Targeting Glioblastoma Cells with Drug-Loaded Targeted Nanocarriers

Pizzocri, Marco (2021). Targeting Glioblastoma Cells with Drug-Loaded Targeted Nanocarriers. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0001342b

Abstract

Glioblastoma (GBM) is the most common and aggressive primary human brain tumor associated with very poor prognosis and survival (Stupp and Hegi, 2019). Despite ongoing research, the outlook on GBM remains quite disappointing with a median survival of ~15 months and 5-year survival rate less than 5%. The fact that treatment and prognosis have remained unchanged for fifteen years leads to the realization that there are major challenges that we have not been able to overcome. Challenges are fundamentally represented by (i) the tumor itself, (ii) the anatomic localization, and in particular the presence of the Blood Brain Barrier (BBB), and (iii) the toxicity of current treatments.

Nanotechnology can be instrumental for all of these issues. The ultimate goal of this project is the development of multi-task targeted, drug-loaded Nanovectors (NVs) able to cross the BBB and target GBM, release chemotherapeutics and induce tumor cell death and disease regression.

Liposome (LIPs) incapsulating Doxorubicin (DOXO) and functionalized with a peptide derived from the ApoE lipoprotein (mApoE), mApoE-DOXO-LIPs, demonstrated the ability to cross BBB and target the Glioblastoma Stem-like cells (GSCs) both in vitro and, especially, in vivo reducing the tumor growth in PDX mice cotreated with radiation (2Gy dose). Moreover, the histological analysis demonstrated that 2Gy/mApoE-DOXO-LIPs treatment induced apoptosis in tumor cells preventing side effects on healthy brain parenchyma, reducing the toxicity of the drug. Interestingly, morphological and histological analysis on Iba1+ cells suggested that GSCs apoptosis could induce Immune cell death (ICD) activation with in turn could activate the immune system against GBM.

However, LIPs treatment still induced systemic toxicity in treated mice, probably due to the high accumulation of the NVs in the liver (approximately 40% of injected LIPs), causing a body weight loss of approximately 12%. To reduce the LIPs side effect different polymeric NVs were tested. Poly(lactic-co-glycol acid) (PLGA) and poly(ε-caprolactone) (PCL) NVs functionalized with a MMP2 Activatable Low Molecular Weight Protamine (ALMWP) were chosen to reduce NVs side toxicity. While linear PLGA NVs wasn’t effective due to their fast drug release, star shaped PCL NVs (ALMWP-DOXO-PCLs) were able to induce in vitro GSCs death at a extremely low DOXO concentration (approximately 10 time lower than LIPs) without affecting healthy cells like the endothelial cells.

The work of this thesis demonstrates that drug-loaded targeted nanovectors can function as a delivery strategy to specifically and effectively drive chemotherapeutics into GBM tumor microenvironment and cells and could represent a key technology to treat GBM.

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