A nanotherapeutic strategy to overcome chemoresistance to irinotecan/7-ethyl-10-hydroxy-camptothecin in colorectal cancer. (1st January 2022) - Huang, Qian
Abstract: 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 BI@PEG-SN38, 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, BI@PEG-SN38 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 BI@PEG-SN38 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, BI@PEG-SN38 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 BI@PEG-SN38. By generating panels of colorectal cancer models, we demonstrate that BI@PEG-SN38 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, BI@PEG-SN38 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. Graphical abstract: Image, graphical abstract