Restitution of Tumor Suppressor MicroRNA-145 Using Magnetic Nanoformulation for Pancreatic Cancer Therapy
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The functional significance of lost microRNAs has been reported in several human malignancies, including pancreatic cancer (PC). Our prior work has identified microRNA-145 (miR-145) as a tumor suppressor microRNA (miRNA) in pancreatic cancer. The restoration of miR-145 downregulates a number of oncogenes including mucin MUC13, a transmembrane glycoprotein that is aberrantly expressed in pancreatic cancer, thus efficiently inhibiting tumor growth in mice. However, lack of an effective tumor-specific delivery system remains an unmet clinical challenge for successful translation of microRNAs.
We developed a miRNA-145-based magnetic nanoparticle formulation (miR-145-MNPF) and assessed its anti-cancer efficacy. Physico-chemical characterization (dynamic light scattering (DLS), transmission electron microscopy (TEM) and miR-binding efficiency), cellular internalization (Prussian blue and confocal microscopy), miR-145 restitution potential (quantitative reverse-transcription PCR (qRT-PCR), and anti-cancer efficacy (proliferation, colony formation, cell migration, cell invasion assays) of this formulation were performed using clinically relevant pancreatic cancer cell lines (HPAF-II, AsPC-1).
miR-145-MNPF exhibited optimal particle size and zeta potential which effectively internalized and restituted miR-145 in pancreatic cancer cells. miR-145 re-expression resulted in downregulation of MUC13, HER2, pAKT, and inhibition of cell proliferation, clonogenicity, migration, and invasion of pancreatic cancer cells.
miR-145-MNPF is an efficient system for miR-145 delivery and restitution in pancreas cancer that may offer a potential therapeutic treatment for PC either alone or in conjunction with conventional treatment.
KeywordsMagnetic nanoparticle miR-145 Pancreatic cancer Therapeutics Nanotherapies
This work was partially supported by grants from the National Institutes of Health (R01 CA142736 to SCC, U01 CA162106A to SCC and MJ, K22CA174841 to MMY), Department of Defense (PC130870 to SCC and MJ), the College of Pharmacy 2015 Dean’s Seed/Instrument Grants of the University of Tennessee Health Science Center (to SCC, MJ, and MMY). Authors acknowledge the Herb Kosten Foundation for pancreatic cancer research support. The authors are also thankful to Cathy Christopherson for editorial assistance.
All the authors listed in the manuscript (Saini Setua, Sheema Khan, Murali M. Yallapu, Stephen W. Behrman, Mohammed Sikander, Shabia Shabir Khan, Meena Jaggi, Subhash C. Chauhan) contributed to the following: substantial contributions to the conception or design of the work; acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Compliance with Ethical Standards
Subhash C. Chauhan: This work was partially supported by grants from the National Institutes of Health (R01 CA142736, U01 CA162106A, and K22CA174841), Department of Defense (PC130870), and financial support from the Kosten Foundation for pancreatic cancer research (UT 14-0558).
Conflicts of interest
The authors declare that they have no conflict of interests.
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