP) inhibitor Ko143, a “combo” nanotherapeutic simultaneously delivering SN38 and Ko143 was constructed and named as [email protected] By generating panels of colorectal cancer models, we demonstrate that [email protected] nanoparticles effectively and selectively reversed BCRP-mediated tumor resistance to SN38/CPT-11 in vitro  and in vivo . As the first nano-formulation of Ko143 and the first systemic co-delivery vehicle of SN38/CPT-11 and a BCRP inhibitor, [email protected] provides a new strategy for clinical development of SN38 and numerous “chemosensitizers”, and exhibits promising applicability in precision cancer medicine. Panels of cancer cell lines established here provides a useful platform for BCRP- and cancer-related research and technology development.