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Targeting Liver Cancer Stem Cells Using Engineered Biological Nanoparticles for the Treatment of Hepatocellular Cancer.

ABSTRACT: By exploiting their biological functions, the use of biological nanoparticles such as extracellular vesicles can provide an efficient and effective approach for hepatic delivery of RNA-based therapeutics for the treatment of liver cancers such as hepatocellular cancer (HCC). Targeting liver cancer stem cells (LCSC) within HCC provide an untapped opportunity to improve outcomes by enhancing therapeutic responses. Cells with tumor-initiating capabilities such as LCSC can be identified by expression of markers such as epithelial cell adhesion molecule (EpCAM) on their cell surface. EpCAM is a target of Wnt/?-catenin signaling, a fundamental pathway in stem-cell growth. Moreover, mutations in the ?-catenin gene are frequently observed in HCC and can be associated with constitutive activation of the Wnt/?-catenin pathway. However, targeting these pathways for the treatment of HCC has been challenging. Using RNA nanotechnology, we developed engineered biological nanoparticles capable of specific and effective delivery of RNA therapeutics targeting ?-catenin to LCSC. Extracellular vesicles isolated from milk were loaded with small interfering RNA to ?-catenin and decorated with RNA scaffolds to incorporate RNA aptamers capable of binding to EpCAM. Cellular uptake of these EpCAM-targeting therapeutic milk-derived nanovesicles in vitro resulted in loss of ?-catenin expression and decreased proliferation. The uptake and therapeutic efficacy of these engineered biological nanotherapeutics was demonstrated in vivo using tumor xenograft mouse models. Conclusion: ?-catenin can be targeted directly to control the proliferation of hepatic cancer stem cells using small interfering RNA delivered using target-specific biological nanoparticles. Application of this RNA nanotechnology-based approach to engineer biological nanotherapeutics provides a platform for developing cell-surface molecule-directed targeted therapeutics.

SUBMITTER: Ishiguro K

PROVIDER: S-EPMC6996342 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Targeting Liver Cancer Stem Cells Using Engineered Biological Nanoparticles for the Treatment of Hepatocellular Cancer.

Ishiguro Kaori K Yan Irene K IK Lewis-Tuffin Laura L Patel Tushar T

Hepatology communications 20200103 2

By exploiting their biological functions, the use of biological nanoparticles such as extracellular vesicles can provide an efficient and effective approach for hepatic delivery of RNA-based therapeutics for the treatment of liver cancers such as hepatocellular cancer (HCC). Targeting liver cancer stem cells (LCSC) within HCC provide an untapped opportunity to improve outcomes by enhancing therapeutic responses. Cells with tumor-initiating capabilities such as LCSC can be identified by expressio ...[more]

PMID: 32025612

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Project description:BackgroundBone metastases are common and devastating to cancer patients. Existing treatments do not specifically target the disease sites and are therefore ineffective and systemically toxic. Here we present a new strategy to treat bone metastasis by targeting both the cancer cells ("the seed"), and their surrounding niche ("the soil"), using stem cells engineered to home to the bone metastatic niche and to maximise local delivery of multiple therapeutic factors.MethodsWe used mesenchymal stem cells engineered using mRNA to simultaneously express P-selectin glycoprotein ligand-1 (PSGL-1)/Sialyl-Lewis X (SLEX) (homing factors), and modified versions of cytosine deaminase (CD) and osteoprotegerin (OPG) (therapeutic factors) to target and treat breast cancer bone metastases in two mouse models, a xenograft intratibial model and a syngeneic model of spontaneous bone metastasis.FindingsWe first confirmed that MSC engineered using mRNA produced functional proteins (PSGL-1/SLEX, CD and OPG) using various in vitro assays. We then demonstrated that mRNA-engineered MSC exhibit enhanced homing to the bone metastatic niche likely through interactions between PSGL-1/SLEX and P-selectin expressed on tumour vasculature. In both the xenograft intratibial model and syngeneic model of spontaneous bone metastasis, engineered MSC can effectively kill tumour cells and preserve bone integrity. The engineered MSC also exhibited minimal toxicity in vivo, compared to its non-targeted chemotherapy counterpart (5-fluorouracil).InterpretationOur combinatorial targeting of both the cancer cells and the niche represents a simple, safe and effective way to treat metastatic bone diseases, otherwise difficult to manage with existing strategies. It can also be applied to other cell types (e.g., T cells) and cargos (e.g., genome editing components) to treat a broad range of cancer and other complex diseases. FUND: National Institutes of Health, National Cancer Institute of the National Institutes of Health, Department of Defense, California Institute of Regenerative Medicine, National Science Foundation, Baylx Inc., and Fondation ARC pour la recherche sur le cancer.

Dataset Information

Targeting Liver Cancer Stem Cells Using Engineered Biological Nanoparticles for the Treatment of Hepatocellular Cancer.

Publications

Targeting Liver Cancer Stem Cells Using Engineered Biological Nanoparticles for the Treatment of Hepatocellular Cancer.

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