Nanoscale
Metal–Organic Frameworks for the
Co-Delivery of Cisplatin and Pooled siRNAs to Enhance Therapeutic
Efficacy in Drug-Resistant Ovarian Cancer Cells
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Abstract
Ovarian cancer is the leading cause
of death among women with gynecological
malignancies. Acquired resistance to chemotherapy is a major limitation
for ovarian cancer treatment. We report here the first use of nanoscale
metal–organic frameworks (NMOFs) for the co-delivery of cisplatin
and pooled small interfering RNAs (siRNAs) to enhance therapeutic
efficacy by silencing multiple drug resistance (MDR) genes and resensitizing
resistant ovarian cancer cells to cisplatin treatment. UiO NMOFs with
hexagonal-plate morphologies were loaded with a cisplatin prodrug
and MDR gene-silencing siRNAs (Bcl-2, P-glycoprotein [P-gp], and survivin)
via encapsulation and surface coordination, respectively. NMOFs protect
siRNAs from nuclease degradation, enhance siRNA cellular uptake, and
promote siRNA escape from endosomes to silence MDR genes in cisplatin-resistant
ovarian cancer cells. Co-delivery of cisplatin and siRNAs with NMOFs
led to an order of magnitude enhancement in chemotherapeutic efficacy <i>in vitro</i>, as indicated by cell viability assay, DNA laddering,
and Annexin V staining. This work shows that NMOFs hold great promise
in the co-delivery of multiple therapeutics for effective treatment
of drug-resistant cancers