Journal
ADVANCED SCIENCE
Volume 9, Issue 7, Pages -Publisher
WILEY
DOI: 10.1002/advs.202103895
Keywords
drug delivery; gallbladder cancer; nanomedicine; proteasome inhibitor; targeted therapy
Categories
Funding
- National Natural Science Foundation of China [81827804, 81800540]
- Zhejiang Provincial Natural Science Foundation of China [LQ22H160003]
- Zhejiang Clinical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases [2018E50003]
- Key Research and Development Project of Zhejiang Province [2018C03083]
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This study reports on a targeted therapy for gallbladder cancer using pH-responsive nanoparticles encapsulating bortezomib and mediated by estrogen-induced endocytosis. The treatment effectively inhibits proteasomes and induces apoptosis under tumor microenvironment and laser irradiation.
Gallbladder cancer (GBC) is a rare but the most malignant type of biliary tract tumor. It is usually diagnosed at an advanced stage and conventional treatments are unsatisfactory. As a proteasome inhibitor, bortezomib (BTZ) exhibits excellent antitumor ability in GBC. However, the long-term treatment efficacy is limited by its resistance, poor stability, and high toxicity. Herein, BTZ-encapsulated pH-responsive copolymeric nanoparticles with estrone (ES-NP(BTZ; Ce6)) for GBC-specific targeted therapy is reported. Due to the high estrogen receptor expression in GBC, ES-NP(BTZ; Ce6) can rapidly enter the cells and accumulate near the nucleus via ES-mediated endocytosis. Under acidic tumor microenvironment (TME) and 808 nm laser irradiation, BTZ is released and ROS is generated by Ce6 to destroy the bounce-back response pathway proteins, such as DDI2 and p97, which can effectively inhibit proteasomes and increase apoptosis. Compared to the traditional treatment using BTZ monotherapy, ES-NP(BTZ; Ce6) can significantly impede disease progression at lower BTZ concentrations and improve its resistance. Moreover, ES-NP(BTZ; Ce6) demonstrates similar antitumor abilities in patient-derived xenograft animal models and five other types of solid tumor cells, revealing its potential as a broad-spectrum antitumor formulation.
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