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Cascade-Targeted Nanoparticles for Enhanced Gemcitabine Delivery and Adenosine Metabolism Modulation to Overcome
Hongrui Fan1, Hongyi Chen1, Haolin Song1
1Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201203, China.
Abstract:
KRAS mutations are find in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases, making PDAC exhibit intrinsic resistance to chemotherapy and reshape the immunosuppressive tumor microenvironment (TME), disappointing the clinically preferred chemotherapy-immunotherapy combination. Standing on the cross point of therapeutic resistance, the aberrant adenosine metabolism contributes greatly to chemo- and immunotherapy tolerance. KRAS mutation-induced over-expression of key enzyme CD39 is believed to be involved in shaping the immunosuppressive TME, as it catalyzes the hydrolysis of extracellular ATP into immunosuppressive adenosine. Meanwhile, the loss of equilibrative nucleoside transporters (ENTs) leads to the accumulation of adenosine and the intracellular delivery difficulty of gemcitabine, further vanishing patients' hope of benefiting from either chemotherapy or immunotherapy. The key challenge is to modulate the aberrant metabolism, also enhance gemcitabine intracellular delivery. Therefore, ROS-responsive positively-charged polymer B-PDEA is prepared and assembled into polyplexes for loading CD39-down-regulating small interfering RNA. Gemcitabine-loaded albumin is coupled with the polyplexes through enzyme-cleavable peptide, forming the intact nanoparticles for the co-delivery of the first-line chemotherapeutic drug and CD39-regulating nucleic acid, showing enhanced gemcitabine intracellular delivery and adenosine metabolism regulating capacity. This approach activated antitumor immunity while achieving chemosensitization by changing the metabolic-immune crosstalk of TME, showcasing great potential for PDAC treatment.
Insights
This study developed novel nanoparticles to overcome chemotherapy and immunotherapy resistance in pancreatic cancer. The nanoparticles enhance gemcitabine delivery and regulate adenosine metabolism, activating anti-tumor immunity for improved treatment potential.
Area of Science:
- Oncology
- Nanotechnology
- Cancer Immunology
Background:
- KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) cause resistance to chemotherapy and immunotherapy by promoting an immunosuppressive tumor microenvironment (TME).
- Aberrant adenosine metabolism, driven by KRAS mutations and CD39 enzyme activity, contributes to therapeutic resistance and an immunosuppressive TME.
- Reduced expression of equilibrative nucleoside transporters (ENTs) hinders gemcitabine delivery and promotes adenosine accumulation, further limiting treatment efficacy.
Purpose of the Study:
- To develop a co-delivery system for gemcitabine and CD39-targeting nucleic acids to overcome therapeutic resistance in PDAC.
- To enhance intracellular gemcitabine delivery and modulate aberrant adenosine metabolism within the TME.
- To activate anti-tumor immunity and improve the efficacy of combined chemotherapy and immunotherapy in PDAC.
Main Methods:
- Preparation of ROS-responsive, positively-charged polymer nanoparticles (B-PDEA) encapsulating CD39-siRNA.
- Coupling gemcitabine-loaded albumin with the polyplexes via enzyme-cleavable peptides to form intact nanoparticles.
- Evaluation of nanoparticle efficacy in enhancing gemcitabine delivery, regulating adenosine metabolism, and activating anti-tumor immunity in the TME.
Main Results:
- The developed nanoparticles successfully co-delivered gemcitabine and CD39-siRNA, enhancing gemcitabine intracellular delivery.
- The nanoparticles effectively regulated aberrant adenosine metabolism by down-regulating CD39.
- The treatment activated anti-tumor immunity and demonstrated chemosensitization by altering the metabolic-immune crosstalk within the TME.
Conclusions:
- The novel nanoparticle system shows significant potential for overcoming chemo- and immunotherapy resistance in PDAC.
- Modulating adenosine metabolism and enhancing gemcitabine delivery represent a promising strategy for PDAC treatment.
- This approach highlights the therapeutic potential of targeting metabolic-immune crosstalk in the PDAC tumor microenvironment.
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