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Co-delivery of microRNA-21 antisense oligonucleotides and gemcitabine using nanomedicine for pancreatic cancer
Yaqing Li1,2, Yinting Chen1,2, Jiajia Li1,2
1Department of Gastroenterology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China.
Abstract:
Tumor metastasis occurs naturally in pancreatic cancer, and the efficacy of chemotherapy is usually poor. Precision medicine, combining downregulation of target genes with chemotherapy drugs, is expected to improve therapeutic effects. Therefore, we developed a combined therapy of microRNA-21 antisense oligonucleotides (ASO-miR-21) and gemcitabine (Gem) using a targeted co-delivery nanoparticle (NP) carrier and investigated the synergistic inhibitory effects on pancreatic cancer cells metastasis and growth. Polyethylene glycol-polyethylenimine-magnetic iron oxide NPs were used to co-deliver ASO-miR-21 and Gem. An anti-CD44v6 single-chain variable fragment (scFvCD44v6 ) was used to coat the particles to obtain active and targeted delivery. Our results showed that the downregulation of the oncogenic miR-21 by ASO resulted in upregulation of the tumor-suppressor genes PDCD4 and PTEN and the suppression of epithelial-mesenchymal transition, which inhibited the proliferation and induced the clonal formation, migration, and invasion of pancreatic cancer cells in vitro. The co-delivery of ASO-miR-21 and Gem induced more cell apoptosis and inhibited the growth of pancreatic cancer cells to a greater extent than single ASO-miR-21 or Gem treatment in vitro. In animal tests, more scFvCD44v6 -PEG-polyethylenimine/ASO-magnetic iron oxide NP/Gem accumulated at the tumor site than non-targeted NPs and induced a potent inhibition of tumor proliferation and metastasis. Magnetic resonance imaging was used to observed tumor homing of NPs. These results imply that the combination of miR-21 gene silencing and Gem therapy using an scFv-functionalized NP carrier exerted synergistic antitumor effects on pancreatic cancer cells, which is a promising strategy for pancreatic cancer therapy.
Insights
This study combines microRNA-21 silencing with gemcitabine chemotherapy using targeted nanoparticles to inhibit pancreatic cancer growth and metastasis. The novel nanoparticle delivery system shows synergistic antitumor effects, offering a promising new strategy for pancreatic cancer treatment.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- Pancreatic cancer exhibits significant tumor metastasis and poor chemotherapy response.
- Precision medicine strategies, like gene silencing combined with chemotherapy, are crucial for improving therapeutic outcomes.
Purpose of the Study:
- To develop and evaluate a targeted nanoparticle system for co-delivery of microRNA-21 antisense oligonucleotides (ASO-miR-21) and gemcitabine (Gem).
- To investigate the synergistic inhibitory effects of this combined therapy on pancreatic cancer cell metastasis and growth.
Main Methods:
- Co-delivery of ASO-miR-21 and Gem using polyethylene glycol-polyethylenimine-magnetic iron oxide nanoparticles.
- Functionalization of nanoparticles with anti-CD44v6 single-chain variable fragments (scFvCD44v6) for targeted delivery.
- In vitro assessment of effects on pancreatic cancer cell proliferation, migration, invasion, and apoptosis.
- In vivo studies in animal models to evaluate tumor growth inhibition and metastasis, with magnetic resonance imaging for nanoparticle tracking.
Main Results:
- ASO-miR-21 downregulated oncogenic miR-21, upregulated tumor-suppressor genes (PDCD4, PTEN), and suppressed epithelial-mesenchymal transition, inhibiting cancer cell proliferation, clonal formation, migration, and invasion.
- Co-delivery of ASO-miR-21 and Gem demonstrated enhanced apoptosis and greater inhibition of cancer cell growth compared to single treatments.
- Targeted nanoparticles showed increased accumulation at tumor sites and potent inhibition of tumor proliferation and metastasis in vivo.
Conclusions:
- The combination of miR-21 gene silencing and gemcitabine therapy via scFv-functionalized nanoparticles exhibits synergistic antitumor effects in pancreatic cancer.
- This targeted co-delivery approach represents a promising therapeutic strategy for combating pancreatic cancer progression and metastasis.
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