TD: IV route

Question 1

What are drug targeting delivery systems?

Answer 1

Drug targeting sysyems are used to acheive site specific delivery of a drug

Question 2

Describe the difference between conventional IV infusions and targeted drug delivery IV

Answer 2

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

Question 3

What are the advantages of drug targeting delivery systems

Answer 3

—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

Question 4

What are examples of site specific delivery systems that although their is some specificy to site of drug taregtting it is still not perfect

Answer 4

• 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.

Question 5

What are the levels of drug targeting?

Answer 5

1. First level
   
   • to the organ, e.g. liver.
2. Second level
   
   • to the particular type of tissue within the organ, tumour.
3. Third level
   
   • selective uptake by the diseased cell, e.g. specific tumour cells.
   • Also target invading organism/foreign body, e.g. HIV

Question 6

What level is the most desirable?

Why is this not always possible?

Answer 6

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

Question 7

What are the 2 main types or targeting?

Answer 7

Passive or active

Question 8

Describe passive targeting and give examples

What level does passive tend to target?

Answer 8

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

Question 9

Describe the EPR effect

Answer 9

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)

Question 10

Describe the use of active targeting.

What level does this acheive?

What is an important consideration?

Answer 10

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.

Question 11

What is an example of active targeting?

Answer 11

e.g. use over expression of folate receptors on tumour cells to facilitate specific uptake in breast tumours

Question 12

What is a limitation of active targeting systems?

Answer 12

More difficult to achieve due to additional synthesis and purification due to attachment of ligands. - need the right chemistry for attachment

Question 14

What are examples of drug carrier systems?

Answer 14

1. Liposomes (most common)
   
   • Conventional
   • ‘Stealth’
2. Polymeric Micelles
3. Protein Nanoparticles (Directed Study)
4. Lipoproteins (Directed Study)

Most in nanoparticle range

Question 15

How do conventional lipid liposomes work?

Answer 15

—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.

Question 16

Describe the structure of conventional liposomes.

What is the advantage of this structure?

Answer 16

• 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

Question 17

For conventional lipoproteins what can these be used for?

Answer 17

Depending on the physicochemical properties of the drug, it can either be:

• Encapsulated in the aqueous phase (hydrophilic drugs).
• Interact with the bilayer (electrostatic interaction – DNA/peptide/protein).
• Taken up in the bilayer structure (lipophilic drugs).
• Serve as carriers for a wide variety of drugs including antitumour and antimicrobial agents, peptides, proteins & DNA.
• About 8 commercially available including: AmBisome® (hydrophobic - amphotericin B), DaunoXome® (hydrophilic - doxorubicin)

Question 18

What are advantages of conventional liposomes in relation to tranditional IV drug release?

Answer 18

• Due to some targeted delivery it:
  
  • Lowers toxicity (less in healthy tissue)
  • Higher specificity
• Due to interaction between liposome and immune system it can have a slow release of drug which allows for recovery of non-lethally damaged target cells

Question 19

Disadvantages of conventional liposomes to tranditional IV drug treatment?

Answer 19

• Higher cost (£100/vial) £6000-£7000 for 2 weeks.
• Anaphylactic reactions towards liposomes.
• Can release drug outside target site (‘leaky’)

Question 20

What is the difference between conventional and stealth liposomes?

Answer 20

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

Question 21

What are the 2 types of stealth liposomes?

Answer 21

• Long circulating liposomes
• Immunoliposomes

Question 22

Describe how long circulating liposomes work

Answer 22

• Covalently attach the hydrophilic polymer (polyethylene glycol (PEG)) to the liposome bilayers.
• Highly hydrated PEG groups create a steric barrier against interaction with molecular and cellular components, i.e. prevent immune system uptake.
• Therefore much more likely to achieve passive targeting compared to conventional.

Attahcment of PEG allows to avoid immune system detection therefore more passive targeting - type 2

Question 23

Describe how immunoliposomes work

Answer 23

• Specific antibodies or antibody fragments on the surface of liposomes which are specific to tumour cell receptors and therefore enhance target site binding.
• Allows for active targeting of anticancer agents - therefore level 3. So is safer and more effective
• PEG is also attached to allow for passive targeting prior to active

Question 24

Conventional vs ‘Stealth’
Doxorubicin in breast cancer

Answer 24

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

Question 25

Describe polymetric micelles

Answer 25

* Mainly used in passive targeting, i.e. EPR effect. * Amphiphilic polymers – consist of a hydrophilic segment and a hydrophobic segment within the same macromolecule. * Micelles form based on two competing forces: hydrophobic attraction and hydrophilic/electrostatic repulsion. * In aqueous solutions, above critical micellar concentration (CMC), form polymeric micelles. * Nano size range (5 - 100 nm).

Question 26

What is the most common molecular architecture of an amphiphilic polymer? Describe this

Answer 26

—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

Question 27

What drugs can polymeric micelles be used for and why?

Answer 27

Hydrophobic due to formation of hydrophobic core

Question 28

What is the benefit of polymeric micelles over conventional liposomes?

Answer 28

The hydrophillic portion is normally PEG or polyethelene oxide which acts as a stearic barrier so is more likely to give passive diffusion than conventional so improves safety and efficiy

Question 29

What are immunomicelles?

Answer 29

Can also have targeting ligands attached to them (as with stealth liposomes) to achieve active targeting – Immunomicelles.

Question 30

Advantages of polymeric micelles?

Answer 30

* Much more stable than conventional surfactants upon dilution with a remarkably low critical micellar concentrations (~ 10-3 mgmL-1). * This is due to polymeric micelles being polymers/ macromolecules which has much larger molecular weights therefore a lower conc is required to form micelles compared to surfactants with low mwt. * Solubilisation: Hydrophobic drugs are physically entrapped in the hydrophobic core (purely non covalent interaction) and can retain their activity once removed from the core. * Drugs in the core are protected from exposure to aqueous degradation processes. * High drug loading capacity. * Can carry a wide range of hydrophobic drugs including anticancer agents (doxorubicin, paclitaxel), anaesthetic agent (propofol), steroids (prednisolone, progesterone). * Can avoid detection by immune system due to hydrophilic surface.

Question 31

Limitations of polymeric micelles

Answer 31

* Very limited number commercial formulations available (Fungizone ® – Amphotericin B) although clinical trials ongoing. * Complicated synthesis and purification, particularly on large scale. * Drug release mechanisms not well understood. * ◦Degradation of polymer * Diffusion of drug into aqueous enviroment * ◦Particle collapsing

Question 32

What are Polymer-drug conjugates?

Answer 32

Question 33

What is an example of polymer-drug conjugate? Describe this

Answer 33

Question 34

Limitations of polymer-drug conjugates?

Answer 34

* Creation of a covalent bond between the drug and polymer is dependant of the availability of functional groups (COOH, NH2 etc) on both molecules. * The reaction employed must be mild in order to avoid unwanted chemical alteration of drug and polymers. * Cleavable bonds are essential to ensure the drug retains its activity once it is released. * Rely on endogenous enzymes/hydrolysis which may be non-specific to target site * Limited drug carrying capacity. * No polymer-drug conjugates yet available commercially, only polymer-peptide. * Number undergoing clinical trials: Opaxio® (Poly(glutamic acid)-paclitaxel via ester link) with promising results so far

Question 35

What type of targeting is nanoparticles Give an example of this type of carrier and how it works

Answer 35

* 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.

Question 36

What is the difference between Cremophor - free pacliaxel product and Abraxene protein nanoparticles?

Answer 36

§First Cremophor®-free paclitaxel product * Taxol® is traditional formulation of paclitaxel (hydrophobic) in Cremophor® (oil) * Requires special infusion sets. Infusion lasts 3 hours and requires pre-treatment with antihistamines and corticosteroids to limit chance of hypersensitivity reaction. Cremophor® =\> neuropathy (nerve damage) and neutropenia (low white cell count). §Albumin nanoparticles increase of 33 % in intratumour accumulation of paclitaxel compared to Taxol®. §No immune system response.

Question 37

What are lipoprotein carriers? What are they used for?

Answer 37

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.

Question 38

What is LDL and why could it potentially be used?

Answer 38

LDL (low density lipoproteins) §LDL is a normal constituent of plasma involved in the transport of cholesterol to tissues from the liver. –‘Bad Cholesterol’ - Statins §The receptor protein (apoprotein B) is responsible for the uptake of the LDL by cells which require cholesterol. §LDL has a plasma half life of 3-4 days. §On some tumour cells, LDL receptor density is increased. §Therefore LDL may able to achieve site specific delivery. §No immune system response.

Question 39

Why might LDL be problematic?

Answer 39

§However, research into the use of LDL has been problematic for a variety of reasons. –LDL can only be prepared by isolation from plasma samples using a complex and time consuming process. –Large batch-to-batch variations due to different biological sources. –Potential for infection from donor. –Plasma samples will at most produce 100 mg of LDL, insufficient for major studies.