Induced pluripotent stem cells (iPSCs) can be derived from differentiated cells from a patient, thus allogeneic cell administration can be avoided. Different therapeutic agents can be delivered with iPSC carriers to gliomas. These agents include therapeutic genes, prodrug conversion, oncolytic viruses, NPs, and antibodies. iPSC-based novel therapy method has become a promising research point.
Both iPSC-derived neural stem cells (NSCs) and mesenchymal stem cells (MSCs) have similar properties as traditional stem cell populations. For example, iPS-derived NSCs possess the same tumor-tropic abilities as endogenous NSCs. This tumor tropism is predictably related to tumor-associated growth factors, such as VEGF, stromal-derived factor-la (SDF-1a), stem cell factor, and platelet-derived growth factor BB. Furthermore, iPS cells-derived MSCs have similar immunosuppressive and anti-inflammatory properties as traditional MSCs. In addition, these stem cell carriers need to be administered systemically, so they must possess the ability to cross the blood-brain barrier (BBB). Additional work on the interaction and influence of the normal and pathological BBB (i.e., the BBB is typically disrupted in brain tumors) on stem cell carriers will help facilitate the development of an intravascular approach.
In addition to engineering stem cells for the delivery of cancer therapy, iPSCs can act as vehicles for therapeutic cargo. Agents such as oncolytic viruses that can selectively replicate in glioma cells and NP drug delivery platforms have repeatedly shown therapeutic promise in preclinical experiments, but consistently the therapeutic benefit of these agents in clinical trials has not lived up to expectations. Using stem cells as a delivery system could improve the distribution of these agents in the tumor, minimize their off-target toxicity, and enhance their benefit.
Fig.1 Tumor-tropic stem cells as carriers of therapeutic cargo. (Young, 2014)
Both iPS-derived NSCs and MSCs have similar properties as traditional stem cell populations. Stem cells like MSCs and NSCs can be infected with oncolytic viruses and act as factories for viral replication while simultaneously allowing for migration to tumor sites and shielding the virus from the immune system. These engineered, conditionally replicating viruses have been modified so they can selectively infect and replicate in tumor cells. Restricting the viral infection and protein transcription so that it is limited to tumor cells are two ways of creating these conditionally replicative viruses. For example, adding a poly-L-lysine modification to adenovirus serotype 5 (Ad5-pk7) allows the virus to interact with surface heparin sulfate proteoglycans found on NSCs and other polyanion motifs present on tumor cells.
NPs are another class of agents that can be delivered via iPSCs to a tumor site. Some early studies coated the surface of the stem cells with NPs loaded with a chemotherapeutic drug. Alternatively, NPs can be loaded inside of the stem cell, although additional work is needed to improve the loading and release of NPs from their stem cell carriers. For such delivery systems to work, the NP platform cannot induce premature toxicity to the carrier cell or impair migration. One mechanism for ensuring delayed-drug release in these carriers is to conjugate agents to the NPs surface via a pH-sensitive linker. As these pH-sensitive NPs are taken up into cells via the endosomal lysosomal trafficking pathway, drug release occurs when these vesicles have a low pH of 4.5-6. The NSCs were able to survive and migrate for about 48 h before the low pH of these intracellular vesicles caused the release of the therapeutic payload, allowing sufficient time for NSCs to migrate to cancer cells both in vitro and in vivo.
As antibodies emerge as important tools for cancer therapy, they are currently limited by their poor penetration into solid tumors and nonspecific toxicity. Stem cells can be used as antibody-producing factories and deliver these antibodies specifically to a tumor site. Both whole antibodies and single-chain antibodies (scFv) have been shown to have therapeutic effects after delivery by stem cells. Researchers have demonstrated that anti-HER2 antibody could be encoded in NSCs, the stem cells would secrete properly assembled antibodies and these secreted antibodies would bind to breast cancer cells. This antibody binding inhibited the proliferation of HER2 overexpressing breast cancer cells in vitro. Importantly, after intravenous administration of these loaded NSCs, the anti-HER2 antibody was measured in the tumor foci, but it was not detectable in the blood, which suggests that stem cells can localize the delivery of therapeutic antibodies to the tumor site. Additionally, MSCs have been engineered to express a surface-bound scFv targeting the glioma-associated EGFR variant III (EGFRvIII). Not only did these EGFRvIII-scFv-expressing MSCs extend survival in mice bearing xenograft human gliomas, but these stem cells also displayed better tumor binding and retention, which suggests this method might also be able to enhance stem cell accumulation at the tumor site.
Although there are still several challenges facing the clinical application of stem cells and iPSC cells as drug delivery vehicles for cancer therapy, such as quantifying how many of the administered cells reach the tumor site(s), their properties make them ideal candidates for therapeutic gene, drug and viral delivery to tumors. Focusing on the stem cell therapy development for years, Creative Biolabs has established a comprehensive platform offering high-quality iPSC reprogramming, differentiation, characterization services to our customers all over the world. Please feel free to contact us for detailed information.
Reference
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