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Self-Luminescing Theranostic Nanoreactors with Intraparticle Relayed Energy Transfer for Tumor Microenvironment Activated Imaging and Photodynamic Therapy.

ABSTRACT: The low tissue penetration depth of external excitation light severely hinders the sensitivity of fluorescence imaging (FL) and the efficacy of photodynamic therapy (PDT) in vivo; thus, rational theranostic platforms that overcome the light penetration depth limit are urgently needed. To overcome this crucial problem, we designed a self-luminescing nanosystem (denoted POCL) with near-infrared (NIR) light emission and singlet oxygen (¹O₂) generation abilities utilizing an intraparticle relayed resonance energy transfer strategy. Methods: Bis[3,4,6-trichloro-2-(pentyloxycarbonyl) phenyl] oxalate (CPPO) as a chemical energy source with high reactivity toward H₂O₂, poly[(9,9'-dioctyl-2,7-divinylene-fluorenylene)-alt-2-methoxy- 5-(2-ethyl-hexyloxy)-1,4-phenylene] (PFPV) as a highly efficient chemiluminescence converter, and tetraphenylporphyrin (TPP) as a photosensitizer with NIR emission and ¹O₂ generation abilities were coencapsulated by self-assembly with poly(ethyleneglycol)-co-poly(caprolactone) (PEG-PCL) and folate-PEG-cholesterol to form the POCL nanoreactor, with folate as the targeting group. A series of in vitro and in vivo analyses, including physical and chemical characterizations, tumor targeting ability, tumor microenvironment activated imaging and photodynamic therapy, as well as biosafety, were systematically investigated to characterize the POCL. Results: The POCL displayed excellent NIR luminescence and ¹O₂ generation abilities in response to H₂O₂. Therefore, it could serve as a specific H₂O₂ probe to identify tumors through chemiluminescence imaging and as a chemiluminescence-driven PDT agent for inducing tumor cell apoptosis to inhibit tumor growth due to the abnormal overproduction of H₂O₂ in the tumor microenvironment. Moreover, the folate ligand on the POCL surface can further improve the accumulation at the tumor site via a receptor-mediated mechanism, thus enhancing tumor imaging and the therapeutic effects both in vitro and in vivo but without any observable systemic toxicity. Conclusion: The nanosystem reported here might serve as a targeted, smart, precise, and noninvasive strategy triggered by the tumor microenvironment rather than by an outside light source for cancer NIR imaging and PDT treatment without limitations on penetration depth.

SUBMITTER: Wu M

PROVIDER: S-EPMC6332793 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description:BackgroundPhotodynamic therapy (PDT), a typical reactive oxygen species (ROS)-dependent treatment with high controllability, has emerged as an alternative cancer therapy modality but its therapeutic efficacy is still unsatisfactory due to the limited light penetration and constant oxygen consumption. With the development of another ROS-dependent paradigm ferroptosis, several efforts have been made to conquer the poor efficacy by combining these two approaches; however the biocompatibility, tumor-targeting capacity and clinical translation prospect of current studies still exist great concerns. Herein, a novel hypoxia-responsive nanoreactor BCFe@SRF with sorafenib (SRF) loaded inside, constructed by covalently connecting chlorin e6 conjugated bovine serum albumin (BSA-Ce6) and ferritin through azobenzene (Azo) linker, were prepared to offer unmatched opportunities for high-efficient PDT and ferroptosis synergistic therapy.ResultsThe designed BCFe@SRF exhibited appropriate size distribution, stable dispersity, excellent ROS generation property, controllable drug release capacity, tumor accumulation ability, and outstanding biocompatibility. Importantly, the BCFe@SRF could be degraded under hypoxia environment to release BSA-Ce6 for laser-triggered PDT, ferritin for iron-catalyzed Fenton reaction and SRF for tumor antioxidative defense disruption. Meanwhile, besides PDT effects, it was found that BCFe@SRF mediated treatment upon laser irradiation in hypoxic environment not only could accelerate lipid peroxidation (LPO) generation but also could deplete intracellular glutathione (GSH) and decrease glutathione peroxidase (GPX4) expression, which was believed as three symbolic events during ferroptosis. All in all, the BCFe@SRF nanoreactor, employing multiple cascaded pathways to promote intracellular ROS accumulation, presented remarkably outstanding antitumor effects both in vitro and in vivo.ConclusionBCFe@SRF could serve as a promising candidate for synergistic PDT and ferroptosis therapy, which is applicable to boost oxidative damage within tumor site and will be informative to future design of ROS-dependent therapeutic nanoplatforms.

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Self-Luminescing Theranostic Nanoreactors with Intraparticle Relayed Energy Transfer for Tumor Microenvironment Activated Imaging and Photodynamic Therapy.

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