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Combination non-targeted and sGRP78-targeted nanoparticle drug delivery outperforms either component to treat
Jenna N Sjoerdsma1, Emily K Bromley1, Jaeho Shin1
1Department 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.
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.
Insights
A novel nanoparticle combination therapy effectively targets metastatic ovarian cancer (MOC). This treatment significantly reduced tumor burden and showed potential immune system involvement, offering new hope for MOC patients.
Area of Science:
- Oncology
- Nanotechnology
- Immunology
Background:
- Metastatic ovarian cancer (MOC) presents a significant challenge due to limited chemotherapy efficacy against disseminated tumors and free-floating cancer cells.
- Overexpression of cell surface GRP78 on MOC cells presents a viable target for selective drug delivery systems.
Purpose of the Study:
- To evaluate the efficacy of a combination therapy using GRP78-targeted (TNPGRP78pep) and non-targeted (NP) nanoparticles delivering a DM1-prodrug for treating metastatic ovarian cancer.
- To investigate the synergistic mechanisms of action for the nanoparticle combination therapy in a syngeneic mouse model.
Main Methods:
- A syngeneic mouse model of metastatic ovarian cancer was utilized.
- Treatment involved a combination of GRP78-targeted nanoparticles (TNPGRP78pep) and non-targeted nanoparticles (NP) loaded with a DM1-prodrug.
- Tumor burden, immune cell infiltration (T cells, macrophages), and drug distribution were assessed.
Main Results:
- The combination therapy (NP + TNPGRP78pep) resulted in a 15-fold reduction in tumor burden compared to untreated controls.
- Elevated levels of T cells and macrophages were observed in treated groups, suggesting an activated antitumor immune response.
- TNPGRP78pep nanoparticles targeted non-adherent cells in the peritoneal cavity, inhibiting new tumor formation, while NP nanoparticles targeted solid tumors for sustained drug release.
Conclusions:
- The synergistic combination of targeted and non-targeted nanoparticles offers a potent therapeutic strategy for metastatic ovarian cancer.
- This approach effectively reduces tumor burden by simultaneously addressing disseminated cancer cells and solid tumors while potentially engaging the immune system.
- Targeting GRP78 provides a selective delivery mechanism for nanoparticles, enhancing treatment efficacy in MOC.
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