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

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.

Nanotechnology-based combinatorial phototherapy for enhanced cancer treatment

“…The pPhD NPs were also employed to reverse the drug resistance by inhibiting dual AKT/ERK pathways and efficiently ablate bladder cancer. 82 The complex modification might lead to manufacturing complexities that impede their clinical translation. 83 Hence, the FAPIN-like nanomedicine can significantly simplify nanoscale drug formulations, which may shed new light on large-scale production and clinical translation.…”

Emerging photodynamic/sonodynamic therapies for urological cancers: progress and challenges

“…c Schematic illustration of two-stage degradation of PhD NPs to release DOX and PhD NPs-mediated photochemotherapy blocked both Akt and Erk pathways to overcome the resistance of chemotherapy and PI3K inhibitor (GDC-0941). Reprinted with permission [ 48 ]. Copyright 2020, John Wiley and Sons.…”

“…In terms of overcoming drug resistance, a novel multifunctional nanoparticle, Pheophorbide a (Ppa)-hydrazone-DOX (PhD) NPs, was developed by self-assembly of dimers formed by DOX conjugated to Ppa through a hydrazone bond, with PEGylation cross-linkage introduced onto the surface of NPs [ 48 ]. The PhD NPs exhibited a pH-responsive feature because the hydrazone bond is relatively stable under physiological pH conditions and can be cleaved to release DOX in an acidic (pH 5.0–6.0) TME (Fig.…”

“…Herein, it was confirmed in chemo- and GDC-resistant PDX BC models that PhD NPs-mediated-photochemotherapy suppressed both Erk and protein kinase B (Akt) pathways to overcome drug resistance and resulted in BC eradication (Fig. 4 c) [ 48 ].…”

“…Unique surface components of mammalian cells (e.g., erythrocytes, platelets and macrophages) or pathogens (e.g., viruses and bacteria) are most often used to impart biomimetic coatings to nanoparticles [ 178 ]. In combination therapy, combining PDT/SDT with clinically mature drugs is promising to help overcome resistance to these drugs or to induce expression of drug targets [ 48 , 50 ].…”