Quatramer™ mediated co-delivery of PI3-Kδ/HDAC6 dual inhibitor augments the anti-cancer efficacy of Epirubicin in breast cancer

Abstract

The disruption and overexpression of phosphatidylinositol 3-kinase (PI3K)–AKT signaling pathway in cancer results in tumor growth, metastasis, and survival. Treatment with common anthracyclines has confirmed cancer cells' dependence on PI3K pathway through overexpression of AKT. Moreover, combining HDAC inhibitor with anthracycline has shown the targeting of breast cancer stem cells. Therefore, it has been hypothesized that the co-delivery of PI3-Kδ/HDAC6 dual inhibitor with Epirubicin using polymeric nanoparticle could increase the anti-cancer treatment efficacy with reduced toxicity. Pluronic modified polylactic acid block copolymer (quatramer) was used for co-encapsulation of PI3-Kδ/HDAC6 and Epirubicin. The co-encapsulated nanoparticles, PI3-Kδ/HDAC6-Epi-NPs have shown size of 99 ± 3 nm, PDI of 0.18 ± 0.07 with a sustained and slow-release profile in non-physiological buffer (PBS, pH 7.4). The in-vitro cell proliferation inhibition studies done on 2D and 3D culture of breast cancer cell lines have confirmed the synergistic effect of PI3-Kδ/HDAC6-Epi-NPs with lower IC50 values compared to PI3-Kδ/HDAC6-NPs and Epi-NPs. Additionally, intravenous twice a week treatment for three weeks with PI3-Kδ/HDAC6-Epi-NPs resulted in complete tumor eradication in the syngeneic breast tumor mice model. In comparison, the PI3-Kδ/HDAC6-NPs and Epi-NPs resulted in tumor growth inhibition of 15.86% and 81.59%, respectively. These studies predicted that clinical use of PI3-Kδ/HDAC6-Epi-NPs will be effective in breast cancer treatments.