Elucidating the cellular uptake mechanisms of heptamethine cyanine dye analogues for their use as an anticancer drug-carrier molecule for the treatment of glioblastoma
© 2022 The Authors. Chemical Biology & Drug Design published by John Wiley & Sons Ltd..
The development of chemotherapies for glioblastoma is hindered by their limited bioavailability and toxicity on normal brain function. To overcome these limitations, we investigated the structure-dependent activity of heptamethine cyanine dyes (HMCD), a group of tumour-specific and BBB permeable near-infrared fluorescent dyes, in both commercial (U87MG) and patient-derived GBM cell lines. HMCD analogues with strongly ionisable sulphonic acid groups were not taken up by patient-derived GBM cells, but were taken up by the U87MG cell line. HMCD uptake relies on a combination of transporter uptake through organic anion-transporting polypeptides (OATPs) and endocytosis into GBM cells. The uptake of HMCDs was not affected by p-glycoprotein efflux in GBM cells. Finally, we demonstrate structure-dependent cytotoxic activity at high concentrations (EC50 : 1-100 μM), likely due to mitochondrial damage-induced apoptosis. An in vivo orthotopic glioblastoma model highlights tumour-specific accumulation of our lead HMCD, MHI-148, for up to 7 days following a single intraperitoneal injection. These studies suggest that strongly ionisable groups like sulphonic acids hamper the cellular uptake of HMCDs in patient-derived GBM cell lines, highlighting cell line-specific differences in HMCD uptake. We envisage these findings will help in the design and structural modifications of HMCDs for drug-delivery applications for glioblastoma.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:101 |
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| Enthalten in: |
Chemical biology & drug design - 101(2023), 3 vom: 01. März, Seite 696-716 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cooper, Elizabeth [VerfasserIn] |
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| Links: |
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| Themen: |
Antineoplastic Agents |
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| Anmerkungen: |
Date Completed 15.02.2023 Date Revised 19.03.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/cbdd.14171 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM348376227 |
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| 245 | 1 | 0 | |a Elucidating the cellular uptake mechanisms of heptamethine cyanine dye analogues for their use as an anticancer drug-carrier molecule for the treatment of glioblastoma |
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| 520 | |a © 2022 The Authors. Chemical Biology & Drug Design published by John Wiley & Sons Ltd. | ||
| 520 | |a The development of chemotherapies for glioblastoma is hindered by their limited bioavailability and toxicity on normal brain function. To overcome these limitations, we investigated the structure-dependent activity of heptamethine cyanine dyes (HMCD), a group of tumour-specific and BBB permeable near-infrared fluorescent dyes, in both commercial (U87MG) and patient-derived GBM cell lines. HMCD analogues with strongly ionisable sulphonic acid groups were not taken up by patient-derived GBM cells, but were taken up by the U87MG cell line. HMCD uptake relies on a combination of transporter uptake through organic anion-transporting polypeptides (OATPs) and endocytosis into GBM cells. The uptake of HMCDs was not affected by p-glycoprotein efflux in GBM cells. Finally, we demonstrate structure-dependent cytotoxic activity at high concentrations (EC50 : 1-100 μM), likely due to mitochondrial damage-induced apoptosis. An in vivo orthotopic glioblastoma model highlights tumour-specific accumulation of our lead HMCD, MHI-148, for up to 7 days following a single intraperitoneal injection. These studies suggest that strongly ionisable groups like sulphonic acids hamper the cellular uptake of HMCDs in patient-derived GBM cell lines, highlighting cell line-specific differences in HMCD uptake. We envisage these findings will help in the design and structural modifications of HMCDs for drug-delivery applications for glioblastoma | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a HMCD | |
| 650 | 4 | |a brain tumour | |
| 650 | 4 | |a drug-delivery | |
| 650 | 4 | |a glioblastoma | |
| 650 | 4 | |a orthotopic GBM mouse model | |
| 650 | 4 | |a patient-derived | |
| 650 | 7 | |a heptamethine cyanine dye |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Fluorescent Dyes |2 NLM | |
| 700 | 1 | |a Choi, Peter J |e verfasserin |4 aut | |
| 700 | 1 | |a Hwang, Kihwan |e verfasserin |4 aut | |
| 700 | 1 | |a Nam, Kyung M |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Chae-Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Shaban, Tina |e verfasserin |4 aut | |
| 700 | 1 | |a Schweder, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Mee, Edward |e verfasserin |4 aut | |
| 700 | 1 | |a Correia, Jason |e verfasserin |4 aut | |
| 700 | 1 | |a Turner, Clinton |e verfasserin |4 aut | |
| 700 | 1 | |a Faull, Richard L M |e verfasserin |4 aut | |
| 700 | 1 | |a Denny, William A |e verfasserin |4 aut | |
| 700 | 1 | |a Noguchi, Katsuya |e verfasserin |4 aut | |
| 700 | 1 | |a Dragunow, Mike |e verfasserin |4 aut | |
| 700 | 1 | |a Jose, Jiney |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Thomas I-H |e verfasserin |4 aut | |
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