Published online Aug 21, 2020. doi: 10.3748/wjg.v26.i31.4589
Peer-review started: June 3, 2020
First decision: June 18, 2020
Revised: June 30, 2020
Accepted: July 30, 2020
Article in press: July 30, 2020
Published online: August 21, 2020
Effective endoscopic management is fundamental for the treatment of extrahepatic cholangiocarcinoma (ECC). However, current biliary stents that are widely used in clinical practice showed no antitumor effect. Drug-eluting stents (DESs) may achieve a combination of local chemotherapy and biliary drainage to prolong stent patency and improve prognosis.
To develop novel DESs coated with gemcitabine (GEM) and cisplatin (CIS)-coloaded nanofilms that can maintain the continuous and long-term release of antitumor agents in the bile duct to inhibit tumor growth and reduce systemic toxicity.
Stents coated with different drug-eluting components were prepared by the mixed electrospinning method, with poly-L-lactide-caprolactone (PLCL) as the drug-loaded nanofiber membrane and GEM and/or CIS as the antitumor agents. Four different DESs were manufactured with four drug-loading ratios (5%, 10%, 15%, and 20%), including bare-loaded (PLCL-0), single-drug-loaded (PLCL-GEM and PLCL-CIS), and dual-drug-loaded (PLCL-GC) stents. The drug release property, antitumor activity, and biocompatibility were evaluated in vitro and in vivo to confirm the feasibility and efficacy of this novel DES for ECC.
The in vitro drug release study showed the stable, continuous release of both GEM and CIS, which was sustained for over 30 d without an obvious initial burst, and a higher drug-loaded content induced a lower release rate. The drug-loading ratio of 10% was used for further experiments due to its ideal inhibitory efficiency and relatively low toxicity. All drug-loaded nanofilms effectively inhibited the growth of EGI-1 cells in vitro and the tumor xenografts of nude mice in vivo; in addition, the dual-loaded nanofilm (PLCL-GC) had a significantly better effect than the single-drug-loaded nanofilms (P < 0.05). No significant differences in the serological analysis (P > 0.05) or histopathological changes were observed between the single-loaded and drug-loaded nanofilms after stent placement in the normal porcine biliary tract.
This novel PLCL-GEM and CIS-eluting stent maintains continuous, stable drug release locally and inhibits tumor growth effectively in vitro and in vivo. It can also be used safely in normal porcine bile ducts. We anticipate that it might be considered an alternative strategy for the palliative therapy of ECC patients.
Core tip: Drug-eluting stent is a new therapeutic concept for malignant biliary obstructions; however, studies on such stents have been limited, and all of them used single-drug-loaded nanofilms with a simple design and lacked complete serial in vitro and in vivo data. Our study was the first to apply dual chemotherapeutic medications to a drug-eluting stent with several improvements in the design compared to previous stents for the palliative therapy of extrahepatic cholangiocarcinoma, with a relatively complete preclinical evaluation. Our results indicate that this brand new stent can be a promising alternative to realize the dual functions of biliary drainage and local chemotherapy.