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ZIF Polymorphs for Nucleic Acid Delivery and Targeted Knockdown of Gene Expression in Prostate Cancer
preprintsubmitted on 05.02.2020, 12:07 and posted on 06.02.2020, 23:18 by Arpita Poddar, Suneela Pyreddy, Francesco Carraro, Sudip Dhakal, Andrea Rassell, Matthew R. Field, T. Srinivasa Reddy, paolo falcaro, Cara M. Doherty, Ravi Shukla
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.