Intelligent Nanodelivery System‐Generated ¹O₂ Mediates Tumor Vessel Normalization by Activating Endothelial TRPV4‐eNOS Signaling

Abstract

Tumor microenvironment (TME)‐responsive intelligent photodynamic therapy (PDT) systems have attracted increasing interest in anticancer therapy, due to their potential to address significant and unsatisfactory therapeutic issues, such as limited tissue penetration, inevitable normal tissue damage, and excessive impaired vessels. Here, an H2O2‐triggered intelligent LCL/ZnO PDT nanodelivery system is elaborately designed. LCL/ZnO can selectively regulate tumor‐derived endothelial cells (TECs) and specifically kill tumor cells, by responding to different H2O2 gradients in TECs and tumor cells. The LCL/ZnO is able to normalize tumor vessels, thereby resulting in decreased metastases, and ameliorating the immunosuppressive TME. Further analysis demonstrates that singlet oxygen (1O2)‐activated transient receptor potential vanilloid‐4‐endothelial nitric oxide synthase signals generated in TECs by LCL/ZnO induce tumor vascular normalization, which is identified as a novel mechanism contributing to the increased ability of PDT to promote cancer therapy. In conclusion, designing an intelligent PDT nanodelivery system response to the TME, that includes both selective TECs regulation and specific tumor‐killing, will facilitate the development of effective interventions for future clinical applications.

Antitumor Activity of the Zinc Oxide Nanoparticles Coated with Low-Molecular-Weight Heparin and Doxorubicin Complex In Vitro and In Vivo

“…As shown in Figure I, both ZnO-LD NPs and ZnO NPs could produce oxygen, and oxygen production increased over time, while H 2 O 2 solutions cannot generate oxygen. We previously investigated and confirmed that ZnO NPs can relieve hypoxia at the tumor site and normalize tumor vessels . Considering the present results, we suggested that ZnO-LD NPs could have potential application in tumor vascular normalization therapy.…”

“…We previously investigated and confirmed that ZnO NPs can relieve hypoxia at the tumor site and normalize tumor vessels. 43 Considering the present results, we suggested that ZnO-LD NPs could have potential application in tumor vascular normalization therapy.…”

“…41,42 Recently, we designed an H 2 O 2 -triggered intelligent photodynamic therapy (PDT) nano delivery system, LCL/ZnO, that could selectively regulate the tumor-derived endothelial cells (TECs) and specifically kill tumor cells by producing different singlet oxygen ( 1 O 2 ) in response to different H 2 O 2 gradients in TECs and tumor cells. 43 In the LCL/ZnO system, the ZnO NPs, as nanozymes, act as a catalyst for the reaction between luminol and H 2 O 2 and can regulate the sensitivity of the response to H 2 O 2 , further regulating the intramolecular chemiluminescent resonance energy transfer (CRET) from luminol (donor) to Ce6 (acceptor) to generate different 1 It has been reported that the chemotherapeutic drug could be also adsorbed to the surface of ZnO NPs through electrostatic attraction or chelation, forming hybrid NPs, achieving pH-triggered on-demand drug release for producing more antitumor efficiency. 35 In our previous research, we synthesized low-molecular-weight heparin−doxorubicin complex (LMHP-DOX) and prepared LMHP-DOX NPs.…”

“…Acidity is a unique hallmark of the tumor microenvironment. − Many pH-sensitive nanomedicines were designed and prepared to respond to the acidic tumor microenvironment promoting antitumor efficiency. − Inorganic nanomaterials, which possess a diverse range of structure, composition, morphology, and physicochemical properties have been used in cancer treatment and diagnosis as delivery carriers. − Recently, various metal oxides or calcium-based nanomaterials have been widely used as pH-sensitive inorganic nanomaterials. − It has been reported that ZnO NPs could be used as pH-responsive drug carriers, which possess pH-triggered drug release characteristics displaying a response to acid and a rapid dissolution to Zn 2+ at pH <5.5, especially in lysosomes used for intracellular drug delivery platforms. − The intracellular Zn 2+ produced by ZnO NPs has cytotoxic effects in tumor cells. , In addition, ZnO NPs could significantly induce the generation of ROS in tumor cells. − In particular, ZnO NPs can make full utilization of disproportional reaction, Haber–Weiss reaction, or Fenton reaction to compensate for O 2 -depletion, thus greatly improving the therapeutic efficacy against hypoxic tumors . ZnO NPs also have good optical properties and high stability to be a promising candidate for bioimaging. , ZnO NPs could be used to in situ upconvert NIR to visible light through the second harmonic generation (SHG) mechanism for tumor imaging. , Recently, we designed an H 2 O 2 -triggered intelligent photodynamic therapy (PDT) nano delivery system, LCL/ZnO, that could selectively regulate the tumor-derived endothelial cells (TECs) and specifically kill tumor cells by producing different singlet oxygen ( 1 O 2 ) in response to different H 2 O 2 gradients in TECs and tumor cells . In the LCL/ZnO system, the ZnO NPs, as nanozymes, act as a catalyst for the reaction between luminol and H 2 O 2 and can regulate the sensitivity of the response to H 2 O 2 , further regulating the intramolecular chemiluminescent resonance energy transfer (CRET) from luminol (donor) to Ce6 (acceptor) to generate different 1 O 2 gradients.…”

Research progress of stimuli-responsive ZnO-based nanomaterials in biomedical applications

“…As mentioned above, many researchers have reported visible/NIR mediated PDT of ZnO-based nanomaterials for antimicrobial infection, inflammation regulation and antitumor therapy. 62–64…”