Fluorination of Aza-BODIPY for Cancer Cell Plasma Membrane-Targeted Imaging and Therapy

Overview

Journal ACS Appl Mater Interfaces

Publisher American Chemical Society

Specialties Biomedical Engineering
Biotechnology

Date 2025 Jan 2

PMID 39744788

Authors

Anfeng Li

Fang Wang

Yu Li

Xingxing Peng

Yanqi Liu

Lijun Zhu

Pei He

Tingting Yu

Daiqin Chen

Mojie Duan

Xin Zhou

Zhong-Xing Jiang

Shizhen Chen

Affiliations

Soon will be listed here.

Abstract

Photodynamic therapy (PDT) holds great potential in cancer treatment, leveraging photosensitizers (PSs) to deliver targeted therapy. Fluorination can optimize the physicochemical and biological properties of PSs for better PDT performance. Here, we report some high-performance multifunctional PSs specifically designed for cancer PDT by fluorinating aza-BODIPY with perfluoro--butoxymethyl (PFBM) groups. Fluorination plays several roles, including enhancing selective cancer cell uptake, plasma membrane (PM) targeting, and inducing pyroptosis. It also enables fluorescence imaging (FLI) and fluorine-19 magnetic resonance imaging (F MRI) as well as facilitates oxygen delivery and oxygen partial pressure (pO) measurements. Comparative physicochemical and biological studies, along with molecular dynamics simulations, reveal that fluorinated PSs selectively eradicate cancer cells by oxidizing PM phospholipids with singlet oxygen (O) and inducing pyroptosis, which enables effectively suppressed tumor growth by self-oxygenated F MRI-FLI-guided PDT in mice. This study demonstrates a fluorination strategy for tailoring high-performance multifunctional cancer PM-targeting materials for cancer therapy and beyond.

References

Zhang X, Yu H, Xiao Y . Replacing phenyl ring with thiophene: an approach to longer wavelength aza-dipyrromethene boron difluoride (Aza-BODIPY) dyes. J Org Chem. 2011; 77(1):669-73. DOI: 10.1021/jo201413b. View

Krafft M . Alleviating tumor hypoxia with perfluorocarbon-based oxygen carriers. Curr Opin Pharmacol. 2020; 53:117-125. DOI: 10.1016/j.coph.2020.08.010. View

Bray F, Laversanne M, Sung H, Ferlay J, Siegel R, Soerjomataram I . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3):229-263. DOI: 10.3322/caac.21834. View

Zheng B, Tian Y, Liu S, Yang J, Wu F, Xiong H . Non-Solvatochromic Cell Membrane-Targeted NIR Fluorescent Probe for Visualization of Polarity Abnormality in Drug-Induced Liver Injury Mice. Anal Chem. 2023; 95(32):12054-12061. DOI: 10.1021/acs.analchem.3c02005. View

Gu Y, Lai H, Chen Z, Zhu Y, Sun Z, Lai X . Chlorination-Mediated π-π Stacking Enhances the Photodynamic Properties of a NIR-II Emitting Photosensitizer with Extended Conjugation. Angew Chem Int Ed Engl. 2023; 62(25):e202303476. DOI: 10.1002/anie.202303476. View

He M, Guo S, Ren J, Li Z . In Situ Characterizing Membrane Lipid Phenotype of Human Lung Cancer Cell Lines Using Mass Spectrometry Profiling. J Cancer. 2016; 7(7):810-6. PMC: 4860797. DOI: 10.7150/jca.14310. View

Adarsh N, Avirah R, Ramaiah D . Tuning photosensitized singlet oxygen generation efficiency of novel aza-BODIPY dyes. Org Lett. 2010; 12(24):5720-3. DOI: 10.1021/ol102562k. View

Zhang H, Yu Q, Li Y, Yang Z, Zhou X, Chen S . Fluorinated cryptophane-A and porphyrin-based theranostics for multimodal imaging-guided photodynamic therapy. Chem Commun (Camb). 2020; 56(25):3617-3620. DOI: 10.1039/d0cc00694g. View

Hu W, Jones P, Decoen W, King L, Fraker P, Newsted J . Alterations in cell membrane properties caused by perfluorinated compounds. Comp Biochem Physiol C Toxicol Pharmacol. 2003; 135(1):77-88. DOI: 10.1016/s1532-0456(03)00043-7. View

10.

Yang L, Chen Q, Gan S, Huang C, Zhang H, Sun H . Rational Design of Self-Reporting Photosensitizers for Cell Membrane-Targeted Photodynamic Therapy. Anal Chem. 2023; 95(32):11988-11996. DOI: 10.1021/acs.analchem.3c01659. View

11.

Mo Y, Huang C, Liu C, Duan Z, Liu J, Wu D . Recent Research Progress of F Magnetic Resonance Imaging Probes: Principle, Design, and Their Application. Macromol Rapid Commun. 2022; 44(16):e2200744. DOI: 10.1002/marc.202200744. View

12.

Liu H, Qian F . Exploiting macropinocytosis for drug delivery into KRAS mutant cancer. Theranostics. 2022; 12(3):1321-1332. PMC: 8771556. DOI: 10.7150/thno.67889. View

13.

Tsubone T, Baptista M, Itri R . Understanding membrane remodelling initiated by photosensitized lipid oxidation. Biophys Chem. 2019; 254:106263. DOI: 10.1016/j.bpc.2019.106263. View

14.

Beckwith K, Beckwith M, Ullmann S, Saetra R, Kim H, Marstad A . Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection. Nat Commun. 2020; 11(1):2270. PMC: 7210277. DOI: 10.1038/s41467-020-16143-6. View

15.

Le Guennic B, Maury O, Jacquemin D . Aza-boron-dipyrromethene dyes: TD-DFT benchmarks, spectral analysis and design of original near-IR structures. Phys Chem Chem Phys. 2011; 14(1):157-64. DOI: 10.1039/c1cp22396h. View

16.

Wang J, Wu Y, Sheng W, Yu C, Wei Y, Hao E . Synthesis, Structure, and Properties of β-Vinyl Ketone/Ester Functionalized AzaBODIPYs from FormylazaBODIPYs. ACS Omega. 2019; 2(6):2568-2576. PMC: 6641003. DOI: 10.1021/acsomega.7b00393. View

17.

Moan J, Berg K . The photodegradation of porphyrins in cells can be used to estimate the lifetime of singlet oxygen. Photochem Photobiol. 1991; 53(4):549-53. DOI: 10.1111/j.1751-1097.1991.tb03669.x. View

18.

Zhang X, Wan J, Mo F, Tang D, Xiao H, Li Z . Targeting Bone Tumor and Subcellular Endoplasmic Reticulum via Near Infrared II Fluorescent Polymer for Photodynamic-Immunotherapy to Break the Step-Reduction Delivery Dilemma. Adv Sci (Weinh). 2022; 9(24):e2201819. PMC: 9404413. DOI: 10.1002/advs.202201819. View

19.

Yang Y, Liu Y, Jiang Y . Recent Advances in Perfluorocarbon-Based Delivery Systems for Cancer Theranostics. Mol Pharm. 2023; 20(7):3254-3277. DOI: 10.1021/acs.molpharmaceut.3c00116. View

20.

Pham T, Nguyen V, Choi Y, Lee S, Yoon J . Recent Strategies to Develop Innovative Photosensitizers for Enhanced Photodynamic Therapy. Chem Rev. 2021; 121(21):13454-13619. DOI: 10.1021/acs.chemrev.1c00381. View