ZIF Polymorphs for Nucleic Acid Delivery and Targeted Knockdown of Gene Expression in Prostate Cancer
2020-02-06T23:18:15Z (GMT) by
Prostate cancer (PC) is the second leading cause of male cancer deaths, the advanced form of which continues to be incurable; and nature of the disease being such that it is highly suitable for gene therapy. However, therapy is hampered by lack of appropriate gene delivery agents available. Recently, metal-organic-framework (MOF) biocomposites have seen increasing applications in DNA technologies, including gene delivery. In this work, a polymorph of zeolitic imidazolate framework-8 (ZIF-8) MOF nanoparticles called ZIF-C are used as gene delivery agents to cause knockdown (KD) of a protein overexpressed by the gene ribosomal protein SA in PC. Feasibility of ZIF-C mediated KD at cytoplasmic levels in PC is demonstrated by RNA interference, whereby RPSA specific siRNA is delivered using ZIF-C. Feasibility of ZIF-C mediated KD at genomic levels is demonstrated by CRISPR/Cas9, whereby RPSA specific CRISPR/Cas9 plasmids are delivered using ZIF-C. Specific targeting is further achieved by coating of ZIF-C with epigallocatechin-gallate (EGCG). Cellular transfection assays reveal the gradual expression of ZIF-C delivered RPSA-targeting nucleic acids for up to 96 hours. Quantitative polymerase chain reactions and genomic cleavage detection demonstrate gradual KD, with ~20% reduction in RPSA expression that is almost doubled to ~40% on EGCG-mediated targeted cellular uptake.
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