Folate-targeted amphiphilic cyclodextrin nanoparticles incorporating a fusogenic peptide deliver therapeutic siRNA and inhibit the invasive capacity of 3D prostate cancer tumours
Autor: | Colleen C. Nelson, Katrina Sweeney, Meenakshi Malhotra, Brett G. Hollier, Raphael Darcy, Caitriona M. O'Driscoll, James C. Evans |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Male siRNA delivery Folate Endosome Pharmaceutical Science Biology Metastasis 03 medical and health sciences Prostate cancer Folic Acid RNA interference Cell Line Tumor Spheroids Cellular LNCaP Neuropilin 1 medicine Cyclodextrin Humans RNA Small Interfering chemistry.chemical_classification Messenger RNA Cyclodextrins Prostatic Neoplasms Zinc Finger E-box-Binding Homeobox 1 GALA medicine.disease Neuropilin-1 030104 developmental biology chemistry Biochemistry RNAi Cancer research Nanoparticles Peptides |
Zdroj: | International journal of pharmaceutics. 532(1) |
ISSN: | 1873-3476 |
Popis: | The main barrier to the development of an effective RNA interference (RNAi) therapy is the lack of a suitable delivery vector. Modified cyclodextrins have emerged in recent years for the delivery of siRNA. In the present study, a folate-targeted amphiphilic cyclodextrin was formulated using DSPE-PEG5000-folate to target prostate cancer cells. The fusogenic peptide GALA was included in the formulation to aid in the endosomal release of siRNA. Targeted nanoparticles were less than 200 nm in size with a neutral surface charge. The complexes were able to bind siRNA and protect it from serum nucleases. Incubation with excess free folate resulted in a significant decrease in the uptake of targeted nanoparticles in LNCaP and PC3 cells, both of which have been reported to have differing pathways of folate uptake. There was a significant reduction in the therapeutic targets, ZEB1 and NRP1 at mRNA and protein level following treatment with targeted complexes. In preliminary functional assays using 3D spheroids, treatment of PC3 tumours with targeted complexes with ZEB1 and NRP1 siRNA resulted in more compact colonies relative to the untargeted controls and inhibited infiltration into the Matrigel™ layer. |
Databáze: | OpenAIRE |
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