ABSTRACT
Nanoghosts (NGs) are nanovesicles reconstructed from the cytoplasmic membranes of mesenchymal stem cells (MSCs). By retaining MSC membranes, the NGs retain the ability of these cells to home in on multiple tumors, laying the foundations, thereby, for the development of a targeted drug delivery platform. The susceptibility of MSCs to functional changes, following their exposure to cytokines or cancer-derived conditioned-media (CM), presents the opportunity to modify the NGs by conditioning their source cells. This opportunity is investigated by comparing the membrane protein composition and the tumor uptake of NGs derived from naïve MSCs (N-NG) against conditioned NGs made from MSCs pre-treated with conditioned-media (CM-NG) or with a mix of the proinflammatory cytokines TNF-α and IL-1ß (Cyto-NG). CM-NGs are found to be more targeted towards immune cells than Cyto- or N-NGs, while Cyto-NGs are the most tumor-targeted ones, with similar immune-targeting capacity as N-NGs but with a higher affinity towards endothelial cells. Proteomic variations were wider in the CM-NGs, with exceptionally higher levels of ICAM-1 compared to N- and Cyto-NGs. From a translational point of view, the data show that the tumor-targeting ability of the NGs, and possibly that of other MSC-derived extracellular vesicles, can be enhanced by simple conditioning of their source cells.
Subject(s)
Cell Membrane/metabolism , Culture Media, Conditioned/pharmacology , Cytokines/pharmacology , Mesenchymal Stem Cells/drug effects , Animals , Cell Line , Cell Membrane/chemistry , Humans , Integrins/metabolism , Intercellular Adhesion Molecule-1/metabolism , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Mice , Mice, Nude , Nanostructures/chemistry , Neoplasms/immunology , Neoplasms/metabolism , Neoplasms/pathology , Proteome/metabolismABSTRACT
Nanoghosts derived from mesenchymal stem cells and retaining their unique surface-associated tumor-targeting capabilities were redesigned as a selective and safe universal nonviral gene-therapy platform. pDNA-loaded nanoghosts efficiently targeted and transfected diverse cancer cells, in vitro and in vivo, in subcutaneous and metastatic orthotopic tumor models, leading to no adverse effects. Nanoghosts loaded with pDNA encoding for a cancer-toxic gene inhibited the growth of metastatic orthotopic lung cancer and subcutaneous prostate cancer models and dramatically prolonged the animals' survival.
Subject(s)
DNA/administration & dosage , Gene Transfer Techniques , Genetic Therapy , Lung Neoplasms/therapy , Mesenchymal Stem Cells , Nanostructures , Prostatic Neoplasms/therapy , Animals , Cell Line, Tumor , DNA/genetics , DNA/therapeutic use , Humans , Lung/metabolism , Lung/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Mesenchymal Stem Cells/cytology , Mice, Inbred C57BL , Nanostructures/administration & dosage , Nanostructures/adverse effects , Nanostructures/ultrastructure , Neoplasm Metastasis/genetics , Neoplasm Metastasis/pathology , Neoplasm Metastasis/therapy , Plasmids/administration & dosage , Plasmids/genetics , Plasmids/therapeutic use , Prostate/metabolism , Prostate/pathology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathologyABSTRACT
Acquired resistance to therapy is a major obstacle in clinical oncology, and little is known about the contributing mechanisms of the host response to therapy. Here, we show that the proinflammatory cytokine IL1ß is overexpressed in response to paclitaxel chemotherapy in macrophages, subsequently promoting the invasive properties of malignant cells. In accordance, blocking IL1ß, or its receptor, using either genetic or pharmacologic approach, results in slight retardation of primary tumor growth; however, it accelerates metastasis spread. Tumors from mice treated with combined therapy of paclitaxel and the IL1 receptor antagonist anakinra exhibit increased number of M2 macrophages and vessel leakiness when compared with paclitaxel monotherapy-treated mice, indicating a prometastatic role of M2 macrophages in the IL1ß-deprived microenvironment. Taken together, these findings demonstrate the dual effects of blocking the IL1 pathway on tumor growth. Accordingly, treatments using "add-on" drugs to conventional therapy should be investigated in appropriate tumor models consisting of primary tumors and their metastases.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Interleukin-1beta/genetics , Neoplasms, Experimental/drug therapy , Signal Transduction/drug effects , Animals , Cell Line, Tumor , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Gene Expression Regulation, Neoplastic/drug effects , Humans , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Interleukin-1beta/blood , Interleukin-1beta/metabolism , Macrophages/drug effects , Macrophages/metabolism , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Neoplasm Metastasis , Neoplasms, Experimental/blood supply , Neoplasms, Experimental/genetics , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/prevention & control , Paclitaxel/administration & dosage , Receptors, Interleukin-1/antagonists & inhibitors , Receptors, Interleukin-1/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Burden/drug effectsABSTRACT
The ultimate goal in cancer therapy is achieving selective targeting of cancer cells. We report a novel delivery platform, based on nanoghosts (NGs) produced from the membranes of mesenchymal stem cells (MSCs). Encompassing MSC surface molecules, the MSC-NGs retained MSC-specific in vitro and in vivo tumor targeting capabilities and were cleared from blood-filtering organs. MSC-NGs were found to be biocompatible. Systemic administration of drug loaded MSC-NGs demonstrated 80% inhibition of human prostate cancer.
