Blood Brain Barrier; Nanocarriers; Microbubbles; Glioblastoma; Liposomes; siRNA; Transfection; Calcium phosphate nanoparticles; MGMT; Focused Ultrasound; O6-Benzylguanine; Temozolomide; Drug Delivery
Papachristodoulou Alexandros, Signorell Rea Deborah, Werner Beat, Brambilla Davide, Luciani Paola, Cavusoglu Mustafa, Grandjean Joanes, Silginer Manuela, Rudin Markus, Martin Ernst, Weller Michael, Roth Patrick, Leroux Jean-Christophe (2019), Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes, in Journal of Controlled Release
, 295, 130-139.
Cavusoglu Mustafa, Zhang Jia, Ielacqua Giovanna Diletta, Pellegrini Giovanni, Signorell Rea Deborah, Papachristodoulou Alexandros, Brambilla Davide, Roth Patrick, Weller Michael, Rudin Markus, Martin Ernst, Leroux Jean Christophe, Werner Beat (2018), Closed-loop cavitation control for focused ultrasound-mediated blood-brain-barrier opening by long-circulating microbubbles, in Physics in Medicine and Biology
Signorell Rea, Luciani Paola, Brambilla Davide, Leroux Jean-Christophe (2018), Pharmacokinetics of Lipid-Drug Conjugates Loaded into Liposomes, in European Journal of Pharmaceutics and Biopharmaceutics
, 128, 188-199.
Signorell Rea D, Papachristodoulou Alexandros, Xiao Jiawen, Arpagaus Bianca, Casalini Tommaso, Grandjean Joanes, Thamm Jana, Steiniger Frank, Luciani Paola, Brambilla Davide, Werner Beat, Martin Ernst, Weller Michael, Roth Patrick, Leroux Jean-Christophe (2017), Preparation of PEGylated liposomes incorporating lipophilic lomeguatrib derivatives for the sensitization of chemo-resistant gliomas., in International journal of pharmaceutics
, (1), 388-396.
Glioblastoma is the most malignant primary brain tumor. The current standard of care includes surgery followed by radiotherapy plus temozolomide chemotherapy. However, the benefit from chemotherapy is largely limited to a subgroup of patients (30-35%) with tumors exhibiting methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene. MGMT is a DNA repair protein that reverses lethal methylation damage induced by temozolomide and thus abrogates the therapeutic effects of alkylating agent chemotherapy. The aim of this research project is to develop a new approach to overcome MGMT-mediated resistance which severely limits the efficacy of temozolomide in the majority of glioblastoma patients.Sensitization to temozolomide shall be achieved by developing nanocarriers for O6-benzylguanine (and its main active metabolite), a pseudosubstrate MGMT-depleting agent, or siRNA targeting MGMT. Encapsulating the MGMT-depleting agents into nanocarriers serves the purpose to reduce their hematological toxicity while circulating systemically and to use ultrasound to target them towards tumor tissues where they shall deploy their payload in the local microenvironment.Since the blood brain barrier limits the passage of most neuropharmaceuticals from the circulation into the brain parenchyma, microbubble-enhanced low intensity focused ultrasound will be used to locally and reversibly modulate the permeability of the blood brain barrier to facilitate the passage of the nanocarriers. Intrainterventional Magnetic Resonance Imaging guidance will allow to deliver the nanocarriers preferentially to tumor-bearing brain regions, using infiltrative rodent glioma models.This interdisciplinary project aligns research efforts from basic science (drug nanocarrier formulation), translational science (non-invasive focused ultrasound interventions) and clinical science (tumor treatment) and builds on the highly specialized scientific expertise of the three participating research groups of the University of Zurich and ETH Zurich, to propose a novel treatment approach for one of the most devastating cancers. Since all key components of this research proposal are already actively investigated by the respective partners and preliminary feasibility data have been collected, the principal investigators are optimistic to reach the goals stated in this proposal and to be able to demonstrate proof of principle in relevant preclinical models of temozolomide-resistant glioblastoma. Although MGMT seems to be today the most relevant mediator of resistance to target, our initiative will set the stage for similar approaches to silence the biological activity of further target genes thought to promote cancer progression and resistance to therapy and will established a platform for targeted therapeutic interventions in the brain.