L5: Targeting of CNS Tumours Flashcards
What are challenges of treating brain tumours?
BBB Tumour heterogeneity Resistance Invasiveness of brain delivery Lack of efficacy through systemic circulation Limitations of medicines themselves
Why have eukaryotic virus vectors not been so successful for gene delivery?
Uptake by liver Broad tropism for many tissues Uptake by RES Poor tumour penetration Presence of antiviral neutralising antibodies
How can you osmotically open the BBB?
Hypertonic arabinose or mannitol. Widens endothelial tight junctions
2 techniques for local drug delivery?
Convection enhanced delivery- Continuous injection of drug solution via catheter under positive pressure.
Polymeric vesicles- Gliadel now in use.
What are the targets in anti-angiogenic therapies, and their receptors?
Endothelial Cells: VEGF,VEGFR, PDGFR Receptors. avB3 & avB5 integrins.
Perivascular cells (Pericytes)
Tumour cells
Why are anti angiogenic treatments not effective?
- Short half lives, Rapid renal clearance.
- Non-specific accumulation
- Inefficient accumulation at disease site.
- Severe side effects at high doses
- Poor tissue and cellular membrane permeability in vivo, so cell transduction systems needed when the molecular target is intracellular.
- Tumour resistance, due to GBM heterogeneity
List 4 types of viral vectors.
Retroviruses and lentiviruses
Adenoviruses
Adeno associated viruses
Herpes simplex virus
List 2 non-viral vectors.
Liposomes - Carries therapeutic DNA and passes it through target membrane.
Cationic polymers - Polymer DNA complexes
What are bacteriophages, and list some distinctive advantages for cancer cell therapy.
These are viruses that infect only bacteria, and are harmless to humans.
- Safe to use
- Easy and cheap to produce
- No need to ablate any native tropism
- Ligand directed targeting
What delivery technology did Hajitou et al use and was were the findings?
Used an RGD ligand on capsid. Inserted genome of human virus inside phage. (Used AAV to make a hybrid genome).
the virus destroyed the reporter gene in vivo, and there was directed delivery.
- No TNF-a was found in brain, muscle, heart after AAVP targeting.
- AAVP induces apoptosis in tumour vasculature after systemic delivery.
- Targeted TNF-a suppresses tumour growth after delivery.
- IV injected AAVP caused high expression of cytokines in tumours
- Multiple doses of AAVP-TNFa eradicated tumours in dogs.
3 promising features of RGD4C/AAVP that allow it to treat brain tumours?
- RGD binds to avB3 integrin, overexpressed on tumour surfaces. SPECIFICIT
- IV delivery to brain
- BBB crossing ability (M13 Parent)
How can you treat medulloblastoma?
Downregulate mTOR pathway. To silence this, use shRNA- use this with TMZ to make cells sensitive to drug after a few days.
In mice, using vector with RNA got rid of tumours- next step=use with TMZ.
Give an example of one other childhood brain cancer.
DIPG- Diffuse intrinsic pontine glioma. Almost always fatal. In vitro: Cisplatin shown to be effective. What about in vivo?
