Pre-clinical Development of Nanoparticles and Nanogels for Drug and Gene Delivery to Glioblastoma

Despite extensive surgical resection and adjuvant therapy, the median survival of Glioblastoma multiforme (GBM) patients is only about 12-18 months. Also, many patients are not recommended for surgery due to an inoperable location of the tumor or poor physical performance of the patient. Therefore, on the one hand, it is necessary and promising to study and screen more drugs for adjuvant treatment of GBM. On the other hand, the problem of therapeutic agents, e.g., short circulating half-life, difficulty in accumulating in tumor area, controlling drug release, and overcoming the barriers of GBM need to be solved. In Chapter 2 of this thesis, curcumin-loaded zein nanoparticles that were functionalized with the ganglioside GM1-binding G23 peptide efficiently traversed an in vitro BBB model, stimulated 3D tumor spheroid penetration, inhibited glioblastoma cell growth and exhibited the ability to circulate in the blood. Whether curcumin-loaded nanoparticles (CUR-NPs) can sensitize human glioblastoma U87 cells and GBM patient-derived neurospheres to the chemotherapeutic temozolomide TMZ treatment, administered either as free TMZ or as TMZ-cyclodextrin (TMZ@CD) inclusion complexes was investigated in Chapter 3. CUR-NPs enhanced the inhibitory effects of TMZ and TMZ@CD on the proliferation of U87 cells, GG16 and GSC23 neurospheres. In Chapter 4, we evaluated the ability of the tertiary amine-, quaternized ammonium-, and aliphatic quaternized ammonium-functionalized p(NIPAM) nanogels (i.e., NGs, NGs-MI, and NGs-BDD, respectively) to mediate gene transfection. NGs-BDD/pDNA complexes show a notable gene transfer efficiency, which can be ascribed to their ability to facilitate endosomal escape by perturbing the endosomal/lysosomal membrane