Abstract 2718: Co-loading of a novel PI3-Kdelta/HDAC6 dual inhibitor and navitoclax into QuatramerTM biodegradable polymeric nanoparticles synergistically inhibit growth of ER+breast cancer
Authors: Kharbanda Surender M. , Tiwari Sachchidanand , Kaur Harshdeep , Mohammad Anees , Gupta Priya , Singh Harpal 
Published: April 2023

Abstract
Progression and metastasis of ER+ breast cancer depends on multiple signaling cascades. The available conventional treatment options have limited efficacy in ER+ breast cancer. Simultaneous targeting and inhibition of multiple pathways in ER+ cancer may result in effective therapeutic outcomes. However, combining two or more drugs to treat cancer leads to unsynchronized pharmacokinetics, toxicity and eventual development of drug resistance. To overcome these limitations, a novel nano-formulation of PI3-Kδ/HDAC6 dual inhibitor in combination with Navitoclax (NAV; BCL-2 and BCL-xL inhibitor) is developed using Pluronic modified PLA based hybrid block copolymers (QuatramersTM). The prepared dual drug loaded PI3-Kδ/HDAC6-NAV-Quatramers have shown high encapsulation efficiency, optimum size and polydispersity index (PDI) of ~93%, 159 ± 2.6 nm and 0.13 ± 0.05, respectively. These PI3-Kδ/HDAC6-NAV-Quatramers exhibit slow and sustained release profile of PI3-Kδ/HDAC6 and NAV in a non-physiological buffer (PBS, pH 7.4). Multiple ratios (PI3-Kδ/HDAC6:NAV = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug-loaded Quatramers. The in-vitro proliferation inhibition studies conducted with PI3-Kδ/HDAC6-NAV-Quatramers on ER+ breast cancer cell lines have shown synergistic effect with substantially lower IC50 values as compared to individual PI3-Kδ/HDAC6-Quatramers and NAV-Quatramers. The results also demonstrate that, in contrast to 1:1 and 3:1, treatment of ER+ breast cancer cells with 1:3 ratio of PI3-Kδ/HDAC6:NAV dual drug-loaded Quatramenrs, was associated with substantial inhibition of growth in vitro. The efficacy of PI3-Kδ/HDAC6-NAV-Quatramers was assessed in ER+ breast cancer syngeneic mouse tumor model (EAC). Mice were treated either with PI3-Kδ/HDAC6-Quatramers, NAV-Quatramers or PI3-Kδ/HDAC6-NAV-dual drug loaded Quatramers at 4 mg/kg, i.v, twice a week for 3 weeks. Interestingly, in contrast to PI3-Kδ/HDAC6-Quatramers or NAV-Quatramers alone, the results demonstrate that there was nearly a complete tumor growth inhibition when mice were treated with PI3-Kδ/HDAC6-NAV-Quatramers. Additionally, the treatment with PI3-Kδ/HDAC6-NAV-Quatramers at the efficacious dose of 4 mg/kg did not show any significant body weight loss, confirming no overt toxicity. Taken together, these results demonstrate that a unique formulation of a novel PI3-Kδ/HDAC6 dual inhibitor in combination with Navitoclax in a dual drug-loaded Quatramers in a particular ratio of 1:3, represents an excellent strategy for efficient treatment option for ER+ breast cancer.
Citation Format: Surender M. Kharbanda, Sachchidanand Tiwari, Harshdeep Kaur, Anees Mohammad, Priya Gupta, Harpal Singh. Co-loading of a novel PI3-Kdelta/HDAC6 dual inhibitor and navitoclax into QuatramerTM biodegradable polymeric nanoparticles synergistically inhibit growth of ER+breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2718.