Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer
Chi-Ling Chiang1,2, Yifan Ma1,3, Ya-Chin Hou4,5
1Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) tumours carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation release abundant targeted EVs with high RNA loading. Together with a low dose chemotherapy drug, Gemcitabine, dtEVs suppress large orthotopic PANC-1 and patient derived xenograft tumours and metastasis in mice and extended animal survival. Our work presents a clinically accessible and scalable way to produce abundant EVs for delivering multiple gene cargoes to large solid tumours.
Insights
Dual targeted extracellular vesicles (dtEVs) effectively deliver therapeutic RNA to suppress pancreatic ductal adenocarcinoma (PDAC) tumors. This novel drug delivery system shows promise for treating large solid tumors and improving patient survival.
Area of Science:
- Oncology
- Biotechnology
- Nanomedicine
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents a significant clinical challenge due to multiple gene mutations and poor treatment response.
- Existing drug delivery systems struggle to effectively target and treat large solid tumor burdens characteristic of PDAC.
Purpose of the Study:
- To develop and evaluate a novel dual-targeted extracellular vesicle (dtEV) system for delivering multiple gene cargoes to PDAC tumors.
- To assess the efficacy of dtEVs in suppressing large PDAC tumors and metastasis in preclinical models.
Main Methods:
- Engineered extracellular vesicles (EVs) with CD64 protein, tissue targeting peptide, and a humanized monoclonal antibody on their surface.
- Transwell®-based asymmetric cell electroporation for high RNA loading and efficient EV production.
- Combination therapy using dtEVs and low-dose Gemcitabine in orthotopic PANC-1 and patient-derived xenograft mouse models.
Main Results:
- Successfully produced abundant targeted EVs with high therapeutic RNA loads.
- Demonstrated significant suppression of large orthotopic PDAC tumors and metastasis in mice.
- Observed extended animal survival when treated with dtEVs and Gemcitabine.
Conclusions:
- Dual targeted extracellular vesicles offer a clinically accessible and scalable platform for delivering multiple gene therapies to solid tumors.
- This approach shows significant potential for overcoming treatment resistance in pancreatic cancer.
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