Cell surface engineered neural stem cells for endogenous radiotherapy of glioblastoma

• Applicants: Dr. Agnieszka Morgenroth; Dr. Antje Willuweit
• Subject Area: Pharmacy ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 578955788

Cell surface engineering (CSE) implementing drug conjugation to the cell membrane presents a cellular manipulation strategy for multiple purposes, including targeted drug delivery. An application of neural stem cells (NSC) as drug carriers presents a smart strategy exploiting their natural migration potential towards malignant brain sites. For this, NSCs have to be loaded with the drug to be transported and released specifically at the tumor site. Following the concept of CSE, we designed nanoparticles (NPs) conjugated with nucleoside analogue 5-Ethynyl-2'-deoxycytidine (5-EdC) for grafting of NSC via covalent binding of cell surface exposed thiols. Preliminary studies indicated high loading capacity, stable membrane retention and no impact on the natural tumor tracing potential of NSC. Moreover, the implemented redox-responsive drug release led to specific degradation of NPs and preferential drug uptake in glioblastoma cells. Our goal is to explore NSC as drug delivery system overcoming the challenging blood brain barrier for endogenous radiotherapy of glioblastoma. We see in the combination of natural tumor tracing vehicles with nanomaterials a great potential to overcome the limitations faced in the currently available therapies of primary or metastatic brain tumors. Generally, nanoparticles have been shown to significantly increase the drug concentration around the brain tumor. However, they encounter different resistive forces within the tumor compared to small-molecule cytotoxic agents. The lack of sufficient functional lymphatic drainage in brain tumors results in elevated interstitial fluid pressure, which induces an outward convective force that directs incoming nanoparticles toward the tumor periphery and away from the tumor core. This results in localized accumulation in only a fraction of the peripheral tumor volume and limited therapeutic efficacy. Moreover, the therapeutic outcome is highly dependent on the drug amount delivered which in most cases reaches only a sublethal drug concentration leading to development of drug resistance mechanisms in tumor cells. Here, we will take advantage of the fact that NPs as carriers for highly cytotoxic Auger electron emitting nucleoside analogue do not require a high drug load. The emphases of this project are placed on: 1. Synthesis of nanoparticles (NPs) for neural stem cell surface decoration (via cell membrane exposed thiols) and as polymeric carrier for [125/131I]-labelled EdC analogue linked via stimuli sensitive linker (stable drug retention during transport/limited tracer deiodination/tumor site specific drug release). 2. Evaluation of the therapeutic potential of [125I]IEdC-NP-decorated NSC in vivo (improved endoradiotherapy of glioblastoma).

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Sanjay Mathur