Targeted delivery across blood brain barrier for the treatment of Glioblastoma

Project description

Background
Glioblastoma (GBM) is the most common and aggressive brain tumor, with less than 5% of patients surviving beyond five years. Therapeutic progress has been limited due to physiological barriers, such as the blood-brain barrier (BBB) and blood-tumor barrier (BTB), which impede effective drug delivery. Oncogenic microRNAs, including miR-21 and miR-210, regulate GBM progression, promoting cell proliferation, migration, and therapy resistance. Targeting these miRNAs with antisense oligonucleotides (anti-miRs) offers therapeutic potential but requires an efficient delivery system which is the holy grail in GBM therapy.
Aims
This project has the following objectives:
1. Develop an RNA-based therapeutic platform using ultra-small large pore silica nanoparticles (USLPs) to deliver anti-miRs, targeting miR-21 and miR-210
2. Evaluate the biodistribution of the USLP delivery system, assessing its ability to cross the BBB and reach the tumor in an in vivo spontaneous glioblastoma model.
3. Assess the therapeutic efficacy of the USLP loaded with microRNA system using patient-derived xenografts (PDX) in an in vivo GBM model.
Methodology
-Nanoparticle Development and Characterization: Novel ultrasmall silica (USLPs ~40 nm) will be synthesized and surface-modified with polyethyleneimine (PEI) at an optimized ratio (1:0.025 w/w). Their size, surface charge, and stability will be assessed.
-In Vitro Studies: Anti-miR-21 and anti-miR-210 will be loaded onto USLPs, evaluating sustained release, cellular uptake, miRNA inhibition, and tumor penetration in 2D GBM cell models and 3D spheroids.
-In Vivo Validation: The therapeutic potential of the USLP-PEI complex, loaded with anti-miRs, will be tested in an orthotopic GBM mouse model.
-Biodistribution and Efficacy: The biodistribution and efficacy of USLP delivery will be evaluated in spontaneous GBM and PDX models, respectively.
Significance: This project aims to develop an innovative RNA-based platform to overcome drug delivery challenges in GBM, offering potential for improved patient outcomes by extending survival and enhancing quality of life. By demonstrating efficacy, biodistribution, and safety in preclinical models, this work may lead to more effective and safer GBM therapies.

Outcomes

Our research pioneers two groundbreaking strategies aimed at inducing robust anti-tumor responses, marking a significant departure from current brain tumor therapies. Resistance to conventional treatments, such as temozolomide (TMZ), is common and often develops as early as seven months, limiting their long-term effectiveness. In contrast, our approaches are specifically designed to address these challenges, offering promising options for patients who fail to respond to existing drugs. These innovative strategies are not only effective on their own but are also complementary to leading pipeline therapies, paving the way for combination regimens that leverage synergistic effects, enhancing therapeutic outcomes.
Complementary to Existing Therapies: Our strategies are developed to work synergistically with the leading immunotherapies in the pipeline. By combining these novel approaches with existing treatments, we aim to create a multi-faceted therapeutic regimen that maximizes treatment effectiveness and targets GBM from multiple angles.
Enhanced Safety and Quality of Life: A critical advantage of our approaches is their potential to offer a superior safety profile compared to current treatments. By minimizing adverse effects and improving patient tolerability, these strategies aim to reduce the burden of therapy, ultimately preserving and enhancing patients’ quality of life while providing effective treatment.
Transforming Brain Tumor Treatment: This research has the potential to redefine the treatment paradigm for brain tumors, offering new hope for patients through therapies that are not only more effective but also safer and adaptable. These approaches are designed to benefit patients who are resistant to conventional treatments, ushering in a new era of brain tumor care.
Ultimately, the goal of this project is to lay the groundwork for clinically translatable therapies that improve survival and quality of life for GBM patients. The insights gained will also contribute to overcoming delivery challenges for RNA-based therapies targeting central nervous system diseases, broadening their application and potential benefits.
This project is part of a larger initiative funded by Cure Cancer Australia, Cancer Council Queensland, and the Brain Foundation Australia. It is well-supported by experts in nanomedicine (Prof. Popat, Dr. Janjua) and RNA therapeutics (Prof. Kulshreshtha), ensuring that the research is guided by leaders in the field. Ultimately, the goal of this project is to lay the groundwork for clinically translatable therapies that improve survival and quality of life for GBM patients. The insights gained will also contribute to overcoming delivery challenges for RNA-based therapies targeting central nervous system diseases, broadening their application and potential benefits.

Essential capabilities

Expertise in drug delivery systems including nanomedicine, understanding of tumour biology

Desireable capabilities

Glioblastoma or brain cancer expertise, Mouse handling, Cell Culture handling

Expected qualifications (Course/Degrees etc.)

Pharmacy, Biotechnology, Biology, Nanomedicine, Chemistry, Biomedical Engineering