{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T08:49:46Z","timestamp":1782809386935,"version":"3.54.5"},"reference-count":45,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T00:00:00Z","timestamp":1700784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Research Council, UK"},{"name":"Killing Cancer, UK"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>(1) Background: The protoporphyrin IX (PpIX)-mediated fluorescence-guided resection and interoperative photodynamic therapy (PDT) of remaining cells may be effective adjuvants to the resection of glioma. Both processes may be enhanced by increasing intracellular PpIX concentrations, which can be achieved through iron chelation. AP2-18 is a novel combinational drug, which ester-links a PpIX precursor (aminolaevulinic acid; ALA) to an iron-chelating agent (CP94). (2) Methods: Human glioma U-87 MG cells were cultured in 96-well plates for 24 h and incubated for 3 or 6 h with various test compound combinations: ALA (\u00b1) CP94, methyl aminolevulinate (MAL) (\u00b1) CP94 and AP2-18. PpIX fluorescence was measured at 0, 3 or 6 h with a Bio-tek Synergy HT plate reader, as well as immediately after irradiation with a 635 nm red light (Aktilite CL16 LED array), representing the PDT procedure. Cell viability post-irradiation was assessed using the neutral red assay. (3) Results: AP2-18 significantly increased PpIX fluorescence compared to all other test compounds. All treatment protocols effectively achieved PDT-induced cytotoxicity, with no significant difference between test compound combinations. (4) Conclusions: AP2-18 has potential to improve the efficacy of fluorescence-guided resection either with or without the subsequent intraoperative PDT of glioma. Future work should feature a more complex in vitro model of the glioma microenvironment.<\/jats:p>","DOI":"10.3390\/pharmaceutics15122668","type":"journal-article","created":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T06:51:28Z","timestamp":1700808688000},"page":"2668","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel Iron-Chelating Prodrug Significantly Enhanced Fluorescence-Mediated Detection of Glioma Cells Experimentally In Vitro"],"prefix":"10.3390","volume":"15","author":[{"given":"Charlotte","family":"Reburn","sequence":"first","affiliation":[{"name":"Knowledge Spa, Royal Cornwall Hospital, University of Exeter, Truro TR1 3HD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Gawthorpe","sequence":"additional","affiliation":[{"name":"Knowledge Spa, Royal Cornwall Hospital, University of Exeter, Truro TR1 3HD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Perry","sequence":"additional","affiliation":[{"name":"Knowledge Spa, Royal Cornwall Hospital, University of Exeter, Truro TR1 3HD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Wood","sequence":"additional","affiliation":[{"name":"Knowledge Spa, Royal Cornwall Hospital, University of Exeter, Truro TR1 3HD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1616-4790","authenticated-orcid":false,"given":"Alison","family":"Curnow","sequence":"additional","affiliation":[{"name":"Knowledge Spa, Royal Cornwall Hospital, University of Exeter, Truro TR1 3HD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"301","DOI":"10.2176\/nmc.ra.2017-0010","article-title":"The 2016 WHO Classification of Tumours of the Central Nervous System: The Major Points of Revision","volume":"57","author":"Komori","year":"2017","journal-title":"Neurol. Med. Chir."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1007\/s10143-020-01331-1","article-title":"Assessing the Efficacy of Repeat Resections in Recurrent Glioblastoma: A Systematic Review","volume":"44","author":"Botros","year":"2021","journal-title":"Neurosurg. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Goenka, A., Tiek, D., Song, X., Huang, T., Hu, B., and Cheng, S.-Y. (2021). The Many Facets of Therapy Resistance and Tumor Recurrence in Glioblastoma. Cells, 10.","DOI":"10.3390\/cells10030484"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.wneu.2017.04.053","article-title":"Recurrence Pattern Analysis of Primary Glioblastoma","volume":"103","author":"Rapp","year":"2017","journal-title":"World Neurosurg."},{"key":"ref_5","unstructured":"National Institute for Health and Care Excellence (NICE) (2023, October 21). Brain Tumours (Primary) and Brain Metastases in Adults: Guidance. Available online: https:\/\/www.nice.org.uk\/guidance\/ng99."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ejon.2012.04.006","article-title":"The Impact of a High-Grade Glioma on Everyday Life: A Systematic Review from the Patient\u2019s and Caregiver\u2019s Perspective","volume":"17","author":"Sterckx","year":"2013","journal-title":"Eur. J. Oncol. Nurs."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/S1470-2045(06)70665-9","article-title":"Fluorescence-Guided Surgery with 5-Aminolevulinic Acid for Resection of Malignant Glioma: A Randomised Controlled Multicentre Phase III Trial","volume":"7","author":"Stummer","year":"2006","journal-title":"Lancet Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Mansi, M., Howley, R., Chandratre, S., and Chen, B. (2022). Inhibition of ABCG2 Transporter by Lapatinib Enhances 5-Aminolevulinic Acid-Mediated Protoporphyrin IX Fluorescence and Photodynamic Therapy Response in Human Glioma Cell Lines. Biochem. Pharm., 200.","DOI":"10.1016\/j.bcp.2022.115031"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kiening, M., and Lange, N. (2022). A Recap of Heme Metabolism towards Understanding Protoporphyrin IX Selectivity in Cancer Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147974"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/j.1751-1097.1997.tb08549.x","article-title":"5-Aminolevulinic Acid-Based Photodynamic Therapy: Principles and Experimental Research","volume":"65","author":"Peng","year":"1997","journal-title":"Photochem. Photobiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tyrrell, J., Paterson, C., and Curnow, A. (2019). Regression analysis of protoporphyrin IX measurements obtained during dermatological photodynamic therapy. Cancers, 11.","DOI":"10.3390\/cancers11010072"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1515\/plm-2014-0034","article-title":"The Importance of Iron Chelation and Iron Availability during PpIX-Induced Photodynamic Therapy","volume":"4","author":"Curnow","year":"2015","journal-title":"Photonics Lasers Med."},{"key":"ref_13","first-page":"925","article-title":"Current Methods for Photodynamic Therapy in the US: Comparison of MAL\/PDT and ALA\/PDT","volume":"12","author":"Lee","year":"2013","journal-title":"J. Drugs Dermatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.asjsur.2017.06.004","article-title":"5-Aminolevulinic Acid Fluorescence Guided Resection of Malignant Glioma: Hong Kong Experience","volume":"41","author":"Chan","year":"2018","journal-title":"Asian J. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1093\/neuros\/nyaa475","article-title":"Fluorescence Guidance and Intraoperative Adjuvants to Maximize Extent of Resection","volume":"89","author":"Orillac","year":"2020","journal-title":"Neurosurgery"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1111\/j.1751-1097.2011.00985.x","article-title":"An in Vitro Comparison of the Effects of the Iron-Chelating Agents, CP94 and Dexrazoxane, on Protoporphyrin IX Accumulation for Photodynamic Therapy and\/or Fluorescence Guided Resection","volume":"87","author":"Blake","year":"2011","journal-title":"Photochem. Photobiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Piffaretti, D., Burgio, F., Thelen, M., Kaelin-Lang, A., Paganetti, P., Reinert, M., and D\u2019Angelo, M.L. (2019). Protoporphyrin IX Tracer Fluorescence Modulation for Improved Brain Tumor Cell Lines Visualization. J. Photochem. Photobiol. B Biol., 201.","DOI":"10.1016\/j.jphotobiol.2019.111640"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/bjc.1996.423","article-title":"The Influence of Iron Chelators on the Accumulation of Protoporphyrin IX in 5-Aminolaevulinic Acid-Treated Cells","volume":"74","author":"Berg","year":"1996","journal-title":"Br. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1562\/2006-05-30-RA-906","article-title":"Direct comparison of delta-aminolevulinic acid and methyl-aminolevulinate-derived protoporphyrin IX accumulations potentiated by desferrioxamine or the novel hydroxypyridinone iron chelator CP94 in cultured human cells","volume":"83","author":"Pye","year":"2007","journal-title":"Photochem. Photobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1111\/cas.15637","article-title":"Polymeric iron chelators for enhancing 5-aminolevulinic acid-induced photodynamic therapy","volume":"114","author":"Nomoto","year":"2023","journal-title":"Cancer Sci."},{"key":"ref_21","unstructured":"Curnow, A., Wood, M., and Perry, A. (2014). Novel Iron Chelating Prodrug (AP2-18) for Protoporphyrin IX-Induced Photodynamic Therapy. (WO2014033477A1)."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1002\/lsm.22809","article-title":"An Experimental Investigation of a Novel Iron Chelating Protoporphyrin IX Prodrug for the Enhancement of Photodynamic Therapy","volume":"50","author":"Anayo","year":"2018","journal-title":"Lasers Surg. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1007\/s10103-021-03367-1","article-title":"Experimental Investigation of a Combinational Iron Chelating Protoporphyrin IX Prodrug for Fluorescence Detection and Photodynamic Therapy","volume":"37","author":"Magnussen","year":"2022","journal-title":"Lasers Med. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1093\/neuros\/nyz310_811","article-title":"Possibilities of Photodynamic Therapy in the Complex Treatment of Malignant Gliomas","volume":"66","author":"Rynda","year":"2019","journal-title":"Neurosurgery"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s11060-021-03718-6","article-title":"Standardized Intraoperative 5-ALA Photodynamic Therapy for Newly Diagnosed Glioblastoma Patients: A Preliminary Analysis of the INDYGO Clinical Trial","volume":"152","author":"Vermandel","year":"2021","journal-title":"J. Neurooncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"426","DOI":"10.3171\/2019.11.JNS192443","article-title":"Combination of ALA-Induced Fluorescence-Guided Resection and Intraoperative Open Photodynamic Therapy for Recurrent Glioblastoma: Case Series on a Promising Dual Strategy for Local Tumor Control","volume":"134","author":"Schipmann","year":"2020","journal-title":"J. Neurosurg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1007\/s10103-021-03426-7","article-title":"A systematic review and meta-analysis of fluorescent-guided resection and therapy-based photodynamics on the survival of patients with glioma","volume":"37","author":"Ren","year":"2022","journal-title":"Lasers Med. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1111\/jdv.16017","article-title":"European Dermatology Forum guidelines on topical photodynamic therapy 2019 Part 1: Treatment delivery and established indications\u2013actinic keratoses, Bowen\u2019s disease and basal cell carcinomas","volume":"33","author":"Morton","year":"2019","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1002\/jbio.201500195","article-title":"405 nm versus 633 nm for protoporphyrin IX excitation in fluorescence-guided stereotactic biopsy of brain tumors","volume":"9","author":"Markwardt","year":"2016","journal-title":"J. Biophotonics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.redox.2016.07.002","article-title":"The hydroxypyridinone iron chelator CP94 increases methyl-aminolevulinate-based photodynamic cell killing by increasing the generation of reactive oxygen species","volume":"9","author":"Dogra","year":"2016","journal-title":"Redox Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3411","DOI":"10.1021\/acs.bioconjchem.8b00574","article-title":"Design of Bifunctional Dendritic 5-Aminolevulinic Acid and Hydroxypyridinone Conjugates for Photodynamic Therapy","volume":"29","author":"Zhou","year":"2018","journal-title":"Bioconjug. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3498","DOI":"10.1021\/acs.jmedchem.7b00346","article-title":"Hydroxypyridinone and 5-Aminolaevulinic Acid Conjugates for Photodynamic Therapy","volume":"60","author":"Battah","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1039\/b507325a","article-title":"Light distribution and calibration of commercial PDT LED arrays","volume":"4","author":"Moseley","year":"2005","journal-title":"Photochem. Photobiol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1111\/bjd.17309","article-title":"British Association of Dermatologists and British Photodermatology Group Guidelines for Topical Photodynamic Therapy 2018","volume":"180","author":"Wong","year":"2019","journal-title":"Br. J. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1038\/nprot.2008.75","article-title":"Neutral Red Uptake Assay for the Estimation of Cell Viability\/Cytotoxicity","volume":"3","author":"Repetto","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/s11060-018-03079-7","article-title":"5-Aminolevulinic Acid Induced Protoporphyrin IX (ALA-PpIX) Fluorescence Guidance in Meningioma Surgery","volume":"141","author":"Valdes","year":"2019","journal-title":"J. Neurooncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1038\/sj.bjp.0706668","article-title":"Mechanisms of 5-Aminolevulic Acid Ester Uptake in Mammalian Cells","volume":"147","author":"Rodriguez","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1093\/jnci\/85.6.443","article-title":"Photodynamic Therapy in Oncology: Mechanisms and Clinical Use","volume":"85","author":"Pass","year":"1993","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zhang, S., Li, Y., Dong, R., Li, W., Qian, Z., and Yang, Y. (2023). All-in-One Device for Mapping the Interactive Effects of Photodynamic Therapy Dosimetry in Tumor Gaseous Microenvironment. J. Photochem. Photobiol. B Biol., 239.","DOI":"10.1016\/j.jphotobiol.2022.112645"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7979","DOI":"10.1038\/srep07979","article-title":"The Evidence of Glioblastoma Heterogeneity","volume":"5","author":"Soeda","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1142\/S1088424619300192","article-title":"Application of Photodynamic Therapy Drugs for Management of Glioma","volume":"23","author":"Dubey","year":"2019","journal-title":"J. Porphyr. Phthalocyanines"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1002\/lsm.22934","article-title":"A Preclinical Model to Investigate the Role of Surgically-Induced Inflammation in Tumor Responses to Intraoperative Photodynamic Therapy","volume":"50","author":"Davis","year":"2018","journal-title":"Lasers Surg. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.clineuro.2016.05.004","article-title":"Protective Effects of Dexmedetomidine on Brain Function of Glioma Patients Undergoing Craniotomy Resection and Its Underlying Mechanism","volume":"146","author":"Luo","year":"2016","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1002\/lsm.21135","article-title":"Cerebral Edema Following Photodynamic Therapy Using Endogenous and Exogenous Photosensitizers in Normal Brain","volume":"43","author":"Mathews","year":"2011","journal-title":"Lasers Surg. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"E414","DOI":"10.1093\/neuros\/nyy324","article-title":"INtraoperative photoDYnamic Therapy for GliOblastomas (INDYGO): Study protocol for a phase I clinical trial","volume":"84","author":"Dupont","year":"2019","journal-title":"Neurosurgery"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/12\/2668\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:29:19Z","timestamp":1760131759000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/12\/2668"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,24]]},"references-count":45,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["pharmaceutics15122668"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15122668","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,24]]}}}