Research Project: Nanoparticles Made from iPS Cell-Derived Mesenchymal Stem Cells as Standardized Natural Platforms for Targeted Treatment of Drug-Resistant Prostate Cancer
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- Wang, Fen
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Chemotherapy is the first-line treatment for advanced prostate cancer (PCa), but the early onset of resistance to chemotherapy drugs is common. Nanoparticles are promising platforms for treatment of drug-resistant PCa. Currently, most nanoparticles target tumors passively due to the variable leakage of newly formed blood vessels and the lack of effective lymphatic drainage in tumors; hence, their accumulation in tumors is limited. Nanoghosts (NGs) are a novel type of actively tumor-targeting nanoparticles readily reconstructed from the entire cell membrane (ghost cells) of mesenchymal stem cells (MSC), adult stem cells present in multiple tissues such as bone marrow and fat, and appear safe to use in human by hundreds of clinical trials worldwide. MSC-NGs retain targeting capabilities of MSCs to PCa cells, do not trigger immune response, and are cleared from healthy blood-filtering organs rapidly in a mouse model after intraperitoneal infusion. However, the yield of NGs and the efficiency of loading anti-PCa agents into NGs are very low, and a huge amount of MSCs is needed for preparing enough NGs to study such PCa therapy even in mouse. A similar but simpler method was used to produce nanovesicles (NVs) containing cytoplasm components from other cells with much higher yield and showed superior efficacy of delivering anti-cancer agent via intravenous route than mainstream nanoparticles. But conventional tissue-derived MSCs contain many pro-tumor cytoplasmic factors; hence, the efficacy of NVs made from these MSC to deliver anti-tumor agents might be compromised.
For further research of MSC NGs and NVs in large-animal models and future clinical application, a huge amount of standardized MSCs is required. However, conventional tissue-derived MSCs from different donors vary considerably and cannot be expanded extensively, and their tumor-targeting property decreases after prolonged expansion, which severely hinders the research and application of MSC NGs/NVs for cancer therapy.
To circumvent these issues of tissue-derived MSCs, my laboratory derived MSCs from human induced pluripotent stem cells (iPSCs) that are originated from normal adult cells but can give rise to any kind of cells in the body and have almost unlimited expandability. Our derivation protocol can be readily scaled up to produce an enormous amount of standardized MSCs. Our iPSC-MSCs maintained the expression of tumor targeting membrane proteins during prolonged expansion and in different derivation batches, whereas the expression of multiple pro-tumor factors in our iPSC-MSCs is remarkably lower than that in tissue-derived MSCs. NGs and NVs reconstructed from our iPSC-MSCs did not trigger immune response and exhibited selective binding toward PCa cells over non-tumor cells.
This research addresses the Prostate Cancer Research Program overarching challenge: "Develop effective treatments and address mechanisms of resistance for men with high-risk or metastatic prostate cancer." This research will help drug-resistant PCa patients by providing a nature nanoparticle platform with unlimited supply and uniform biological properties for tumor-targeted delivery of various anti-PCa agents. The potential clinical applications of iPSC-MSC NGs/NVs include tumor-targeted delivery of chemotherapy drugs, anti-PCa proteins, and/or cDNAs encoding these proteins. The anti-PCa proteins can be either recombinant soluble proteins or membrane proteins expressed by iPSC-MSCs. The potential benefits of iPSCMSC NGs/NVs mediated PCa therapy is the uniform PCa-targeting capacity, the decreased pro-tumor risk, and the ease of safe and efficient genetic engineering in immortal iPSCs to enhance penetration of NGs/NVs through endothelium and tumor, which will ultimately help overcoming the resistance of advanced PCa to chemotherapy. No significant potential risks of iPSC-MSC NGs/NVs are expected since MSCs showed no significant risk in hundreds of clinical trials worldwide and NGs made from bone marrow MSCs showed no significant risk in mouse models.
The projected time to achieve a patient-related outcome is about 12 years. The first 3 years, with the support of current applied grant, will provide the proof of principle in mouse models. The following 9 years will optimize the payload and genetic membrane engineering of iPSC-MSCs, scale up the production of iPSC-MSCs and NGs/NVs made from them, confirm the anti-PCa efficacy of NG/NV-mediated therapy in clinically relevant large-animal models, and then start a Phase I clinical trial to test the safety of iPSC-MSCs NG/NVs. The likely contributions of this study to advancing the field of prostate cancer research is to provide a standardized natural tumor-targeting platform for delivering various anti-PCa agents including chemotherapy drugs to improve the treatment of drug-resistant metastatic PCa.
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