Glioblastoma, a grade 4 glioma, is the most common primary malignant brain tumor in adults. It represents a significant unmet clinical need with a median survival of 14-16 months. The standard of care has remained largely unchanged since 2005 (Stupp Protocol), consisting in surgical resection followed by radiation and systemic chemotherapy with Temozolomide combined with corticosteroids. Resistance to current practices is due to several factors, including the blood brain barrier (BBB) that hinder drug passage and delivery after systemic administration, high patient to patient GBM intra and inter heterogenicity and tumor capacity to develop drug resistance. This study proposes the development of brain-penetrating polymeric drug delivery system that will drive the conjugated immunogenic cell death inducer anticancer drug Paclitaxel (PTX), an antimitotic drug, after intracranic administration. By employing nanocarriers composed of crosslinked Hyaluronic Acid (HA) and Poly-L-Lysine (PL) forming HAPL nanoparticles, this drug delivery system aims to improve PTX infiltration into the GBM. HA, due to its similarity with native extracellular matrix (ECM), offers safety and biodegradability, while its low molecular weight variant exhibits potential for immune modulation trough interaction with GBM and immune cells. PL, due to its positive charges, facilitates internalization within the brain’s complex architecture. HAPL nanoparticles are assembled using a pump-based nanoassembler system, through the interaction between the opposite charges of HA and PL. Additionally, the two polymers are conjugated with biorthogonal linkers, ensuring the stability of the nanoparticles in a physiological environment. The nanoparticles were fully chemically-physically analysed using 1H-NMR, Dynamic Light Scattering (DLS, to investigate their size and their zeta potential), Transmission Electron Microscopy (TEM), FT-IR among other to obtain a comprehensive characterization. Next, PTX has been conjugated to the nanoparticles and the novel nanomedicine has been tested in a preliminary study in vitro on murine GBM GL261 cell line.
Glioblastoma, a grade 4 glioma, is the most common primary malignant brain tumor in adults. It represents a significant unmet clinical need with a median survival of 14-16 months. The standard of care has remained largely unchanged since 2005 (Stupp Protocol), consisting in surgical resection followed by radiation and systemic chemotherapy with Temozolomide combined with corticosteroids. Resistance to current practices is due to several factors, including the blood brain barrier (BBB) that hinder drug passage and delivery after systemic administration, high patient to patient GBM intra and inter heterogenicity and tumor capacity to develop drug resistance. This study proposes the development of brain-penetrating polymeric drug delivery system that will drive the conjugated immunogenic cell death inducer anticancer drug Paclitaxel (PTX), an antimitotic drug, after intracranic administration. By employing nanocarriers composed of crosslinked Hyaluronic Acid (HA) and Poly-L-Lysine (PL) forming HAPL nanoparticles, this drug delivery system aims to improve PTX infiltration into the GBM. HA, due to its similarity with native extracellular matrix (ECM), offers safety and biodegradability, while its low molecular weight variant exhibits potential for immune modulation trough interaction with GBM and immune cells. PL, due to its positive charges, facilitates internalization within the brain’s complex architecture. HAPL nanoparticles are assembled using a pump-based nanoassembler system, through the interaction between the opposite charges of HA and PL. Additionally, the two polymers are conjugated with biorthogonal linkers, ensuring the stability of the nanoparticles in a physiological environment. The nanoparticles were fully chemically-physically analysed using 1H-NMR, Dynamic Light Scattering (DLS, to investigate their size and their zeta potential), Transmission Electron Microscopy (TEM), FT-IR among other to obtain a comprehensive characterization. Next, PTX has been conjugated to the nanoparticles and the novel nanomedicine has been tested in a preliminary study in vitro on murine GBM GL261 cell line.
Design of polymer-based nanoparticles for the local treatment of glioblastoma
BOLZAN, ANNA
2023/2024
Abstract
Glioblastoma, a grade 4 glioma, is the most common primary malignant brain tumor in adults. It represents a significant unmet clinical need with a median survival of 14-16 months. The standard of care has remained largely unchanged since 2005 (Stupp Protocol), consisting in surgical resection followed by radiation and systemic chemotherapy with Temozolomide combined with corticosteroids. Resistance to current practices is due to several factors, including the blood brain barrier (BBB) that hinder drug passage and delivery after systemic administration, high patient to patient GBM intra and inter heterogenicity and tumor capacity to develop drug resistance. This study proposes the development of brain-penetrating polymeric drug delivery system that will drive the conjugated immunogenic cell death inducer anticancer drug Paclitaxel (PTX), an antimitotic drug, after intracranic administration. By employing nanocarriers composed of crosslinked Hyaluronic Acid (HA) and Poly-L-Lysine (PL) forming HAPL nanoparticles, this drug delivery system aims to improve PTX infiltration into the GBM. HA, due to its similarity with native extracellular matrix (ECM), offers safety and biodegradability, while its low molecular weight variant exhibits potential for immune modulation trough interaction with GBM and immune cells. PL, due to its positive charges, facilitates internalization within the brain’s complex architecture. HAPL nanoparticles are assembled using a pump-based nanoassembler system, through the interaction between the opposite charges of HA and PL. Additionally, the two polymers are conjugated with biorthogonal linkers, ensuring the stability of the nanoparticles in a physiological environment. The nanoparticles were fully chemically-physically analysed using 1H-NMR, Dynamic Light Scattering (DLS, to investigate their size and their zeta potential), Transmission Electron Microscopy (TEM), FT-IR among other to obtain a comprehensive characterization. Next, PTX has been conjugated to the nanoparticles and the novel nanomedicine has been tested in a preliminary study in vitro on murine GBM GL261 cell line.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/80616