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.
Kamila Butowska  1  2 ,  Xuexiang Han  1 ,  Ningqiang Gong  1 ,  Rakan El-Mayta  1 ,  Rebecca M Haley  1 ,  Lulu Xue  1 ,  Wenqun Zhong  3 ,  Wei Guo  3 ,  Karin Wang  4 ,  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.
PMID: 37139433 DOI: 10.1016/j.apsb.2022.07.011
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.
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