2. Academic Validation
  3. Doxorubicin-conjugated siRNA lipid nanoparticles for combination cancer therapy

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

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.

Figures
Products