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 in vitro, 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.
O varian cancer is the deadliest gynecologic cancer with a high-mortality rate that has remained unchanged in the past four decades. 1,2 The dismal prognosis of ovarian cancer is in large part due to the acquired resistance to chemotherapy. 3 Epithelial ovarian cancer, the most common type of ovarian cancer, is initially responsive to cisplatin therapy. 4 The recurrent disease, however, is often refractory to treatment and leads to mortality. 5 New strategies to overcome drug resistance are urgently needed in order to reduce the mortality rate of ovarian cancer.
The discovery of small interfering RNA (siRNA) in 1998 has provided new avenues of combating resistant cancers. 6 Silencing genes that are involved in drug resistance using RNA interference (RNAi) can reverse cisplatin resistance in ovarian cancer. [7][8][9][10] Successful treatment of ovarian cancer cells with multidrug resistance (MDR) gene-silencing siRNAs and cisplatin requires the development of novel vehicles that can specifically and effectively deliver cisplatin to cell nuclei and siRNAs to cell cytoplasms, respectively. We report here the first use of nanoscale metal-organic frameworks (NMOFs) for the