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Susceptibility of Lung Carcinoma Cells to Nanostructured Lipid Carrier of ARV-825, a BRD4 Degrading Proteolysis Targeting Chimera

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Abstract

The present work was aimed at developing an optimized and modified nanostructured lipid carrier of BRD4 protein degrading Proteolysis Targeting Chimera (PROTAC) against non-small cell lung carcinoma. PROTACs are an emerging class of anticancer molecules with nanomolar activity but associated with significant solubility challenges. Lipid-based colloidal systems like nanostructured lipid carriers are widely explored for such highly lipophilic molecules. ARV-825, a cereblon-based PROTAC was investigated for its anticancer efficacy in vitro in 2D and 3D lung cancer models. ARV-825 loaded PEGylated nanostructured lipid carriers (AP-NLC) was prepared using melt emulsification technique. ARV-825 was stabilized using Precirol® ATO5 and Captex® 300 EP/NF as the solid and liquid lipid, respectively. However, hydrophobic ion-pairing with medium chain fatty acid was required to improve drug loading and stability. A hydrodynamic diameter and polydispersity index of 56.33 ± 0.42 nm and 0.16 respectively with zeta potential of -21 ± 1.24 mV was observed. In vitro migration and colony formation assay confirmed the anticancer activity of ARV-825 alone and AP-NLC. Nearly 38% and 50% apoptotic cell population were observed after ARV-825 and AP-NLC treatment. Immunoblotting assay showed complete suppression of BRD4 and c-Myc protein expression for AP-NLC. Most importantly, significant reduction in the growth of multicellular 3D spheroid of A549 cells confirmed the effectiveness of BRD4 PROTAC and its lipid nanoparticle in non-small cell lung cancer (NSCLC). AP-NLC. Higher amount of red fluorescence throughout the spheroid surface further confirmed superior efficacy of AP-NLC in tumor penetration and cell killing.

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Funding

We are thankful to Department of Pharmaceutical Sciences, St. John’s University, NY for providing the fund for the project.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. Albert Hall, B49, St. John’s University, 8000 Utopia Parkway, Queens, New York, 11439, USA

    Richa Vartak, Aishwarya Saraswat, Yuqi Yang, Zhe-Sheng Chen & Ketan Patel

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  1. Richa Vartak
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  2. Aishwarya Saraswat
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  3. Yuqi Yang
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  4. Zhe-Sheng Chen
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Correspondence to Ketan Patel.

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Vartak, R., Saraswat, A., Yang, Y. et al. Susceptibility of Lung Carcinoma Cells to Nanostructured Lipid Carrier of ARV-825, a BRD4 Degrading Proteolysis Targeting Chimera. Pharm Res 39, 2745–2759 (2022). https://doi.org/10.1007/s11095-022-03184-3

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  • DOI: https://doi.org/10.1007/s11095-022-03184-3

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