TD: IV route Flashcards
What are drug targeting delivery systems?
Drug targeting sysyems are used to acheive site specific delivery of a drug
Describe the difference between conventional IV infusions and targeted drug delivery IV
Conventional IV formulation it is the free drug administered therefore this is not able to permeate throughout the entire body and all of it reach the tumour site. Instead a lot ends up in healthy tissues.
In drug targeted delivery more drug reaches the tumour site so efficacy is increased and reduced in healthy tissues so reduced side effects
What are the advantages of drug targeting delivery systems
Site-specific drug delivery is desirable in therapeutics, in order to improve:
- drug safety => reduce side effects
- drug efficacy => improved effect with lower dose
- patient compliance.
- Patient quality of life while on drug and improve outcome
What are examples of site specific delivery systems that although their is some specificy to site of drug taregtting it is still not perfect
- Conventional dosage forms – achieve site specific delivery by the local administration of the therapeutic compounds, i.e. topical creams. However this can still lead to systemic uptake => side effects.
- Sophisticated oral drug targeting systems – achieve site specific delivery within GI tract, e.g. gastro-resistant tablets (Eudragit S & L) or prodrugs
- M/R local delivery, e.g. Gliadel® – biodegradable wafers implanted in brain
- Most advanced drug targeting systems – parenteral route => target site in body and accumulate there via circulation.
What are the levels of drug targeting?
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First level
- to the organ, e.g. liver.
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Second level
- to the particular type of tissue within the organ, tumour.
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Third level
- selective uptake by the diseased cell, e.g. specific tumour cells.
- Also target invading organism/foreign body, e.g. HIV
What level is the most desirable?
Why is this not always possible?
The higher the level (3rd) the more efficacious, however more complicated to achieve.
This might be due to it being to complex, expensive, time-consuming or difficult to scale-up
What are the 2 main types or targeting?
Passive or active
Describe passive targeting and give examples
What level does passive tend to target?
Passive targeting relies on the physiochemical properties of the delivery system to acheive delivery at a target site. E.g
- Trapping of ‘large particles in the lungs if microparticles of 5-6um used’. These particles will acheive level 1 targeting as they will reach the organ so will therefore affect healthy tissue too and lead to side effects
- Enhanced permeability and retention effect - nanoparticles - acheives level 2
Describe the EPR effect
Due to rapid tumour growth, new blood vessel formation to the tumour is more disorganised and leads to gaps between endothelial cells. The nanoparticles can travel through these gaps to reach the tumour site and therefore acheive level 2 targeting. (permeability)
Lymphatic drainage is also less which means if drug reaches the tumour site it is much less likey to be cleared (retention)
Describe the use of active targeting.
What level does this acheive?
What is an important consideration?
Active taregeting systems acheive level 3 targets.
Again they use nanoparticles which make use of the EPR affect. These nanoparticles have an additional attachment of a ligand or AB which allows for interaction with the receptors on the tumour cell and therefore absorption or uptake into the tumour cell itself.
It is important that the receptor the ligand/AB interacts with is mostly expressed on the tumour cells and prefeably not at all or very little on healthy tissue.
What is an example of active targeting?
e.g. use over expression of folate receptors on tumour cells to facilitate specific uptake in breast tumours
What is a limitation of active targeting systems?
More difficult to achieve due to additional synthesis and purification due to attachment of ligands. - need the right chemistry for attachment
What are examples of drug carrier systems?
- Liposomes (most common)
- Conventional
- ‘Stealth’
- Polymeric Micelles
- Protein Nanoparticles (Directed Study)
- Lipoproteins (Directed Study)
Most in nanoparticle range
How do conventional lipid liposomes work?
Passive targeting possible. However drug release may be more likely due to interaction with immune system, i.e. may not target release at all, but may produce controlled release.
Conventional liposomes are detected by the immune system and broken down in a controlled manner to cause drug release.
Describe the structure of conventional liposomes.
What is the advantage of this structure?
- Vesicular structures based on one (unilamellar) or more (multilamellar) lipid bilayers encapsulating an aqueous core.
- Lipid molecules are usually phospholipids (which are amphiphilic - a hydrophilic head group and two hydrophobic chains).
- Diameter of the vesicles can vary between 10 nm - 3 µm.
Because they have an aqueous core and a lipid bilayer they can encapsulate both hydrophillic and hydrophobic drugs
What is the difference between conventional and stealth liposomes?
Conventional liposomes are detected by the immune system and broken down in a controlled manner to cause drug release.
Stealth liposomes avoid detection from the immune system so are more likely to accumulate at the target site and produce type 2 targeting, more efficacious and less side effects.
They can either be passive or active
See picture of stealth liposome
Conventional vs ‘Stealth’
Doxorubicin in breast cancer
Conventional: safer and more effective than traditional IV
Stealth - less drug required, less frequent dosing, greater efficacy and reduced side effects compared to conventional BUT more costly
What is the most common molecular architecture of an amphiphilic polymer?
Describe this
The most common molecular architecture of amphiphilic polymers is the amphiphilic block copolymer.
This is 2 polymers - one hydrophillic and one hydorphobic covalently bonded together. In water they form polymetric micelles with the hydrophobic part forming an hydrophobic core and the hydrophillic part froming the surface
It is a dynamic system with constant exchange from the amphiphiic block copolymers at the surface to the polymetric miclles in the bulk of solution
What are immunomicelles?
Can also have targeting ligands attached to them (as with stealth liposomes) to achieve active targeting – Immunomicelles.
What are Polymer-drug conjugates?
What is an example of polymer-drug conjugate?
Describe this
What type of targeting is nanoparticles
Give an example of this type of carrier and how it works
- Active targeting
- Abraxene®: 130 nm particles of albumin containing paclitaxel
- Albumin is able to facilitate paclitaxel uptake by tumour cells in same way it does for hydrophobic endogenous substances (hormones).
- –Binds to P-gp60 receptors over expressed on tumour cells => actively taken up.
What are lipoprotein carriers?
What are they used for?
Endogenous lipid carrier systems comprising a lipid core and a coat where apoproteins can be found. The lipid core consists of cholesterol and other lipids.
Active targeting: Have been studied for site-specific delivery of hydrophobic drugs.
