Cancer Drug Delivery Flashcards
What are the challenges in treating solid tumours?
- Extracellular matrix (>50% of total tissues). Having to go through matrix for drug to get through that needs to overcome this.
- Increased interstitial pressure inside the tumour (doesn’t allow drug to go in) which reduces the convection and allows slow diffusion (does not allow drug to go in due to the pressure inside being higher than the pressure outside)
a. Convection is the concerted, collective movement of ensembles of molecules within fluids - Unequal blood distribution (no blood vessels in some areas) Tumour tissue – there is not the same number of blood vessels going around. Some areas don’t have blood vessels, so therefore it’s difficult to allow the drug to combat the tumour. Tumour protects itself.
- Increased blood viscosity and twisting reduce the tumour perfusion (not the same as a normal blood vessel).
Describe the pressure differences within the solid tumour?
¥ Pressure in the interstitial tissue of solid tumours is uniformly elevated, except in the outermost rim, where it drops precipitously.
¥ The elevated pressure in the inner zone can impede movement of large drug molecules into the matrix from the bloodstream—for a simple reason.
¥ Large molecules travel mainly by convection, flowing in fluid from a high-to a low-pressure region. In the outer zone of a tumour, the vascular pressure is higher than it is in the interstitium, and so blood fluid (grey) laden with drug molecules (blue) seeps (arrows) into the interstitium.
How does the mechanism within the tumours help DDS?
- Increased permeability of tumour blood vessels helps the localisation of DDS in solid tumours than in normal tissue
- Lack of tight junctions between adjacent vasculature endothelial cells, which increases their permeability to macromolecules
- The size of the gaps btw the cells lining the tumour blood vessels has been estimated to be 100-600 nm.
So therefore need to design a drug delivery system to get through the gap. - Poor lymphatic drainage helps the retention of DDS in the tumour. They are not drained the same way as normal tissues. EPR (Enhanced permeability retention effect). Whatever goes inside stays inside for a while = THIS IS GOOD.
What are the Characteristics of tumours and their vasculature?
- Low pH
- design drug delivery system to get broken down at that low PH. Want the DDS to reach the tissue and get inside the tumour and then once inside it needs to be released.
- EPR effect
- Extensive angiogenesis and high vascular density: targeting tumour vasculature (anti-angiogenic therapy) is an approach in cancer therapy. If we cut the blood supply to the tumour, or reduce blood vessels around it meaning less nutrients oxygen to tumour so therefore it dies.
1. Vascular mediators i.e. VEGF – growth factors by targeting this. The tumour won’t have any more blood vessels
2. MAb’s against the endothelium/TNF
3. Integrins (adhesion molecules) - Defective vascular architecture i.e. lack of smooth muscle layer, reduced receptors for angiotensin II, large gap in endothelial cell-cell junction and twisting.
- Impaired lymphatic clearance
What is EPR effect?
The enhanced permeability and retention (EPR) effect – molecules of certain sizes (typically liposomes, nanoparticles, and macromolecules) tend to accumulate in tumour tissue more than they do in normal tissue.
What are drug delivery candidates required to achieve EPR effect?
- Apparent MW larger than 50kDa
- Long circulation time: it takes at least 6h to obtain EPR effect so drug has to have large MW above renal clearance threshold to circulate for long time. Most small MW drugs have t1/2of around 20min
- Charge; cationic carriers have short t1/2 and are adsorbed on the negatively charged vascular surface. Helps to be recognized quickly.
• Examples include: nanoparticles, polymeric micelles, lipid nanoparticles, micro emulsions and macromolecular drugs.
What are the
Objectives of Active Targeting?
1) Specifically recognize cells through the interactions of active biomolecules - monoclonal antibodies
2) Enhance drug endocytosis by the cell;
3) Avoid non-specific deposition of biomolecules conjugated nanoparticles on the surface of healthy, non-targeted cells;
4) Increase the concentration of drug product in the tumour environment before it is diluted through the normal circulation or/and excreted via renal clearance;
5) EPR effect
What are the types of targetting ligand?
Macromolecules: Monoclonal antibodies, aptamers, peptides, polysaccharides
Small molecules: Vitamins, sugars
What are the advantages of monoclonal antibodies?
• First and most studied targeting ligands
- Many are in clinical trials, some are in the clinic
- High specificity
• Sufficient techniques for NP Conjugation
What are the Disadvantages
of monoclonal antibodies?
- Complicated molecular engineering ( the need for full humanized MAb)
- Large, complex
- Relatively Expensive
- NP conjugation can increase size of NP (with negative
effects towards passive targeting) - Possible immunogenicity
Describe the differences between fragments and whole of monoclonal antibodies.
Fragments
• Smaller
- Less binding to Fc receptors (macrophage) hence less liver and spleen delivery
- Less Specific (not necessarily bad As allows for deeper tissue penetration)
- Less immunogenic
- Easier produced and identified
Whole
• More stable
• More Specific due to multivalency
(2 binding sites)
• Fc can be used for Antibody dependent cellular cytotoxicity
(enhanced therapy !)
• Easier produced and identified If tumour is readily accessible (eg. highly vascularised) … More specific
What are aptamers?
• A new class of DNA or RNA oligonucleotides Fold into well defined 3D structures.
- Recognizes: proteins, lipids, nucleic acids and sugars
- High affinity and selectivity extracellularly and
- intracellularly.
- SELEX (Systematic Evolution of Ligands by Exponential
- Enrichment)
What are the advantages of aptamers?
¥ Invitroselection
¥ Smaller (15kD) hence cheaper, easier scalable and better
tumour penetration
¥ Any target can be chosen regardless of toxicity (chemical
process which does not involve animals)
¥ Nucleic Acid material (need for modifications otherwise in vivo
degradation by nucleases)
¥ MACUGEN became the first anti-VEGF inhibitor aptamer FDA
approved in 2004 for the treatment of neovascular macular degeneration (concept first mentioned in 1994)
What are the disadvantages of aptamers?
- Less established
* Negatively charged: Hard to reach intracellular targets
Describe liposomes as a DDS for cancer
Accumulation of PEG-liposomes in Solid Tumors via Leaky Tumor Vasculature
(EPR effect)
Introducing PEGylation to increase circulation half-life and hence reach the tumour site
