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A biomimetic nanoreactor for synergistic chemiexcited photodynamic therapy and starvation therapy against tumor metastasis.

ABSTRACT: Photodynamic therapy (PDT) is ineffective against deeply seated metastatic tumors due to poor penetration of the excitation light. Herein, we developed a biomimetic nanoreactor (bio-NR) to achieve synergistic chemiexcited photodynamic-starvation therapy against tumor metastasis. Photosensitizers on the hollow mesoporous silica nanoparticles (HMSNs) are excited by chemical energy in situ of the deep metastatic tumor to generate singlet oxygen (¹O₂) for PDT, and glucose oxidase (GOx) catalyzes glucose into hydrogen peroxide (H₂O₂). Remarkably, this process not only blocks the nutrient supply for starvation therapy but also provides H₂O₂ to synergistically enhance PDT. Cancer cell membrane coating endows the nanoparticle with biological properties of homologous adhesion and immune escape. Thus, bio-NRs can effectively convert the glucose into ¹O₂ in metastatic tumors. The excellent therapeutic effects of bio-NRs in vitro and in vivo indicate their great potential for cancer metastasis therapy.

SUBMITTER: Yu Z

PROVIDER: S-EPMC6262009 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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A biomimetic nanoreactor for synergistic chemiexcited photodynamic therapy and starvation therapy against tumor metastasis.

Yu Zhengze Z Zhou Ping P Pan Wei W Li Na N Tang Bo B

Nature communications 20181128 1

Photodynamic therapy (PDT) is ineffective against deeply seated metastatic tumors due to poor penetration of the excitation light. Herein, we developed a biomimetic nanoreactor (bio-NR) to achieve synergistic chemiexcited photodynamic-starvation therapy against tumor metastasis. Photosensitizers on the hollow mesoporous silica nanoparticles (HMSNs) are excited by chemical energy in situ of the deep metastatic tumor to generate singlet oxygen (<sup>1</sup>O<sub>2</sub>) for PDT, and glucose oxida ...[more]

PMID: 30487569

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Project description:Rationale: Glucose oxidase (GOx)-based biocatalytic nanoreactors can cut off the energy supply of tumors for starvation therapy and deoxygenation-activated chemotherapy. However, these nanoreactors, including mesoporous silica, calcium phosphate, metal-organic framework, or polymer nanocarriers, cannot completely block the reaction of GOx with glucose in the blood, inducing systemic toxicity from hydrogen peroxide (H2O2) and anoxia. The low enzyme loading capacity can reduce systemic toxicity but limits its therapeutic effect. Here, we describe a real 'ON/OFF' intelligent nanoreactor with a core-shell structure (GOx + tirazapamine (TPZ))/ZIF-8@ZIF-8 modified with the red cell membrane (GTZ@Z-RBM) for cargo delivery. Methods: GTZ@Z-RBM nanoparticles (NPs) were prepared by the co-precipitation and epitaxial growth process under mild conditions. The core-shell structure loaded with GOx and TPZ was characterized for hydrate particle size and surface charge. The GTZ@Z-RBM NPs morphology, drug, and GOx loading/releasing abilities, system toxicity, multimodal synergistic therapy, and tumor metastasis suppression were investigated. The in vitro and in vivo outcomes of GTZ@Z-RBM NPs were assessed in 4T1 breast cancer cells. Results: GTZ@Z-RBM NPs could spatially isolate the enzyme from glucose in a physiological environment, reducing systemic toxicity. The fabricated nanoreactor with high enzyme loading capacity and good biocompatibility could deliver GOx and TPZ to the tumors, thereby exhausting glucose, generating H2O2, and aggravating hypoxic microenvironment for starvation therapy, DNA damage, and deoxygenation-activated chemotherapy. Significantly, the synergistic therapy effectively suppressed the breast cancer metastasis in mice and prolonged life without systemic toxicity. The in vitro and in vivo results provided evidence that our biomimetic nanoreactor had a powerful synergistic cascade effect in treating breast cancer. Conclusion: GTZ@Z-RBM NPs can be used as an 'ON/OFF' intelligent nanoreactor to deliver GOx and TPZ for multimodal synergistic therapy and tumor metastasis suppression.

Project description:Although the enzyme catalytic nanoreactors reported so far have achieved excellent therapeutic efficacy, how to accurately exert enzyme activity in the tumor microenvironment to specifically kill tumor cells and avoid systemic oxidative damage would be an inevitable challenge for catalytic nanomedicine. At the present study, we fabricate an advanced biomimetic nanoreactor, SOD-Fe0@Lapa-ZRF for tumor multi-enzyme cascade delivery that combined specifically killing tumor cells and protect cells from oxidative stress. Methods: We first synthesized the FeNP-embedded SOD (SOD-Fe0) by reduction reaction using sodium borohydride. Next, SOD-Fe0 and Lapa cargo were encapsulated in ZIF-8 by self-assembly. In order to protect the cargo enzyme from digestion by protease and prolong blood circulating time, SOD-Fe0@Lapa-Z was further cloaked with RBC membrane and functionalized with folate targeting, resulting in the final advanced biomimetic nanoreactor SOD-Fe0@Lapa-ZRF. Results: Once internalized, ZIF-8 achieves pH-triggered disassembly in weakly acidic tumor microenvironment. The released SOD-Fe0 and Lapa were further endocytosed by tumor cells and the Lapa produces superoxide anion (O2 -•) through the catalysis of NQO1 that is overexpressed in tumor cells, while O2 -• is converted to H2O2 via SOD. At this time, the released ferrous ions from SOD-Fe0 and H2O2 are further transformed to highly toxic hydroxyl radicals (•OH) for specifically killing tumor cells, and there was no obvious toxicological response during long-term treatment. Importantly, SOD-Fe0@Lapa-ZRF enhanced the normal cell's anti-oxidation ability, and thus had little effect on the secretion of TNF-α, IL-6 and IL-1β pro-inflammatory cytokines, while effectively reversed the decreased activity of T-SOD and GSH-Px and remained stable MDA content after tumor treatment. In vitro and in vivo results indicate that the tumor microenvironment-responsive release multi-enzyme cascade have high tumor specificity and effective anti-tumor efficacy, and can protect cells from oxidative stress damage. Conclusion: The biomimetic nanoreactor will have a great potential in cancer nanomedicine and provide a novel strategy to regulate oxidative stress.

Dataset Information

A biomimetic nanoreactor for synergistic chemiexcited photodynamic therapy and starvation therapy against tumor metastasis.

Publications

A biomimetic nanoreactor for synergistic chemiexcited photodynamic therapy and starvation therapy against tumor metastasis.

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