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

Abstract

he 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 μM), 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, ∼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 MDA-MB-231 cells than naked JAa (0.2 μM) treatment alone. Compared to naked JAa (0.2 μM), AFt–JAa achieves enhanced growth inhibition (2.5–14-fold; <0.02 μM < GI50 < 0.15 μM) 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.

Citation

Abuzaid, H., Abdelrazig, S., Ferreira, L., Collins, H. M., Kim, D.-H., Lim, K.-H., …Bradshaw, T. (2022). Apoferritin-Encapsulated Jerantinine A for Transferrin Receptor Targeting and Enhanced Selectivity in Breast Cancer Therapy. ACS Omega, 7(25), 21473-21482. https://doi.org/10.1021/acsomega.2c00997

• Journal Article Type: Article
• Acceptance Date: May 19, 2022
• Online Publication Date: Jun 13, 2022
• Publication Date: Jun 28, 2022
• Deposit Date: May 20, 2022
• Publicly Available Date: Jun 15, 2022
• Electronic ISSN: 2470-1343
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Issue: 25
• Pages: 21473-21482
• DOI: https://doi.org/10.1021/acsomega.2c00997
• Public URL: https://nottingham-repository.worktribe.com/output/8136801
• Publisher URL: https://pubs.acs.org/doi/10.1021/acsomega.2c00997