Combination non-targeted and sGRP78-targeted nanoparticle drug delivery outperforms either component to treat metastatic ovarian cancer

  • J Control Release. 2024 Nov:375:438-453. doi: 10.1016/j.jconrel.2024.09.014.
Jenna N Sjoerdsma  1 ,  Emily K Bromley  1 ,  Jaeho Shin  1 ,  Tyvette Hilliard  2 ,  Yueying Liu  2 ,  Caitlin Horgan  3 ,  Gyoyeon Hwang  1 ,  Michael Bektas  2 ,  David Omstead  4 ,  Tanyel Kiziltepe  1 ,  M Sharon Stack  5 ,  Basar Bilgicer  6
Affiliations
  • 1. Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Berthiaume Institute for Precision Health, University of Notre Dame, Notre Dame, IN 46556, USA.
  • 2. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
  • 3. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Berthiaume Institute for Precision Health, University of Notre Dame, Notre Dame, IN 46556, USA; Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
  • 4. Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.
  • 5. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA. Electronic address: [email protected].
  • 6. Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Berthiaume Institute for Precision Health, University of Notre Dame, Notre Dame, IN 46556, USA; Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; Center for Rare & Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA. Electronic address: [email protected].
PMID: 39271060 DOI: 10.1016/j.jconrel.2024.09.014
Abstract

Metastatic ovarian Cancer (MOC) is highly deadly, due in part to the limited efficacy of standard-of-care chemotherapies to metastatic tumors and non-adherent Cancer cells. Here, we demonstrated the effectiveness of a combination therapy of GRP78-targeted (TNPGRP78pep) and non-targeted (NP) nanoparticles to deliver a novel DM1-prodrug to MOC in a syngeneic mouse model. Cell surface-GRP78 is overexpressed in MOC, making GRP78 an optimal target for selective delivery of nanoparticles to MOC. The NP + TNPGRP78pep combination treatment reduced tumor burden by 15-fold, compared to untreated control. Increased T cell and macrophage levels in treated groups also suggested antitumor immune system involvement. The NP and TNPGRP78pep components functioned synergistically through two proposed mechanisms of action. The TNPGRP78pep targeted non-adherent Cancer cells in the peritoneal cavity, preventing the formation of new solid tumors, while the NP passively targeted existing solid tumor sites, providing a sustained release of the drug to the tumor microenvironment.

Keywords
Antitumor immune response; Lipid nanoparticle; Metastasis; Ovarian cancer; Targeted drug delivery; women's health.
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