Iron oxide@chlorophyll clustered nanoparticles eliminate bladder cancer by photodynamic immunotherapy-initiated ferroptosis and immunostimulation

Abstract

The escape of bladder cancer from immunosurveillance causes monotherapy to exhibit poor efficacy; therefore, designing a multifunctional nanoparticle that boosts programmed cell death and immunoactivation has potential as a treatment strategy. Herein, we developed a facile one-pot coprecipitation reaction to fabricate cluster-structured nanoparticles (CNPs) assembled from Fe3O4 and iron chlorophyll (Chl/Fe) photosensitizers. This nanoassembled CNP, as a multifunctional theranostic agent, could perform red-NIR fluorescence and change the redox balance by the photoinduction of reactive oxygen species (ROS) and attenuate iron-mediated lipid peroxidation by the induction of a Fenton-like reaction. The intravesical instillation of Fe3O4@Chl/Fe CNPs modified with 4-carboxyphenylboronic acid (CPBA) may target the BC wall through glycoproteins in the BC cavity, allowing local killing of cancer cells by photodynamic therapy (PDT)-induced singlet oxygen and causing chemodynamic therapy (CDT)-mediated ferroptosis. An interesting possibility is reprogramming of the tumor microenvironment from immunosuppressive to immunostimulatory after PDT-CDT treatment, which was demonstrated by the reduction of PD-L1 (lower “off” signal to the effector immune cells), IDO-1, TGF-β, and M2-like macrophages and the induction of CD8+ T cells on BC sections. Moreover, the intravesical instillation of Fe3O4@Chl/Fe CNPs may enhance the large-area distribution on the BC wall, improving antitumor efficacy and increasing survival rates from 0 to 91.7%. Our theranostic CNPs not only demonstrated combined PDT-CDT-induced cytotoxicity, ROS production, and ferroptosis to facilitate treatment efficacy but also opened up new horizons for eliminating the immunosuppressive effect by simultaneous PDT-CDT.

State-of-the-Art Advances of Nanomedicine for Diagnosis and Treatment of Bladder Cancer

“…In order to transport Met into bladder cancer cells and prolong drug retention time, researchers loaded Met and IR775 into a clinically usable liposome as a two-in-one nanoplatform (IR775@Met@Lip), successfully decreasing the expression of PD-L1 in a bladder cancer cell and reversing tumor hypoxia suppression simultaneously, therefore improving the curative effect of PDT [ 69 ]. Chin et al also developed a special nanoparticle to conduct PDT therapy as well as immune activation, which includes lowering the PD-L1 signal [ 136 ]. Using Fe 3 O 4 and iron chlorophyII (Chl/Fe) as photosensitizers showed a satisfying photodynamic effect.…”

Magnetic Micellar Nanovehicles: Prospects of Multifunctional Hybrid Systems for Precision Theranostics

“…Macrophages exposed to ferumoxytol (Feraheme ® ) displayed increased mRNA associated with pro-inflammatory responses, suggesting that ferumoxytol could be applied “off label” to potentiate macrophage-modulating cancer immunotherapies [ 70 ]. Additionally, iron oxide@chlorophyll clustered nanoparticles modified with 4-carboxyphenylboronic acid were reported to reprogram tumor microenvironment in combination with photo and chemodynamic therapies by the inactivation of programmed death-ligand 1 and suppression of M2-like macrophages accumulation [ 71 ].…”

Ferroptosis: A new therapeutic target for bladder cancer

“…A variety of nano drugs have been reported to specifically adhere to bladder cancer cells and deliver iron through endocytosis when exposed to laser irradiation, resulting in ROS generation and accumulation and subsequent GSH and GPX4 depletion, ultimately leading to ferroptosis ( Liao et al, 2022 ). Another approach is to enhance photodynamic therapy (PDT)-chemodynamic therapy (CDT) sensitivity and induce toxicity ( Chin et al, 2022 ; Liao et al, 2022 ). AuNRs&IONs@Gel is a gel delivery platform with embedded gold nanorods (AuNRs) and iron oxide nanoparticles (IONs).…”