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Author
Ruiz Chamorro, Sara
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Abstract
Non-Small cell lung cancer (NSCLC) accounts for approximately 80% of all cases of lung cancer and has become the leading cause of cancer-related death. Combination chemother-apy is the treatment of choice but unfortunately the 84% of the patients are diagnosed at an advantage stage and present metastatic disease thus making current treatment inefficacious. For this reason, new treatment modalities have emerged in the last years, like RNA mediated gene silencing using small interfering RNA (siRNA) to silence oncogenes such mTOR. Addi-tionally, there is evidence that using combined co-delivery with other treatments enhance ef-ficacy. One of the molecules most used as a combined system is FdU10. To explore the potential of combined therapy for NSCLC, we have developed anisamide-targeted nanopar-ticles composed of Poly(β-aminoesters)s (pBAE) to effectively deliver siRNA mTOR and FdU10 into sigma receptor-expressing NSCLC cells.
First, pBAE nanoparticles were modified as to decrease the promiscuity of the lysine: histidine (KH) and arginine: histidine (RH)- terminated complex. Additionally, they were functionalized with anisamide (AA) in order to increase the selectivity of the nanoparticles and target tumoral cells. The resulting nanoparticles were slightly positive and less than 200 nm in size. Targeted nanoparticles (AA) have showed an increase in the transfection efficiency as compared with those without anisamide. The internalization assay showed that nanoparticles were entering into the cell via receptor-mediated endocytosis, then a more specific systems was achieved.
Second, another challenge of this project focuses on formulating nanomotors that may be able to cross a layer of lung mucosa, as a biological barrier, thus increasing its efficiency and allowing the use of the inhaled route for the administration of genetic material for the treatment of lung cancer. The nanomotors were performed attaching a biocatalyst (specifically catalase) to pBAE nanoparticles to be propelled through hydrogen peroxide, chemical substance gen-erated by lung cancer cells. Optimal values of catalase concentration on the particles were obtained, as well as studies of binding affinity, stability and transfection efficiency of the dif-ferent types of nanocomplexes.
In conclusion, our results demonstrate that the modified pBAE nanoparticles with anisamide is a promising vector to delivery treatments based on nucleic acids into tumors more efficient and selectively. In addition, progresses in the development of nanomotors to improve the route of administration were also achieved.
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