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Updated: May 12, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Rational development of gemcitabine-based nanoplatform for targeting SERPINB9/Granzyme B axis to overcome
Haozhe Huang1,2, Yiqing Mu1,2, Yixian Huang1,2
1Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Abstract:
SERPINB9, an endogenous inhibitor of granzyme B (GzmB), has emerged as a critical factor in the resistance to immunotherapy by protecting cancer cells from GzmB-induced cytotoxicity. However, its role in chemosensitivity remains unknown. In this study, we show that gemcitabine (GEM) treatment upregulates SERPINB9 through transcription factor ATF-3. Interestingly, GEM also induces the expression of GzmB and knockout or knockdown of SERPINB9 results in enhanced response of tumor cells to GEM, suggesting a role of GzmB/SERPINB9 axis in regulating chemosensitivity. To facilitate the therapeutic translation of these findings, we engineer POEM nanocarrier (consisting of lipid-derivatized polylysine (PEG-PLL-Oleic acid, PPO), and GEM-conjugated polylysine (PEG-PLL-OA-GEM, PPOGEM), PPO/PPOGEM (POEM)) that is highly effective in codelivery of built-in GEM and loaded SERPINB9 short interfering RNA (siSPB9). GEM conjugation introduces an additional mechanism of carrier/siRNA interaction in addition to charge-mediated interaction and enables efficient i.v. delivery at lower N/P ratios. Here, we show that co-delivery of GEM and siSPB9 significantly improves antitumor efficacy and remodels the tumor immune microenvironment in pancreatic cancer models, supporting a promising therapeutic strategy.
Insights
SERPINB9 protein promotes cancer cell survival against gemcitabine (GEM) chemotherapy. Inhibiting SERPINB9 with nanocarrier-delivered siRNA enhances GEM efficacy, offering a new pancreatic cancer treatment strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- SERPINB9 inhibits granzyme B (GzmB), protecting cancer cells from GzmB-induced death and contributing to immunotherapy resistance.
- The role of SERPINB9 in chemosensitivity, particularly to gemcitabine (GEM), was previously unknown.
Purpose of the Study:
- To investigate the role of SERPINB9 in gemcitabine (GEM) chemosensitivity in cancer.
- To develop a novel nanocarrier system for co-delivery of GEM and SERPINB9-targeting siRNA (siSPB9) to enhance antitumor efficacy.
Main Methods:
- Investigated the effect of GEM on SERPINB9 and GzmB expression in cancer cells.
- Utilized gene knockout and knockdown techniques to assess SERPINB9's role in GEM response.
- Engineered a POEM nanocarrier for co-delivery of GEM and siSPB9.
- Evaluated the therapeutic efficacy of co-delivery in pancreatic cancer models.
Main Results:
- GEM treatment upregulates SERPINB9 via ATF-3, while also inducing GzmB.
- SERPINB9 knockdown or knockout enhances cancer cell sensitivity to GEM, indicating a GzmB/SERPINB9 axis role.
- The engineered POEM nanocarrier efficiently co-delivered GEM and siSPB9.
- Co-delivery of GEM and siSPB9 significantly improved antitumor effects and remodeled the tumor immune microenvironment in pancreatic cancer.
Conclusions:
- The GzmB/SERPINB9 axis plays a crucial role in regulating chemosensitivity to GEM.
- Co-delivery of GEM and siSPB9 using the POEM nanocarrier represents a promising therapeutic strategy for pancreatic cancer.
- This approach effectively overcomes GEM resistance and enhances antitumor immunity.
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