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Biomimetic Cascade Polymer Nanoreactors for Starvation and Photodynamic Cancer Therapy.

ABSTRACT: The selective disruption of nutritional supplements and the metabolic routes of cancer cells offer a promising opportunity for more efficient cancer therapeutics. Herein, a biomimetic cascade polymer nanoreactor (GOx/CAT-NC) was fabricated by encapsulating glucose oxidase (GOx) and catalase (CAT) in a porphyrin polymer nanocapsule for combined starvation and photodynamic anticancer therapy. Internalized by cancer cells, the GOx/CAT-NCs facilitate microenvironmental oxidation by catalyzing endogenous H2O2 to form O2, thereby accelerating intracellular glucose catabolism and enhancing cytotoxic singlet oxygen (1O2) production with infrared irradiation. The GOx/CAT-NCs have demonstrated synergistic advantages in long-term starvation therapy and powerful photodynamic therapy (PDT) in cancer treatment, which inhibits tumor cells at more than twice the rate of starvation therapy alone. The biomimetic polymer nanoreactor will further contribute to the advancement of complementary modes of spatiotemporal control of cancer therapy.

SUBMITTER: Liu S

PROVIDER: S-EPMC8470963 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Biomimetic Cascade Polymer Nanoreactors for Starvation and Photodynamic Cancer Therapy.

Liu Shengda S Yan Tengfei T Sun Jianxin J Li Fei F Xu Jiayun J Sun Hongcheng H Yu Shuangjiang S Liu Junqiu J

Molecules (Basel, Switzerland) 20210916 18

The selective disruption of nutritional supplements and the metabolic routes of cancer cells offer a promising opportunity for more efficient cancer therapeutics. Herein, a biomimetic cascade polymer nanoreactor (GOx/CAT-NC) was fabricated by encapsulating glucose oxidase (GOx) and catalase (CAT) in a porphyrin polymer nanocapsule for combined starvation and photodynamic anticancer therapy. Internalized by cancer cells, the GOx/CAT-NCs facilitate microenvironmental oxidation by catalyzing endoge ...[more]

PMID: 34577080

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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.

Project description:Photodynamic-induced immunotherapy (PDI) is often hampered by low reactive oxygen species (ROS) yield, intra-tumor hypoxia, high glutathione (GSH) concentration, and immunosuppressive microenvironment. In view of this, a ruthenium (Ru)-based nanobattery (termed as IRD) with cascade-charged oxygen (O2), ROS, and photodynamic-induced immunotherapy by coordination-driven self-assembly of transition-metal Ru, photosensitizer indocyanine green (ICG), and organic ligand dithiobispropionic acid (DTPA). Then, IRD is camouflaged with macrophage membranes to obtain a nanobattery (termed as IRD@M) with targeting and immune evasion capabilities. Upon intravenous administration, IRD@M with a core-shell structure, nano diameter, and good stability can specifically hoard in tumor location and internalize into tumor cells. Upon disassembly triggered by GSH, the released Ru³⁺ not only catalyzes the conversion of endogenous hydrogen peroxide (H₂O₂) into O₂ to alleviate tumor hypoxia and reduce the expression of hypoxia-inducible factor-1α (HIF-1α), but also generates hydroxyl radicals (·OH) to elevate intracellular ROS levels. This process significantly enhances the photodynamic therapy (PDT) efficacy of the released ICG. Meanwhile, the released DTPA can significantly downregulate overexpressed GSH to reduce the elimination of ROS deriving from PDT by the exchange reaction of thiol-disulfide bond. It is also found that alleviating the hypoxic tumor microenvironment synergistically enhances the PDT efficacy, which in turn cascades to recharge the subsequent immune response, significantly improving the immunosuppressive tumor microenvironment and activating systemic tumor-specific immunity. Notably, in vitro and in vivo experimental results jointly confirm that such cascade-recharged macrophage-biomimetic Ru-based nanobattery IRD@M can achieve an obvious tumor elimination while results in a minimized side effect. Taken together, this work highlights a promising strategy for simple, flexible, and effective Ru-based immunogenic cell death (ICD) agents within PDI.

Project description: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.

Dataset Information

Biomimetic Cascade Polymer Nanoreactors for Starvation and Photodynamic Cancer Therapy.

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Biomimetic Cascade Polymer Nanoreactors for Starvation and Photodynamic Cancer Therapy.

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