Abstract
Angiogenesis in the tumor microenvironment is the main cause for the insensitivity of tumor cells to chemoradiotherapy. Strategies for increasing the sensitivity of tumor cells to conventional therapies using nanoparticles are limited. In this study, we developed rationally designed microenvironment response nanoparticles with physicochemical and biological features to overcome cisplatin resistance by using decomposition product from Zr-metal-organic framework (MOF) to inhibit the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)/vascular endothelial growth factor (VEGF) pathway in chemoradiotherapy. Cisplatin (CDDP) is encapsulated into Zr-MOF and bovine serum albumin (BSA) is modified into the surface of nanoparticles to create CDDP@Zr-MOF-BSA (abbreviated as CDDP@Zr-MOF), which acts as an excellent radiosensitizer and exhibits microenvironment response, preferable tumor accumulation, high-efficiency inhibition of angiogenesis, and obviously reduced efflux on resistant A549 cells. The rate of angiogenesis inhibition in the combined treatment group is 6-fold higher than that in other control groups. Moreover, CDDP@Zr-MOF not only increases the therapeutic effect remarkably, but also regulates the tumor microenvironment and inhibits the expression of a drug-efflux transporter, namely multidrug resistance-associated protein 1 (MRP1), for reversing drug resistance in A549R cells. Thus, CDDP@Zr-MOF causes synergistic cytotoxicity in A549R cells, and high-efficiency eradication of cisplatin-resistant tumor without regrowth by inhibiting angiogenesis in the tumor microenvironment. The microenvironment responsiveness of CDDP@Zr-MOF provides a multipurpose synergistic approach for treating drug-resistant tumors with chemoradiotherapy.
摘要
肿瘤微环境中的血管生成是肿瘤细胞对放化疗不敏感的主要原 因. 在本项研究中, 我们设计了一种微环境响应型的纳米颗粒, 利用Zr-MOF的分解产物抑制肿瘤细胞中的PI3K/AKT/mTOR/VEGF通路, 从而 克服A549R细胞对顺铂的耐药性. 我们将顺铂包裹在Zr-MOF中, 并在 表面修饰BSA, 形成了CDDP@Zr-MOF-BSA纳米复合体, 该复合体在肿 瘤微环境中有良好的响应性, 有助于在肿瘤区域蓄积, 展现出卓越的血 管生成抑制能力, 并能明显降低药物的外排. 此外, CDDP@Zr-MOFBSA 能显著抑制多药耐药相关蛋白1 (MRP1)的表达, 从而逆转A549R 细胞的耐药性. 总体而言, CDDP@Zr-MOF-BSA对A549R有细胞毒性, 能抑制肿瘤微环境中的血管生成, 最终有效提高顺铂耐药肿瘤的治疗 效果. CDDP@Zr-MOF-BSA为放化疗治疗耐药肿瘤提供了一种多功能 协同的方法.
Article PDF
Similar content being viewed by others
References
Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature, 2019, 575: 299–309
Chen Q, Chen J, Yang Z, et al. Nanoparticle-enhanced radiotherapy to trigger robust cancer immunotherapy. Adv Mater, 2019, 31: 1802228
Chen Q, Xu L, Liang C, et al. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy. Nat Commun, 2016, 7: 13193
Xu J, Xu L, Wang C, et al. Near-infrared-triggered photodynamic therapy with multitasking upconversion nanoparticles in combination with checkpoint blockade for immunotherapy of colorectal cancer. ACS Nano, 2017, 11: 4463–4474
Zhang LN, Xin T, Chen M, et al. Chemoresistance in mesenchymal lung cancer cells is correlated to high regulatory T cell presence in the tumor microenvironment. IUBMB Life, 2019, 71: 986–991
Naghizadeh S, Mohammadi A, Baradaran B, et al. Overcoming multiple drug resistance in lung cancer using siRNA targeted therapy. Gene, 2019, 714: 143972
Yang G, Xu L, Chao Y, et al. Hollow MnO2 as a tumor-microenvironment-responsive biodegradable nano-platform for combination therapy favoring antitumor immune responses. Nat Commun, 2017, 8: 902
Xu J, Lv J, Zhuang Q, et al. A general strategy towards personalized nanovaccines based on fluoropolymers for post-surgical cancer immunotherapy. Nat Nanotechnol, 2020, 15: 1043–1052
Xing Y, Liu Y, Liu T, et al. TNFAIP8 promotes the proliferation and cisplatin chemoresistance of non-small cell lung cancer through MDM2/p53 pathway. Cell Commun Signal, 2018, 16: 43
Li Y, Deng Y, Tian X, et al. Multipronged design of light-triggered nanoparticles to overcome cisplatin resistance for efficient ablation of resistant tumor. ACS Nano, 2015, 9: 9626–9637
Fang L, Qin X, Zhao J, et al. Construction of dual stimuli-responsive platinum(IV) hybrids with NQO1 targeting ability and overcoming cisplatin resistance. Inorg Chem, 2019, 58: 2191–2200
Bao X, Sun Y, Bao C, et al. Design, synthesis and evaluation of N-hydroxypropenamides based on adamantane to overcome resistance in NSCLC. Bioorg Chem, 2019, 86: 696–704
Liu W, Du Y, Wen R, et al. Drug resistance to targeted therapeutic strategies in non-small cell lung cancer. Pharmacol Ther, 2020, 206: 107438
Zhao H, Xu J, Li Y, et al. Nanoscale coordination polymer based nanovaccine for tumor immunotherapy. ACS Nano, 2019, 13: 13127–13135
Tang Z, Liu Y, He M, et al. Chemodynamic therapy: Tumour microenvironment-mediated Fenton and Fenton-like reactions. Angew Chem Int Ed, 2019, 58: 946–956
Zhuang W, Xu Y, Li G, et al. Redox and pH dual-responsive polymeric micelles with aggregation-induced emission feature for cellular imaging and chemotherapy. ACS Appl Mater Interfaces, 2018, 10: 18489–18498
Zheng DW, Lei Q, Zhu JY, et al. Switching apoptosis to ferroptosis: Metal-organic network for high-efficiency anticancer therapy. Nano Lett, 2017, 17: 284–291
Dong X, Pan P, Zheng DW, et al. Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer. Sci Adv, 2020, 6: 1590
Xu Y, Han X, Li Y, et al. Sulforaphane mediates glutathione depletion via polymeric nanoparticles to restore cisplatin chemosensitivity. ACS Nano, 2020, 13: 13445–13455
Zheng DW, Dong X, Pan P, et al. Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy. Nat Biomed Eng, 2019, 3: 717–728
Zhang J, Chen C, Fu H, et al. MicroRNA-125a-loaded polymeric nanoparticles alleviate systemic lupus erythematosus by restoring effector/regulatory T cells balance. ACS Nano, 2020, 14: 4414–4429
Gadhave D, Gorain B, Tagalpallewar A, et al. Intranasal teriflunomide microemulsion: An improved chemotherapeutic approach in glioblastoma. J Drug Deliver Sci Tech, 2019, 51: 276–289
Akbarzadeh A, Rezaei-Sadabady R, Davaran S, et al. Liposome: Classification, preparation, and applications. Nanoscale Res Lett, 2013, 8: 102
Zhang Y, Dong Y, Fu H, et al. Multifunctional tumor-targeted PLGA nanoparticles delivering Pt(IV)/siBIRC5 for US/MRI imaging and overcoming ovarian cancer resistance. Biomaterials, 2021, 269: 120478
Xia Y, Sun J, Zhao L, et al. Magnetic field and nano-scaffolds with stem cells to enhance bone regeneration. Biomaterials, 2018, 183: 151–170
Li T, Wang P, Guo W, et al. Natural berberine-based Chinese herb medicine assembled nanostructures with modified antibacterial application. ACS Nano, 2019, 13: 6770–6781
Gong N, Zhang Y, Teng X, et al. Proton-driven transformable nanovaccine for cancer immunotherapy. Nat Nanotechnol, 2020, 15: 1053–1064
Zeng X, Wang Y, Han J, et al. Fighting against drug-resistant tumors using a dual-responsive Pt(IV)/Ru(II) bimetallic polymer. Adv Mater, 2020, 32: 2004766
Yang B, Chen Y, Shi J. Exosome biochemistry and advanced nanotechnology for next-generation theranostic platforms. Adv Mater, 2019, 31: 1802896
Yue W, Chen L, Yu L, et al. Checkpoint blockade and nanosonosensitizer-augmented noninvasive sonodynamic therapy combination reduces tumour growth and metastases in mice. Nat Commun, 2019, 10: 2025
Xia D, Xu P, Luo X, et al. Overcoming hypoxia by multistage nanoparticle delivery system to inhibit mitochondrial respiration for photodynamic therapy. Adv Funct Mater, 2019, 29: 1807294
Dai L, Li X, Duan X, et al. A pH/ROS cascade-responsive charge-reversal nanosystem with self-amplified drug release for synergistic oxidation-chemotherapy. Adv Sci, 2019, 6: 1801807
Zhu W, Shan X, Wang T, et al. miR-181b modulates multidrug resistance by targeting BCL2 in human cancer cell lines. Intl J Cancer, 2010, 127: 2520–2529
Huo M, Wang L, Chen Y, et al. Tumor-selective catalytic nanomedicine by nanocatalyst delivery. Nat Commun, 2017, 8: 357
Cheng YJ, Hu JJ, Qin SY, et al. Recent advances in functional mesoporous silica-based nanoplatforms for combinational photo-chemotherapy of cancer. Biomaterials, 2020, 232: 119738
Jiang P, Xu H, Xu C, et al. NEAT1 contributes to the CSC-like traits of A549/CDDP cells via activating Wnt signaling pathway. Chem-Biol Interact, 2018, 296: 154–161
Zhang W, Zhang Z, Tung CH. Beyond chemotherapeutics: Cisplatin as a temporary buckle to fabricate drug-loaded nanogels. Chem Commun, 2017, 53: 779–782
Zhou R, Yan L, Dong X, et al. Fractionated regimen-suitable immunoradiotherapy sensitizer based on ultrasmall Fe4Se2W18 nanoclusters enable tumor-specific radiosensitization augment and antitumor immunity boost. Nano Today, 2021, 36: 101003
Wang L, Gao F, Wang A, et al. Defect-rich adhesive molybdenum disulfide/rGO vertical heterostructures with enhanced nanozyme activity for smart bacterial killing application. Adv Mater, 2020, 32: 2005423
Yan L, Zhao F, Wang J, et al. Clinical nanomaterials: A safe-by-design strategy towards safer nanomaterials in nanomedicines. Adv Mater, 2019, 31: 1970325
Mautschke HH, Drache F, Senkovska I, et al. Catalytic properties of pristine and defect-engineered Zr-MOF-808 metal organic frameworks. Catal Sci Technol, 2018, 8: 3610–3616
Cong Y, Xiao H, Xiong H, et al. Dual drug backboned shattering polymeric theranostic nanomedicine for synergistic eradication of patient-derived lung cancer. Adv Mater, 2018, 30: 1706220
Wu X, Wu Y, Ye H, et al. Interleukin-15 and cisplatin co-encapsulated thermosensitive polypeptide hydrogels for combined immuno-chemotherapy. J Control Release, 2017, 255: 81–93
Chu PC, Wu YC, Chen CY, et al. Novel HIF-1α inhibitor CDMP-TQZ for cancer therapy. Future Med Chem, 2021, 13: 1057–1072
Wu H, Jin H, Wang C, et al. Synergistic cisplatin/doxorubicin combination chemotherapy for multidrug-resistant cancer via polymeric nanogels targeting delivery. ACS Appl Mater Interfaces, 2017, 9: 9426–9436
Min H, Wang J, Qi Y, et al. Biomimetic metal-organic framework nanoparticles for cooperative combination of antiangiogenesis and photodynamic therapy for enhanced efficacy. Adv Mater, 2019, 31: 1808200
Li Z, Di C, Li S, et al. Smart nanotherapeutic targeting of tumor vasculature. Acc Chem Res, 2019, 52: 2703–2712
Wang B, Ding Y, Zhao X, et al. Delivery of small interfering RNA against Nogo-B receptor via tumor-acidity responsive nanoparticles for tumor vessel normalization and metastasis suppression. Biomaterials, 2018, 175: 110–122
Ma T, Liu Y, Wu Q, et al. Quercetin-modified metal-organic frameworks for dual sensitization of radiotherapy in tumor tissues by inhibiting the carbonic anhydrase IX. ACS Nano, 2019, 13: 4209–4219
Acknowledgements
This work was supported by the National Natural Science Foundation of China (82172041 and 81801808), Harbin Medical University Cancer Hospital Haiyan Foundation (JJZD202101, JJQN2019-02, and JJZD2018-02), Heilongjiang Postdoctoral Fund (LBH-Z18160 and LBH-TZ2018), the Natural Science Foundation of Heilongjiang (YQ2023H023 and LH2020H127), and Heilongjiang Province Youth Innovative Talents Training Program (UNPYSCT-2020162).
Author information
Authors and Affiliations
Contributions
Author contributions Song C, Xie C, and Guan X designed and performed the experiments, analyzed the data, and wrote the manuscript. Wu Q provided the technical or material support. Jiang S and Hong Z conducted the data analysis and gave insightful suggestions and comments on the outline of this manuscript. Qu G, Ma T, and Cui Y supervised the entire project, obtained the fundings, designed the experiments, and revised the manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest The authors declare that they have no conflict of interest.
Additional information
Supplementary information Supporting data are available in the online version of the paper.
Chunyu Song received his master’s degree in oncology from Harbin Medical University (2014). His primary focus is on clinical diagnosis, treatment, and fundamental research of bone and soft tissue tumors.
Guofan Qu received his PhD degree in oncology from Harbin Medical University in 2007. Prof. Qu is currently a chief physician and doctoral supervisor at the Department of Orthopedics, Harbin Medical University Cancer Hospital, focusing on clinical diagnosis, treatment, and basic research of bone tumors and soft tissue tumors.
Electronic Supplementary Material
40843_2023_2774_MOESM1_ESM.pdf
Inhibiting PI3K/AKT/mTOR signaling by metal-organic frameworks for overcoming multiple drug resistance in chemoradiotherapy
Rights and permissions
About this article
Cite this article
Song, C., Guan, X., Xie, C. et al. Inhibiting PI3K/AKT/mTOR signaling by metal-organic frameworks for overcoming multiple drug resistance in chemoradiotherapy. Sci. China Mater. (2024). https://doi.org/10.1007/s40843-023-2774-8
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s40843-023-2774-8