Synergistic effect of Zinc Phthalocyanine (ZnPC)@MIL-101 framework and laser radiation on mcf-7 breast cancer cells: an experimental combination study

Document Type : Research Paper

Authors

1 Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

2 Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Medical Laser, Medical Laser Research Center, Yara Institute, ACECR, Tehran, Iran

5 Nuclear Medicine Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

10.22038/nmj.2026.89968.2274

Abstract

Objective(s): Zinc phthalocyanine (ZnPC), a potent photosensitizer for photodynamic therapy (PDT), often suffers from poor solubility and aggregation, limiting its efficacy. Metal-organic frameworks (MOFs) like MIL-101 can serve as nanocarriers to overcome these issues. This experimental study investigates the synthesis, characterization, and synergistic anticancer efficacy of ZnPC incorporated within the MIL-101 framework (ZnPC@MIL-101) against MCF-7 breast cancer cells. ZnPC was chosen for its strong red-light absorption and high reactive oxygen species (ROS) generation, while MIL-101 offers a stable, porous platform to enhance ZnPC delivery and photoactivity.
Materials and Methods: ZnPC@MIL-101 (Cr) was synthesized via a double-solvent method. Characterization involved PXRD, BET analysis, FESEM, DLS, EDX spectroscopy, and UV-Vis spectroscopy. The loading capacity was determined, and singlet oxygen generation was quantified. Anticancer efficacy and PDT synergy with 660 nm laser radiation were evaluated on MCF-7 cells using MTT assays. Statistical analysis was performed using ANOVA.
Result: Successful synthesis of crystalline ZnPC@MIL-101 was confirmed. The loading capacity of ZnPC was found to be 8.5%. BET analysis showed reduced surface area (1709.4 m²/g) and pore size (1.71 nm) post-ZnPC loading, indicating effective incorporation. FESEM/DLS showed particle sizes around 368/439.7 nm, respectively. EDX confirmed uniform Zn distribution. The UV-Vis spectrum of ZnPC@MIL-101 displayed the characteristic Q-band of ZnPC, and the nanocomposite exhibited significant singlet oxygen generation upon laser irradiation. ZnPC@MIL-101 exhibited moderate dark toxicity (IC50: 25 µg/mL), which was significantly enhanced upon laser irradiation (IC50: 10 µg/mL, p < 0.01).
Conclusion: ZnPC@MIL-101 combined with laser radiation demonstrated a significant synergistic reduction in MCF-7 cell viability. This highlights its potential as an effective PDT agent, offering a promising strategy to enhance ZnPC-based cancer treatment.

Keywords

Main Subjects


  1. Correia JH, Rodrigues JA, Pimenta S, Dong T, Yang Z. Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions. Pharmaceutics. 2021;13(9):1332.‏
  2. Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, et al. Photodynamic therapy. J Natl Cancer Inst. 1998;90(12):889-905.
  3. Tunç T, Karakuş G, Sümer Z. Investigation of Cytotoxic and Antimicrobial Effects of Polyanhydride-Based Poly[(maleic anhydride)-co-(vinyl Acetate)] Conjugates Combined with Methotrexate and Gemcitabine in Breast Cancer Treatment. ACS Omega. 2025;10(12):12152-12162.
  4. Khan SY, Bah T, Layeequr Rahman R. The Role of Molecular Profiling in De-Escalation of Toxic Therapy in Breast Cancer. Int J Mol Sci. 2025;26(3):1332.
  5. Fakudze N, Abrahamse H, George B. Nanoparticles improved pheophorbide-a mediated photodynamic therapy for cancer. Lasers Med Sci. 2025;40(1): 1-8.
  6. Erdemir GY, Kuruçay A, Ates B, Altundas A. Development of 1,2,3-Triazolopyridazinone Derivatives as Potential Caspase 3 and Apoptosis Inducers: Design, Synthesis and Anticancer Activity Studies. J Biochem Mol Toxicol. 2025;39(3):e70216.‏
  7. Khosrojerdi S, Gholami L, Khazaei M, Hashemzadeh A, Darroudi M, Oskuee RK. Synthesis and evaluation of gene delivery vectors based on PEI-modified metal-organic framework (MOF) nanoparticles. Iran J Basic Med Sci. 2024;27(2):203.
  8. Hashemzadeh A, Drummen GP, Avan A, Darroudi M, Khazaei M, Khajavian R, et al. When metal–organic framework–mediated smart drug delivery meets gastrointestinal cancers. J Mater Chem B 2021;9(19):3967-3982.
  9. Xue Z, Zhu M, Dong Y, Feng T, Chen Z, Feng Y, et al. An integrated targeting drug delivery system based on the hybridization of graphdiyne and MOFs for visualized cancer therapy. Nanoscale. 2019;11(24):11709-11718.
  10. Li B, Ashrafizadeh M, Jiao T. Biomedical application of metal-organic frameworks (MOFs) in cancer therapy: Stimuli-responsive and biomimetic nanocomposites in targeted delivery, phototherapy and diagnosis. Int J Biol Macromol. 2024; 260:129391.
  11. Shaabani A, Sepahvand H, Amini MM, Hashemzadeh A, Boroujeni MB, Badali E. Tandem oxidative isocyanide-based cycloaddition reactions in the presence of MIL-101 (Cr) as a reusable solid catalyst. Tetrahedron. 2018;74(15):1832-1837.
  12. Boroujeni MB, Hashemzadeh A, Faroughi M-T, Shaabani A, Amini MM. Magnetic MIL-101-SO 3 H: a highly efficient bifunctional nanocatalyst for the synthesis of 1, 3, 5-triarylbenzenes and 2, 4, 6-triaryl pyridines. RSC advances. 2016;6(102):100195-100202.
  13. Kocaağa N, Türkkol A, Bilgin MD, Erdoğmuş A. The synthesis of novel water-soluble zinc (II) phthalocyanine based photosensitizers and exploring of photodynamic therapy activities on the PC3 cancer cell line. Photochem Photobiol Sci. 2023;22(9):2037-2053.
  14. Halkiotis KN, Uzunoglu NK, Loukas S, Pantelias GE, Trafalis D, Yova D, editors. Influence of drug and light dose in determining PDT efficacy in human pancreatic cancer cells, treated with zinc tetrasulfonated phthalocyanines (ZnTSPc). Proc SPIE-Int Soc Opt Eng. 1997;3191:243-252.
  15. Feuser PE, Cordeiro AP, de Bem Silveira G, Borges Corrêa MEA, Lock Silveira PC, Sayer C, et al. Co-encapsulation of sodium diethyldithiocarbamate (DETC) and zinc phthalocyanine (ZnPc) in liposomes promotes increases phototoxic activity against (MDA-MB 231) human breast cancer cells. Colloids Surf B. 2021;197:111434.
  16. Wysocki M, Ziental D, Biyiklioglu Z, Jozkowiak M, Baş H, Dlugaszewska J, et al. Non-peripheral octasubstituted zinc(II) phthalocyanines bearing pyridinepropoxy substituents – Antibacterial, anticancer photodynamic and sonodynamic activity. J Inorg Biochem. 2025;262:112751.
  17. Demirbaş Ü, Pişkin M, Durmuş M, Kantekin H. Metal or metal-free phthalocyanines containing morpholine substituents: synthesis, spectroscopic and photophysicochemical properties. J Coord Chem. 2022;75(9-10):1243-1255.
  18. Roguin LP, Chiarante N, García Vior MC, Marino J. Zinc(II) phthalocyanines as photosensitizers for antitumor photodynamic therapy. Int J Biochem Cell Biol. 2019;114:105575.
  19. Nash GT, Luo T, Lan G, Ni K, Kaufmann M, Lin W. Nanoscale Metal-Organic Layer Isolates Phthalocyanines for Efficient Mitochondria-Targeted Photodynamic Therapy. J Am Chem Soc. 2021;143(5):2194-2199.
  20. Yang Z, Li P, Chen Y, Dong E, Feng Z, He Z, et al. Preparation of zinc phthalocyanine-loaded amphiphilic phosphonium chitosan nanomicelles for enhancement of photodynamic therapy efficacy. Colloids Surf B. 2021;202:111693.
  21. Kong J, Cai M, Zhu R, Zhang Y, Du Y, Jing X, et al. The utilization of metal-organic frameworks in tumor-targeted drug delivery systems. J Sci: Adv Mater Devices. 2024;9(3):100770.
  22. Luo T, Nash GT, Xu Z, Jiang X, Liu J, Lin W. Nanoscale Metal-Organic Framework Confines Zinc-Phthalocyanine Photosensitizers for Enhanced Photodynamic Therapy. J Am Chem Soc. 2021;143(34):13519-13524.
  23. Liu J, Kang DW, Fan Y, Nash GT, Jiang X, Weichselbaum RR, et al. Nanoscale Covalent Organic Framework with Staggered Stacking of Phthalocyanines for Mitochondria-Targeted Photodynamic Therapy. J Am Chem Soc. 2024;146(1):849-857.
  24. Mhettar P, Kale N, Pantwalawalkar J, Nangare S, Jadhav N. Metal-organic frameworks: Drug delivery applications and future prospects. Admet dmpk. 2024;12(1):27-62.
  25. Li D, Cai S, Wang P, Cheng H, Cheng B, Zhang Y, et al. Innovative Design Strategies Advance Biomedical Applications of Phthalocyanines. Adv Healthc Mater. 2023;12(22):2300263.
  26. Ye Y, Zhao Y, Sun Y, Cao J. Recent Progress of Metal-Organic Framework-Based Photodynamic Therapy for Cancer Treatment. Int J Nanomedicine. 2022;17:2367-2395.
  27. Zhao W, Wang L, Zhang M, Liu Z, Wu C, Pan X, et al. Photodynamic therapy for cancer: mechanisms, photosensitizers, nanocarriers, and clinical studies. MedComm. 2024;5(7):e603.
  28. Li M, Zhang Z, Yu Y, Yuan H, Nezamzadeh-Ejhieh A, Liu J, et al. Recent advances in Zn-MOFs and their derivatives for cancer therapeutic applications. Mater Adv. 2023;4(21):5050-5093.
  29. Zhong YT, Cen Y, Xu L, Li SY, Cheng H. Recent Progress in Carrier-Free Nanomedicine for Tumor Phototherapy. Adv Healthc Mater. 2023;12(4):2202307.
  30. Sun J, Zhang X, Zhang D, Chen YP, Wang F, Li L, et al. Building Block Symmetry Relegation Induces Mesopore and Abundant Open-Metal Sites in Metal-Organic Frameworks for Cancer Therapy. CCS Chem. 2022;4(3):996-1006.
  31. Kalhori F, Yazdyani H, Khademorezaeian F, Hamzkanloo N, Mokaberi P, Hosseini S, et al. Enzyme activity inhibition properties of new cellulose nanocrystals from Citrus medica L. pericarp: A perspective of cholesterol lowering. Luminescence. 2022;37(11):1836-1845.
  32. Ghoochani SH, Hosseini HA, Sabouri Z, Soheilifar MH, Neghab HK, Hashemzadeh A, et al. Zn(II) porphyrin–encapsulated MIL-101 for photodynamic therapy of breast cancer cells. Lasers Med Sci. 2023;38(1):151.
  33. Chota A, Abrahamse H, George BP. Green synthesis and characterization of AgNPs, liposomal loaded AgNPs, and ZnPcS4 photosensitizer for enhanced photodynamic therapy effects in MCF-7 breast cancer cells. Photodiagn Photodyn Ther. 2024;48:104252.
  34. Chota A, Abrahamse H, George BP. Chemotoxic and phototoxic effects of liposomal co-delivery of green synthesized silver nanoparticles and ZnPcS4 for enhanced photodynamic therapy in MCF-7 breast cancer cells: An in vitro study. Biomed Pharmacother. 2025;185:117986.
  35. Larroque C, Pelegrin A, Van Lier JE. Serum albumin as a vehicle for zinc phthalocyanine: Photodynamic activities in solid tumour models. BR J CANCER. 1996;74(12):1886-1890.
  36. Hashemzadeh A, Amini MM, Tayebee R, Sadeghian A, Durndell LJ, Isaacs MA, et al. A magnetically-separable H3PW12O40@ Fe3O4/EN-MIL-101 catalyst for the one-pot solventless synthesis of 2H-indazolo [2, 1-b] phthalazine-triones. Mol Catal. 2017;440:96-106.
  37. Yeganeh AD, Amini MM, Safari N. In situ synthesis and encapsulation of copper phthalocyanine into MIL-101 (Cr) and MIL-100 (Fe) pores and investigation of their catalytic performance in the epoxidation of styrene. J Porphyrins Phthalocyanines. 2019;23(10):1118-1131.
  38. Manoto SL, Houreld N, Hodgkinson N, Abrahamse H. Modes of Cell Death Induced by Photodynamic Therapy Using Zinc Phthalocyanine in Lung Cancer Cells Grown as a Monolayer and Three-Dimensional Multicellular Spheroids. Molecules. 2017;22(5):791.
  39. Xu D, You Y, Zeng F, Wang Y, Liang C, Feng H, et al. Disassembly of Hydrophobic Photosensitizer by Biodegradable Zeolitic Imidazolate Framework-8 for Photodynamic Cancer Therapy. ACS Appl Mater Interfaces. 2018;10(18):15517-15523.
  40. Ben-Hur E, Chan WS. Phthalocyanines in Photobiology and Their Medical Applications. The Porphyrin Handbook: Multporphyrins, Multiphthalocyanines and Arrays. 2012;19:1-35.
  41. Ramya E, Momen N, Desai N. Preparation of Multiwall Carbon Nanotubes with Zinc Phthalocyanine Hybrid Materials and Their Nonlinear Optical (NLO) Properties. J Nanosci Nanotechnol. 2018;18:4764-4770.
  42. Pişkin M. The novel 2,6-dimethoxyphenoxy substituted phthalocyanine dyes having high singlet oxygen quantum yields. Polyhedron. 2016;104:17-24.
  43. Guo S, Gu D, Yang Y, Tian J, Chen X. Near-infrared photodynamic and photothermal co-therapy based on organic small molecular dyes. J Nanobiotechnol. 2023;21(1):348.
  44. Tu J, Wang T, Shi W, Wu G, Tian X, Wang Y, et al. Multifunctional ZnPc-loaded mesoporous silica nanoparticles for enhancement of photodynamic therapy efficacy by endolysosomal escape. Biomaterials. 2012;33:7903-7914.
  45. Borzęcka W, Domiński A, Kowalczuk M. Recent Progress in Phthalocyanine-Polymeric Nanoparticle Delivery Systems for Cancer Photodynamic Therapy. Nanomaterials. 2021;11(9):2426.
  46. Zhou Z, Song J, Nie L, Chen X. Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy. Chem Soc Rev. 2016;45(23):6597-6626.
  47. Roguin LP, Chiarante N, García Vior MC, Marino J. Zinc(II) phthalocyanines as photosensitizers for antitumor photodynamic therapy. Int J Biochem Cell Biol. 2019;114:105575.
  48. Yan S, Guo H, Su J, Chen J, Song X, Huang M, et al. Effects of hydroxyl radicals produced by a zinc phthalocyanine photosensitizer on tumor DNA. Dyes Pigm. 2020;173:107894.
  49. Çakir V, Çakir D, Pişkin M, Durmuş M, Biyiklioǧlu Z. Water soluble peripheral and non-peripheral tetrasubstituted zinc phthalocyanines: Synthesis, photochemistry and bovine serum albumin binding behavior. J Lumin. 2014;154:274-284.
  50. Li R, Zheng K, Hu P, Chen Z, Zhou S, Chen J, et al. A novel tumor targeting drug carrier for optical imaging and therapy. Theranostics. 2014;4(6):642-659.
  51. Obata M, Ishihara E, Hirohara S. Effect of tertiary amino groups in the hydrophobic segment of an amphiphilic block copolymer on zinc phthalocyanine encapsulation and photodynamic activity. RSC Adv. 2022;12(28):18144-18153.
  52. Zha Z, Miao Y, Huiling T, Herrera-Balandrano D, Yin H, Wang S. Heparosan-based self-assembled nanocarrier for zinc(II) phthalocyanine for use in photodynamic cancer therapy. Int J Biol Macromol. 2022;219:31-43
  53. Tong L, Zhang S, Huang R, Yi H, Wang J-W. Extracellular vesicles as a novel photosensitive drug delivery system for enhanced photodynamic therapy. Front Bioeng Biotechnol. 2022;10:1032318.
  54. Udrea AM, Smarandache A, Dinache A, Mares C, Nistorescu S, Avram S, et al. Photosensitizers-Loaded Nanocarriers for Enhancement of Photodynamic Therapy in Melanoma Treatment. Pharmaceutics. 2023;15(8):2124.
  55. Shaabani A, Mohammadian R, Hashemzadeh A, Afshari R, Amini MM. Amine-functionalized MIL-101 (Cr) embedded with Co (ii) phthalocyanine as a durable catalyst for one-pot tandem oxidative A 3 coupling reactions of alcohols. New J Chem. 2018;42(6):4167-4174.
  56. Mantareva V, Iliev I, Sulikovska I, Durmuş M, Angelov I. Cobalamin (Vitamin B12) in Anticancer Photodynamic Therapy with Zn(II) Phthalocyanines. Int J Mol Sci. 2023;24(5): 4400.
  57. Ma C, Wang Y, Chen W, Hou T, Zhang H, Zhang H, et al. Caspase-1 Regulates the Apoptosis and Pyroptosis Induced by Phthalocyanine Zinc-Mediated Photodynamic Therapy in Breast Cancer MCF-7 Cells. Molecules. 2023;28(16): 5934.
  58. Ahmetali E, Sen P, Süer NC, Nyokong T, Eren T, Şener MK. Photodynamic therapy activities of phthalocyanine-based macromolecular photosensitizers on MCF-7 breast cancer cells. J Macromol Sci Part A Pure Appl Chem. 2021;58(11):748-757.
  59. Yan S, Dong L, Hu Z, Zhang Y, Xu W, Xing J, et al. A Photosensitizer-Loaded Polydopamine Nanomedicine Agent for Synergistic Photodynamic and Photothermal Therapy. Molecules. 2023;28(15): 5874.
  60. Oshiro-Junior JA, Sato MR, Boni FI, Santos KLM, de Oliveira KT, de Freitas LM, et al. Phthalocyanine-loaded nanostructured lipid carriers functionalized with folic acid for photodynamic therapy. Mater Sci Eng C. 2020;108:110462.
  61. Mfouo-Tynga I, Houreld NN, Abrahamse H. Induced cell death pathway post photodynamic therapy using a metallophthalocyanine photosensitizer in breast cancer cells. Photomed Laser Surg. 2014;32(4):205-211.
  62. Valli F, García Vior MC, Roguin LP, Marino J. Crosstalk between oxidative stress-induced apoptotic and autophagic signaling pathways in Zn(II) phthalocyanine photodynamic therapy of melanoma. Free Radic Biol Med. 2020;152:743-754.
  63. Malek-Esfandiari Z, Rezvani-Noghani A, Sohrabi T, Mokaberi P, Amiri-Tehranizadeh Z, Chamani J. Molecular dynamics and multi-spectroscopic of the interaction behavior between bladder cancer cells and calf thymus DNA with rebeccamycin: apoptosis through the down regulation of PI3K/AKT signaling pathway. J Fluoresc. 2023;33(4):1537-1557.
  64. Aydogdu S, Yasa Atmaca G, Erdoğmuş A, Hatipoglu A. Synthesis of a new Zn-phthalocyanine, photophysical, photochemical, and sono-photochemical properties and DFT studies. Polyhedron. 2024;256:116989.