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In vivo bone marrow microenvironment siRNA delivery using lipid-polymer nanoparticles for multiple myeloma therapy.
Guimarães, Pedro P G; Figueroa-Espada, Christian G; Riley, Rachel S; Gong, Ningqiang; Xue, Lulu; Sewastianik, Tomasz; Dennis, Peter S; Loebel, Claudia; Chung, Amanda; Shepherd, Sarah J; Haley, Rebecca M; Hamilton, Alex G; El-Mayta, Rakan; Wang, Karin; Langer, Robert; Anderson, Daniel G; Carrasco, Ruben D; Mitchell, Michael J.
Afiliación
  • Guimarães PPG; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
  • Figueroa-Espada CG; Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil.
  • Riley RS; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
  • Gong N; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
  • Xue L; Department of Biomedical Engineering, Rowan University, Glassboro, NJ 08028.
  • Sewastianik T; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
  • Dennis PS; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
  • Loebel C; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
  • Chung A; Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw 02776, Poland.
  • Shepherd SJ; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
  • Haley RM; Department of Materials Science & Engineering, University of Michigan, North Campus Research Complex, Ann Arbor, MI 48109.
  • Hamilton AG; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
  • El-Mayta R; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
  • Wang K; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
  • Langer R; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
  • Anderson DG; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
  • Carrasco RD; Department of Bioengineering, Temple University, Philadelphia, PA 19122.
  • Mitchell MJ; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
Proc Natl Acad Sci U S A ; 120(25): e2215711120, 2023 06 20.
Article en En | MEDLINE | ID: mdl-37310997
Multiple myeloma (MM), a hematologic malignancy that preferentially colonizes the bone marrow, remains incurable with a survival rate of 3 to 6 mo for those with advanced disease despite great efforts to develop effective therapies. Thus, there is an urgent clinical need for innovative and more effective MM therapeutics. Insights suggest that endothelial cells within the bone marrow microenvironment play a critical role. Specifically, cyclophilin A (CyPA), a homing factor secreted by bone marrow endothelial cells (BMECs), is critical to MM homing, progression, survival, and chemotherapeutic resistance. Thus, inhibition of CyPA provides a potential strategy to simultaneously inhibit MM progression and sensitize MM to chemotherapeutics, improving therapeutic response. However, inhibiting factors from the bone marrow endothelium remains challenging due to delivery barriers. Here, we utilize both RNA interference (RNAi) and lipid-polymer nanoparticles to engineer a potential MM therapy, which targets CyPA within blood vessels of the bone marrow. We used combinatorial chemistry and high-throughput in vivo screening methods to engineer a nanoparticle platform for small interfering RNA (siRNA) delivery to bone marrow endothelium. We demonstrate that our strategy inhibits CyPA in BMECs, preventing MM cell extravasation in vitro. Finally, we show that siRNA-based silencing of CyPA in a murine xenograft model of MM, either alone or in combination with the Food and Drug Administration (FDA)-approved MM therapeutic bortezomib, reduces tumor burden and extends survival. This nanoparticle platform may provide a broadly enabling technology to deliver nucleic acid therapeutics to other malignancies that home to bone marrow.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mieloma Múltiple Tipo de estudio: Prognostic_studies Límite: Animals / Humans País/Región como asunto: America do norte Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mieloma Múltiple Tipo de estudio: Prognostic_studies Límite: Animals / Humans País/Región como asunto: America do norte Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos