Apoferritin-encapsulated jerantinine A for transferrin receptor targeting and enhanced selectivity in breast cancer therapy

The O-acetyl (or acetate) derivative of the Aspidosperma alkaloid Jerantinine A (JAa) elicits anti-tumor activity against cancer cell lines including mammary carcinoma cell lines irrespective of receptor status (0.14 < GI50 < 0.38 mu M), targeting microtubule dynamics. By exploiting breast can...

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Main Authors: Abuzaid, Haneen, Abdelrazig, Salah, Ferreira, Lenny, Collins, Hilary M., Kim, Dong-Hyun, Lim, Kuan-Hon, Kam, Toh-Seok, Turyanska, Lyudmila, Bradshaw, Tracey D.
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Published: American Chemical Society 2022
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Online Access:http://eprints.um.edu.my/41924/
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spelling my.um.eprints.419242023-10-23T08:55:25Z http://eprints.um.edu.my/41924/ Apoferritin-encapsulated jerantinine A for transferrin receptor targeting and enhanced selectivity in breast cancer therapy Abuzaid, Haneen Abdelrazig, Salah Ferreira, Lenny Collins, Hilary M. Kim, Dong-Hyun Lim, Kuan-Hon Kam, Toh-Seok Turyanska, Lyudmila Bradshaw, Tracey D. RC Internal medicine The O-acetyl (or acetate) derivative of the Aspidosperma alkaloid Jerantinine A (JAa) elicits anti-tumor activity against cancer cell lines including mammary carcinoma cell lines irrespective of receptor status (0.14 < GI50 < 0.38 mu M), targeting microtubule dynamics. By exploiting breast cancer cells' upregulated transferrin receptor 1 (TfR1) expression and apoferritin (AFt) recognition, we sought to develop an AFt JAa-delivery vehicle to enhance tumor-targeting and reduce systemic toxicity. Optimizing pH-mediated reassembly, similar to 120 JAa molecules were entrapped within AFt. Western blot and flow cytometry demonstrate TfR1 expression in cancer cells. Enhanced internalization of 5-carboxyfluorescein-conjugated human AFt in SKBR3 and MDA-MB-231 cancer cells is observed compared to MRC5 fibroblasts. Accordingly, AFt-JAa delivers significantly greater intracellular JAa levels to SKBR3 and MDAMB-231 cells than naked JAa (0.2 mu M) treatment alone. Compared to naked JAa (0.2 mu M), AFt-JAa achieves enhanced growth inhibition (2.5-14-fold; <0.02 mu M < GI50 < 0.15 mu M) in breast cancer cells; AFt-JAa treatment results in significantly reduced clonal survival, more profound cell cycle perturbation including G2/M arrest, greater reduction in cell numbers, and increased apoptosis compared to the naked agent (p < 0.01). Decreased PLK1 and Mcl-1 expression, together with the appearance of cleaved poly (ADP-ribose)polymerase, corroborate the augmented potency of AFt-JAa. Hence, we demonstrate that AFt represents a biocompatible vehicle for targeted delivery of JAa, offering potential to minimize toxicity and enhance JAa activity in TfR1-expressing tumors. American Chemical Society 2022-06 Article PeerReviewed Abuzaid, Haneen and Abdelrazig, Salah and Ferreira, Lenny and Collins, Hilary M. and Kim, Dong-Hyun and Lim, Kuan-Hon and Kam, Toh-Seok and Turyanska, Lyudmila and Bradshaw, Tracey D. (2022) Apoferritin-encapsulated jerantinine A for transferrin receptor targeting and enhanced selectivity in breast cancer therapy. ACS Omega, 7 (25). pp. 21473-21482. ISSN 2470-1343, DOI https://doi.org/10.1021/acsomega.2c00997 <https://doi.org/10.1021/acsomega.2c00997>. 10.1021/acsomega.2c00997
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic RC Internal medicine
spellingShingle RC Internal medicine
Abuzaid, Haneen
Abdelrazig, Salah
Ferreira, Lenny
Collins, Hilary M.
Kim, Dong-Hyun
Lim, Kuan-Hon
Kam, Toh-Seok
Turyanska, Lyudmila
Bradshaw, Tracey D.
Apoferritin-encapsulated jerantinine A for transferrin receptor targeting and enhanced selectivity in breast cancer therapy
description The O-acetyl (or acetate) derivative of the Aspidosperma alkaloid Jerantinine A (JAa) elicits anti-tumor activity against cancer cell lines including mammary carcinoma cell lines irrespective of receptor status (0.14 < GI50 < 0.38 mu M), targeting microtubule dynamics. By exploiting breast cancer cells' upregulated transferrin receptor 1 (TfR1) expression and apoferritin (AFt) recognition, we sought to develop an AFt JAa-delivery vehicle to enhance tumor-targeting and reduce systemic toxicity. Optimizing pH-mediated reassembly, similar to 120 JAa molecules were entrapped within AFt. Western blot and flow cytometry demonstrate TfR1 expression in cancer cells. Enhanced internalization of 5-carboxyfluorescein-conjugated human AFt in SKBR3 and MDA-MB-231 cancer cells is observed compared to MRC5 fibroblasts. Accordingly, AFt-JAa delivers significantly greater intracellular JAa levels to SKBR3 and MDAMB-231 cells than naked JAa (0.2 mu M) treatment alone. Compared to naked JAa (0.2 mu M), AFt-JAa achieves enhanced growth inhibition (2.5-14-fold; <0.02 mu M < GI50 < 0.15 mu M) in breast cancer cells; AFt-JAa treatment results in significantly reduced clonal survival, more profound cell cycle perturbation including G2/M arrest, greater reduction in cell numbers, and increased apoptosis compared to the naked agent (p < 0.01). Decreased PLK1 and Mcl-1 expression, together with the appearance of cleaved poly (ADP-ribose)polymerase, corroborate the augmented potency of AFt-JAa. Hence, we demonstrate that AFt represents a biocompatible vehicle for targeted delivery of JAa, offering potential to minimize toxicity and enhance JAa activity in TfR1-expressing tumors.
format Article
author Abuzaid, Haneen
Abdelrazig, Salah
Ferreira, Lenny
Collins, Hilary M.
Kim, Dong-Hyun
Lim, Kuan-Hon
Kam, Toh-Seok
Turyanska, Lyudmila
Bradshaw, Tracey D.
author_facet Abuzaid, Haneen
Abdelrazig, Salah
Ferreira, Lenny
Collins, Hilary M.
Kim, Dong-Hyun
Lim, Kuan-Hon
Kam, Toh-Seok
Turyanska, Lyudmila
Bradshaw, Tracey D.
author_sort Abuzaid, Haneen
title Apoferritin-encapsulated jerantinine A for transferrin receptor targeting and enhanced selectivity in breast cancer therapy
title_short Apoferritin-encapsulated jerantinine A for transferrin receptor targeting and enhanced selectivity in breast cancer therapy
title_full Apoferritin-encapsulated jerantinine A for transferrin receptor targeting and enhanced selectivity in breast cancer therapy
title_fullStr Apoferritin-encapsulated jerantinine A for transferrin receptor targeting and enhanced selectivity in breast cancer therapy
title_full_unstemmed Apoferritin-encapsulated jerantinine A for transferrin receptor targeting and enhanced selectivity in breast cancer therapy
title_sort apoferritin-encapsulated jerantinine a for transferrin receptor targeting and enhanced selectivity in breast cancer therapy
publisher American Chemical Society
publishDate 2022
url http://eprints.um.edu.my/41924/
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score 13.188404