Self-Assembled Nanoparticle-Mediated Chemophototherapy Reverses the Drug Resistance of Bladder Cancers through Dual AKT/ERK Inhibition

Weimin Yu, Xiangdong Xue, Ai Hong Ma, Yuan Ruan, Hongyong Zhang, Fan Cheng, Yuanpei Li, Chong Xian Pan, Tzu Yin Lin

Research output: Contribution to journalArticlepeer-review

Abstract

Current treatments for both non-myoinvasive and advanced bladder cancer are suboptimal, associated with high disease recurrence rate and poor quality of life. In this work, the efficacy and mechanistic studies of the newly developed pheophorbide a (Ppa)-hydrazone-doxorubicin (DOX) (PhD) nanoparticles (NPs) as a triple-modal therapeutic agent, including chemotherapy, photothermal therapy, and photodynamic therapy, to improve bladder cancer care are reported. Spherical PhD NPs are ≈71 nm in diameter. Treatments with light and/or pH similar to the acidic tumor microenvironment accelerate DOX drug release. In comparison with DOX, trimodal therapy with PhD NPs increases cytotoxicity by 58 and 109 times in 5637 and TCCSUP cell lines, respectively, and antitumor efficacy is light-dose dependent. In vivo studies on patient-derived xenografts reveal that trimodal therapy of PhD NPs induces anti-tumor effects and overcomes drug resistance to cytotoxic chemotherapy and molecularly targeted therapy matches the underlying genetic alteration of PI3K activation mutation. Both the in vitro cytotoxicity and in vivo anti-tumor activity are realized by the inhibition of both AKT and ERK pathways and caspase-3 mediated apoptosis. In conclusion, PhD NPs with multiple therapeutic functions show enormous potential to improve bladder cancer treatment and overcome resistance.

Original languageEnglish (US)
Article number2000032
JournalAdvanced Therapeutics
Volume3
Issue number8
DOIs
StatePublished - Aug 1 2020

Keywords

  • bladder cancer
  • chemotherapy
  • drug resistance
  • nanomedicine
  • phototherapies

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, medical
  • Pharmacology (medical)
  • Genetics(clinical)
  • Pharmaceutical Science
  • Pharmacology

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