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ZIF polymorphs for Nucleic Acid Delivery and Targeted Knockdown of Gene Expression in Prostate Cancer.pdf (1.23 MB)
ZIF Polymorphs for Nucleic Acid Delivery and Targeted Knockdown of Gene Expression in Prostate Cancer
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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.