Elucidating the cellular uptake mechanisms of heptamethine cyanine dye analogues for their use as an anticancer drug‐carrier molecule for the treatment of glioblastoma
Abstract 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, Seite 696-716 |
| Beteiligte Personen: |
Cooper, Elizabeth [VerfasserIn] |
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| Anmerkungen: |
Copyright © 2023 John Wiley & Sons A/S |
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| Umfang: |
21 |
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| doi: |
10.1111/cbdd.14171 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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WLY015246639 |
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| 520 | |a Abstract 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. | ||
| 700 | 1 | |a Choi, Peter J. |4 aut | |
| 700 | 1 | |a Hwang, Kihwan |4 aut | |
| 700 | 1 | |a Nam, Kyung M. |4 aut | |
| 700 | 1 | |a Kim, Chae‐Yong |4 aut | |
| 700 | 1 | |a Shaban, Tina |4 aut | |
| 700 | 1 | |a Schweder, Patrick |4 aut | |
| 700 | 1 | |a Mee, Edward |4 aut | |
| 700 | 1 | |a Correia, Jason |4 aut | |
| 700 | 1 | |a Turner, Clinton |4 aut | |
| 700 | 1 | |a Faull, Richard L. M. |4 aut | |
| 700 | 1 | |a Denny, William A. |4 aut | |
| 700 | 1 | |a Noguchi, Katsuya |4 aut | |
| 700 | 1 | |a Dragunow, Mike |4 aut | |
| 700 | 1 | |a Jose, Jiney |4 aut | |
| 700 | 1 | |a Park, Thomas I.‐H. |4 aut | |
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