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

• 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.
• Format: Article
• Published: American Chemical Society 2022
• Subjects: RC Internal medicine
• Online Access: http://eprints.um.edu.my/41924/

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.