Doxorubicin-conjugated siRNA lipid nanoparticles for combination cancer therapy

Kamila Butowska; Xuexiang Han; Ningqiang Gong; Rakan El-Mayta; Rebecca M Haley; Lulu Xue; Wenqun Zhong; Wei Guo; Karin Wang; Michael J Mitchell

doi:10.1016/j.apsb.2022.07.011

Doxorubicin-conjugated siRNA lipid nanoparticles for combination cancer therapy

Acta Pharm Sin B. 2023 Apr;13(4):1429-1437. doi: 10.1016/j.apsb.2022.07.011. Epub 2022 Jul 21.

Authors

Kamila Butowska^{1

2}, Xuexiang Han¹, Ningqiang Gong¹, Rakan El-Mayta¹, Rebecca M Haley¹, Lulu Xue¹, Wenqun Zhong³, Wei Guo³, Karin Wang⁴, Michael J Mitchell^{1

5

6

7

8}

Affiliations

¹ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Intercollegiate Faculty of Biotechnology, University of Gdańsk & Medical University of Gdańsk, Gdańsk 80-307, Poland.
³ Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Department of Bioengineering, Temple University, Philadelphia, PA 19122, USA.
⁵ Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Abstract

Evasion of apoptosis is a hallmark of cancer, attributed in part to overexpression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2). In a variety of cancer types, including lymphoma, Bcl-2 is overexpressed. Therapeutic targeting of Bcl-2 has demonstrated efficacy in the clinic and is the subject of extensive clinical testing in combination with chemotherapy. Therefore, the development of co-delivery systems for Bcl-2 targeting agents, such as small interfering RNA (siRNA), and chemotherapeutics, such as doxorubicin (DOX), holds promise for enabling combination cancer therapies. Lipid nanoparticles (LNPs) are a clinically advanced nucleic acid delivery system with a compact structure suitable for siRNA encapsulation and delivery. Inspired by ongoing clinical trials of albumin-hitchhiking doxorubicin prodrugs, here we developed a DOX-siRNA co-delivery strategy via conjugation of doxorubicin to the surface of siRNA-loaded LNPs. Our optimized LNPs enabled potent knockdown of Bcl-2 and efficient delivery of DOX into the nucleus of Burkitts' lymphoma (Raji) cells, leading to effective inhibition of tumor growth in a mouse model of lymphoma. Based on these results, our LNPs may provide a platform for the co-delivery of various nucleic acids and DOX for the development of new combination cancer therapies.

Keywords: Bcl-2; Chemotherapy; Doxorubicin; Lipid nanoparticles; Lymphoma; siRNA delivery.