ROS-responsive self-activatable photosensitizing agent for photodynamic-immunotherapy of cancer

Cancer remains a global health concern [1]. Although many therapeutic methods have been developed for cancer treatment, such as surgery, radiotherapy, chemotherapy, and immunotherapy [2], the clinical therapeutic efficacies are still restricted to serious side effects. Notably, PDT has emerged as a new cancer therapy strategy in recent years [3]. Compared with chemotherapy or radiotherapy, PDT is non-invasive, spatiotemporally controllable, and presents no drug-resistant modality [4,5]. Upon appropriate laser irradiation, photoinduced electron transfer in photosensitizers (PSs) can convert oxygen into reactive oxygen species (ROS), especially singlet oxygen (1O2) [3,[6], [7], [8]]. The 1O2 exerts a selective cytotoxic activity and causes irreversible damage to malignant cells and tissue [9], [10], [11]. However, the hydrophobic characteristics, short blood circulation and aggregation-caused quenching (ACQ) of PSs still restrict the efficiency of ROS production in the PDT process, which affect the application of PDT in clinical practice [12,13]. Hence, it is urgent to develop novel strategies to overcome these shortages of PSs.

Nanotechnology has emerged as an emerging technology to improve delivery efficiency of hydrophobic PSs [14]. To meet clinical application requirements, varieties of nanoparticles have been developed for improving PDT efficacy by increasing water solubility of PSs, involving polymeric nanoparticles, liposomes, micelles, dendrimers and inorganic nanoparticles [15,16]. Generally, the aforementioned nanoparticles can be classified as conventional physically encapsulated nanoparticles and polymeric self-assembled nanoparticles. These nanoparticles can effectively increase water solubility and prolong blood circulation, but some limitations still exist, such as low loading efficiency, poor stability, inevitable premature leakage, non-selective release of photosensitizers and the π-π stacking effect of aggregated PSs in nanoparticles induce ACQ [17,18]. Deng et al. reported an oxidation-sensitive amphiphilic encapsulated polymeric micelles for cancer PDT with a PSs loading capacity of 1.3% and the tumor showed the strongest fluorescence signal at 1 h [19]. While, the main limitation is the aggregated PSs in the nanoparticle able to cause ACQ, weaken fluorescence emission and the quantum yield of 1O2 production when exposure to laser [20,21]. Therefore, numerous self-assembled stimuli-responsive nanoparticles had been developed to overcome the ACQ effect by conjugating PSs. The vast majority of stimuli-responsive nanoparticles were in response to endogenous stimuli in tumor microenvironments, containing acidity, redox (glutathione or ROS), specific enzymes, then cause nanoparticles degradation and PSs release [15,22,23]. Ruan and co-workers reported a GSH-responsive chemically conjugated macrophotosensitizers nanoparticle (with a GSH responsive concentration of 10 mM) to deliver macrophotosensitizers for near-infrared (NIR) imaging-guided PDT [24]. Nevertheless, the heterogeneously distributed endogenous stimuli in tumors affect the response of these stimuli-responsive nanoparticles, and thus not adequate for effective regulation of drug release [25,26]. Consequently, it is a great challenge to develop a susceptible stimuli-responsive nanoparticle that can suppress ACQ and amplify photodynamic therapeutic efficiency.

Additionally, PDT can cause acute inflammation and immunogenic cell death (ICD) [3]. The highly cytotoxic ROS caused oxidative stress damage to tumor cell inducing calreticulin (CRT) translates from the endoplasmic reticulum (ER) lumen to the cell surface, high mobility group box 1 (HMGB-1) release from nuclei and adenosine triphosphate (ATP) secretion [10,17]. Then these damage-associated molecular patterns (DAMPs) act as immunoadjuvant capable of triggering antigen-presenting cell activation and anti-tumor immunity [27,28]. Although PDT has a certain efficacy in immune activation, the process of converting ICD into cancer immunotherapy remains restricted by the ROS generation capacity of PSs, resulting in transitory and limited ICD and consequently, incomplete immune-stimulation [18,17]. And some reports concerning that elevated intracellular ROS is an effective approach to enhance the ICD effect of tumor cells [27,[29], [30], [31], [32], [33]]. In this context, it is eagerly that developing a simple and effective strategy to improve the ROS production capacity adequate for converting ICD to facilitate the tumor immune response.

To address the aforementioned problems, we developed a ROS-responsive self-activatable nano system PEG-TK-Pa (denoted as PTKPa) for suppressing ACQ of PSs and amplifying the effect of PDT. The PTKPa was constitutive of amphiphilic poly(ethylene glycol), ROS-responsive self-activatable poly(thioketal) bond (PTK-SS) and ROS-generating photosensitizer Ppa (Scheme 1), which can self-assemble to form PTKPa nanoparticles (PTKPa NPs). Upon 660 nm laser irradiation, the ROS generated from the conjugated Ppa of PTKPa NPs serves as a trigger to cause poly(thioketal) bond cleavage and promote the release of Ppa molecules. The abundant ROS produced from the released Ppa bind with intracellular albumin, contributing to disintegrating the remaining PTKPa NPs and amplifying the efficacy of PDT with even more ROS generated. Moreover, the abundant ROS result severe oxidative damage to the tumor and release of DAMPs release. And the DAMPs contribute to immunogenic cell death and activate antitumor immunity to kill tumor cells [3,34,35]. Furthermore, PTKPa can be a carrier of oleic acid (OA)-coated superparamagnetic iron oxide nanoparticles (OA-Fe3O4) and as a contrast agent for magnetic resonance imaging (MRI), which has the advantages of high spatial resolution and accurate anatomical localization to guide PDT. In addition, we designed a control material which employs the thioether linkage to replace poly(thioketal) bond (denoted as PSDPa). Collectively, this ROS self-activated nano system may provide a promising strategy for enhancing photodynamic-immunotherapy PDT of tumors.

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