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Nanoscale metal-organic frameworks for the co-delivery of cisplatin and pooled siRNAs to enhance therapeutic efficacy in drug-resistant ovarian cancer cells.

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 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.

SUBMITTER: He C

PROVIDER: S-EPMC4210117 | biostudies-other | 2014 Apr

REPOSITORIES: biostudies-other

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Nanoscale metal-organic frameworks for the co-delivery of cisplatin and pooled siRNAs to enhance therapeutic efficacy in drug-resistant ovarian cancer cells.

He Chunbai C Lu Kuangda K Liu Demin D Lin Wenbin W

Journal of the American Chemical Society 20140331 14

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 h ...[more]

PMID: 24669930

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Project description:Cancer immunotherapy, particularly checkpoint blockade immunotherapy (CBI), has revolutionized the treatment of some cancers by reactivating the antitumor immunity of hosts with durable response and manageable toxicity. However, many cancer patients with low tumor antigen exposure and immunosuppressive tumor microenvironments do not respond to CBI. A variety of methods have been investigated to reverse immunosuppressive tumor microenvironments and turn "cold" tumors "hot" with the goal of extending the therapeutic benefits of CBI to a broader population of cancer patients. Immunostimulatory adjuvant treatments, such as cancer vaccines, photodynamic therapy (PDT), radiotherapy (RT), radiotherapy-radiodynamic therapy (RT-RDT), and chemodynamic therapy (CDT), promote antigen presentation and T cell priming and, when used in combination with CBI, reactivate and sustain systemic antitumor immunity. Cancer vaccines directly provide tumor antigens, while immunoadjuvant therapies such as PDT, RT, RT-RDT, and CDT kill cancer cells in an immunogenic fashion to release tumor antigens in situ. Direct administration of tumor antigens or indirect intratumoral immunoadjuvant therapies as in situ cancer vaccines initiate the immuno-oncology cycle for antitumor immune response.With the rapid growth of cancer nanotechnology in the past two decades, a large number of nanoparticle platforms have been studied, and some nanomedicines have been translated into clinical trials. Nanomedicine provides a promising strategy to enhance the efficacy of immunoadjuvant therapies to potentiate cancer immunotherapy. Among these nanoparticle platforms, nanoscale metal-organic frameworks (nMOFs) have emerged as a unique class of porous hybrid nanomaterials with metal cluster secondary building units and organic linkers. With molecular modularity, structural tunability, intrinsic porosity, tunable stability, and biocompatibility, nMOFs are ideally suited for biomedical applications, particularly cancer treatments.In this Account, we present recent breakthroughs in the design of nMOFs as nanocarriers for cancer vaccine delivery and as nanosensitizers for PDT, CDT, RT, and RT-RDT. The versatility of nMOFs allows them to be fine-tuned to effectively load tumor antigens and immunoadjuvants as cancer vaccines and significantly enhance the local antitumor efficacy of PDT, RT, RT-RDT, and CDT via generation of reactive oxygen species (ROS) for in situ cancer vaccination. These nMOF-based treatments are further combined with cancer immunotherapies to elicit systemic antitumor immunity. We discuss novel strategies to enhance light tissue penetration and overcome tumor hypoxia in PDT, to increase energy deposition and ROS diffusion in RT, to combine the advantages of PDT and RT to enable RT-RDT, and to trigger CDT by hijacking aberrant metabolic processes in tumors. Loading nMOFs with small-molecule drugs such as an indoleamine 2,3-dioxygenase inhibitor, the toll-like receptor agonist imiquimod, and biomacromolecules such as CpG oligodeoxynucleotides and anti-CD47 antibody synergizes with nMOF-based radical therapies to enhance their immunotherapeutic effects. Further combination with immune checkpoint inhibitors activates systemic antitumor immune responses and elicits abscopal effects. With structural and compositional tunability, nMOFs are poised to provide a new clinically deployable nanotechnology platform to promote immunostimulatory tumor microenvironments by delivering cancer vaccines, mediating PDT, enhancing RT, enabling RT-RDT, and catalyzing CDT and potentiate cancer immunotherapy.

Dataset Information

Nanoscale metal-organic frameworks for the co-delivery of cisplatin and pooled siRNAs to enhance therapeutic efficacy in drug-resistant ovarian cancer cells.

Publications

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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