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Cationic microRNA-delivering nanocarriers for efficient treatment of colon carcinoma in xenograft model
1School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China.
Abstract:
Manipulation of tumor microRNAs (miRNAs) may offer novel avenues for treatment of cancer. However, development of safe, robust, non-viral delivery methods remains a main challenge to obtain the promise of gene therapy. The miR-145 is dysregulated in many cancers, including colon carcer, and further in vitro investigation established antiproliferative and proapoptotic roles of miR-145. Herein, we study a PLGA/PEI (poly (d, l-lactide-co-glycolide)/polyethylenimine)-mediated miRNA vector delivery system; the validation of the method was carried out using a colon cancer xenograft model with miR-145 vector encoding for the expression of miR-145 (pDNA). First, high-molecular-weight PEI (25000 Da) was conjugated with cetyl to formulate reducible cetylated PEI (PEI-cet), and then PEI-cet was introduced to PLGA suspension. Next, PLGA/PEI-cet was crosslinked with hyaluronic acid (HA) to facilitate cellular uptake of miRNA plasmid vector via HA receptor-mediated endocytosis. After local administration of PLGA/PEI/HA complexes, intact miRNA plasmid vectors were delivered into HCT-116 colon cancer cells and xenograft tumor-bearing mice, and significant antitumor effects were achieved. The results show that the HA-based miR-145 nanocarrier could efficiently facilitate cellular uptake and significantly enhance miR-145 expression in HCT-116 cells. Consequently, the increased miR-145 induced G1 cell cycle arrest, reduced tumor proliferation and increased apoptosis, inhibited HCT-116 cell migration and suppressed c-MYC expressions, a regulatory target of miR-145. Of particular importance is the significant decrease in tumor growth in the mice model of colon cancer with the targeting miR-145 delivery system. The results in this work show that miR-145 has been effectively delivered to colon carcinomas through a PLGA/PEI/HA vehicle, indicating a promising miRNA replacement therapy strategy.
Insights
This study presents a novel non-viral delivery system using PLGA/PEI/HA nanoparticles to deliver miR-145 for colon cancer treatment. The system effectively reduced tumor growth and increased apoptosis in a mouse model.
Area of Science:
- Biomedical Engineering
- Oncology
- Gene Therapy
Background:
- MicroRNA (miRNA) manipulation shows promise for cancer therapy, but safe, non-viral delivery remains a challenge.
- miR-145 is frequently dysregulated in cancers and exhibits antiproliferative and proapoptotic functions.
- Effective delivery of miRNA therapeutics is crucial for successful gene therapy in oncology.
Purpose of the Study:
- To develop and validate a novel PLGA/PEI/HA nanocarrier system for targeted delivery of miR-145 to colon cancer cells.
- To evaluate the therapeutic efficacy of this miR-145 delivery system in vitro and in a colon cancer xenograft mouse model.
- To investigate the molecular mechanisms underlying the antitumor effects of miR-145 delivered via the nanocarrier.
Main Methods:
- Formulation of reducible cetylated PEI (PEI-cet) and its complexation with PLGA nanoparticles.
- Crosslinking of PLGA/PEI-cet with hyaluronic acid (HA) to create HA-based nanocarriers for receptor-mediated endocytosis.
- Local administration of PLGA/PEI/HA/miR-145 plasmid DNA (pDNA) complexes in HCT-116 colon cancer cells and xenograft models.
- Assessment of cellular uptake, miR-145 expression, cell cycle, apoptosis, migration, and tumor growth inhibition.
Main Results:
- The HA-based nanocarrier efficiently facilitated cellular uptake and enhanced miR-145 expression in HCT-116 cells.
- Increased miR-145 levels induced G1 cell cycle arrest, reduced proliferation, and promoted apoptosis.
- The delivery system significantly inhibited HCT-116 cell migration and suppressed c-MYC expression.
- A significant reduction in tumor growth was observed in the colon cancer xenograft mouse model.
Conclusions:
- The PLGA/PEI/HA nanocarrier system effectively delivers miR-145 pDNA to colon cancer cells and tumors.
- This targeted miR-145 delivery demonstrates significant antitumor effects, including reduced proliferation and increased apoptosis.
- The developed nanocarrier represents a promising strategy for miRNA replacement therapy in colon cancer treatment.
