Advanced Nanosystems for Multidirectional Inhibition of Glioblastoma Growth and Recurrence

Wentao Wang

Research output: Book/ReportPh.D. thesis

Abstract

Glioblastoma (GBM) is one of the most common malignant primary tumors in the central nervous system (CNS), characterized by high incidence, extremely easy metastasis and recurrence, and high mortality rate. Currently, the main treatment method for GBM is surgery, assisting with radiotherapy and chemotherapy. However, the prognosis of patients with GBM is still poor and the recurrence rate is high. Abundant evidence has demonstrated the existence of GBM stem cells (GSCs) could be the root cause of tumor formation, growth, metastasis, and recurrence since they have excellent self-renewal ability, rapid proliferation rate, and resistance to radiotherapy and chemotherapy. In addition, the existence of the blood-brain barrier (BBB) blocks most small molecules and almost all macromolecules, resulting in the low delivery efficiency of chemotherapy drugs. Meanwhile, the lack of targeting property of free drugs induces low efficiency of GBM cell and GSC elimination. In recent decades, the development of biocompatible nano-delivery systems has brought new ideas for the treatment of GBM. In this work, in order to improve GBM prognosis, we developed two novel nano-delivery systems to efficiently cross BBB and combat GSCs:
(1) In the first nanoplatform, we constructed multifunctional magnetic therapeutic nanoparticles (MTNPs), which are coated with [Des-arg9]bradykinin (BK) to transiently open the BBB (BK@MTNPs). This NP contains the magnetite (Fe3O4) NPs, cysteine, crizotinib (CZT), and anti-PDL1 antibody (aPDL1). BK@MTNPs were demonstrated to induce DNA damage, activate the transcription of tumor suppressor gene-PTEN, inhibit GSC function, promote intratumoral infiltration of cytotoxic T lymphocytes (CTLs), and increase M1 type macrophages. Based on the in vivo and in vitro results, we identified that BK@MTNPs have a synergistic tumoricidal effect in modulating the tumor microenvironment (TME), boosting immune response, and inhibiting GBM recurrence.
(2) In the second work, we proposed a nanoplatform that is coated with an engineered T cell membrane to target GBM and kill GSCs by local photothermal therapy (PTT). The human primary T cells were genetically engineered to express chimeric antigen receptor (CAR) on the surface— against CD133 and epidermal growth factor receptor (EGFR), which contribute to targeting both GSCs and GBM cells. Then the engineering T cell membrane (CM) was extracted and coated onto aggregation-induced emission (AIE) nanoparticles (CM@AIE NPs). The T-cell-mimic CM shell endows CM@AIE NPs to cross the BBB naturally by triggering an intracellular signaling cascade to modulate the opening of tight junctions (TJs). The dual-target molecules provide CM@AIE NPs with excellent in vivo accumulation in the tumor region that allows the generated photothermal effect to completely inhibit the tumorigenesis and recurrence under 980 nm laser irradiation.
Original languageEnglish
PublisherDTU Health Technology
Number of pages110
Publication statusPublished - 2022

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