“Dual-Lock”-Controlled activatable nanotheranostics for chemiluminescence resonance energy transfer (CRET)-driven enhanced photoimmunotherapy

Abstract

Photoimmunotherapy is a promising therapeutic modality which utilizes phototherapy to trigger immune responses for cancer therapy. However, the requirement of light to trigger the therapeutic procedure greatly suppress its efficacy against deep-seated tumor because of the low tissue penetration of light. Herein, we design a chemiluminescence resonance energy transfer (CRET)-driven photoimmunotherapeutic nanosystem (RCblC@ZTP). Such nanosystem uses chemiluminescence instead of exogenous light as the energy source to trigger photoimmunotherapy. RCblC@ZTP is prepared by encapsulating bis[2,4,5-trichloro-6-(pentyl­oxycarbonyl)phenyl]oxalate (CPPO) and a hypoxia-responsive prodrug RCbl with an amphiphilic copolymer ZTP, which is composed of zinc-tetraphenylporphyrin (ZnTPP), copper bipyridine and polyethylene glycol (PEG). The photodynamic efficacy of RCblC@ZTP is quenched by copper bipyridine under physiological condition. In contrast, the overexpressed hydrogen sulfide (H₂S) in colorectal cancer can react with copper ion to form CuS and eliminate the quenching effect. After that, tumor overexpressed hydrogen peroxide (H₂O₂) reacts with CPPO to generate the intermediate 1,2-dioxetanedione, which further transfer the energy into ZnTPP via CRET. The excited ZnTPP can generate singlet oxygen (¹O₂). On the other hand, RCbl can release R848 and N¹,N¹-bis(2-chloroethyl)benzene-1,4-diamine (Cbl) under hypoxia. The generated ¹O₂ and Cbl can induce cancer cell apoptosis and trigger immunogenic cell death (ICD), while R848 can help the maturation of dendritic cells (DCs). The activated immune responses can not only kill primary tumor, but also inhibit liver and lung metastasis. Thus, our study reports a H₂S/H₂O₂ “dual-lock”-controlled nanosystem for activated photoimmunotherapy without the excitation of exogenous light.