Advanced drug monitoring: Drug targeting Flashcards
What is meant by passive targeting
All strategies that employ the natural body response to the administration of a foreign molecule
What ways can passive targeting be optimised
-Adjusting the particle size
-Opination of the foreign molecule
> Phagocytosis transports it to the liver in macrophages
>used to target the liver
-MPS (mononuclear phagocytosis system)and RES(reticuloedothelial system) for particle between 0.4-2 micrometers
What are the MPS and RES targeting used to treat
Macrophage associated microbial diseases
Deficiencies of lysosomal enzymes
Immunopotentiation of vaccines
How can opsonisation be avoided to stop the RES and MPS, and promote the EPR
-Coat the particles in hydrophilic polymers that absorb water.
>Polyethylene glycol
Characteristics/ benefits of the EPR(enhanced permeability and retention) strategy.
- does not reach the liver
- Prolonged circulation time
- can move to damaged tissue
- Passive targeting to tumour of inflammed tissue by enhanced permeability
- Accumulates in damaged tissue due to poor lymphatic drainage therefore has enhanced retention
How does the EPR strategy work
Leaky blood vessels in the tumour tissue or inflamed tissue allows big polymeric molecules to exit from the blood stream and accumulate at the site of the tumour
The particle doesn’t drain out due to in effective lymphatic systems.
What is active targeting
a method that delivers a certain amount of a therapeutic or diagnostic agent or both of them to a targeted diseased area within the special organ in the body
What are the 3 different types of active targeting systems
Drug
Homing device
Carrier
What are the homing devices available in active targeting system
Antibodies
Aptamers
Carbohydrates
Other molecules
What are the carriers available in active targeting system
Polymer conjugates
Micelles
Nano/micro particles
Lipid carriers
What are the advantages and disadvantages of the antibody homing device
Advantages:
>High degree of specificity
Disadvantages >Complex and large molecules >Expensive > immunogenic >scarce tumour penetration
What are the advantages and disadvantages of the oligonucleotides/Aptamer homing device
Advantages: >Small sizes >low immunogenicity >Good cell penetration >Ease of production
Disadvantages
>Rapid blood clearance
What are the advantages and disadvantages of carbohydrates as homing device
Advantages
>Small molecules
>Cheap
Disadvantages
>Low specificity
>Low binding affinity so high density of surface modification
What are the advantages and disadvantages of other small molecule as homing device
Eg: folic Acids
Recognised by folate receptor overexpressed on certain tumour cell surfaces
What are the components/structure/moieties of a polymer conjugate carrier?
Molecular weight: must ensure access to target tissue
Target moiety (homing device) can be pendant or included in the backbone
Spacer between the drug and polymer can avoid shielding the active site an facilitate/control release
>eg degrade under specific conditions
What is the function of moieties on polymer conjugated
Increase absorption of the drug
- Control the release
- Provide protection from premature inactivation of the drug
- Improve solubility profile of both the drug and the carrier
- Targeting the system to its site of action
List the advantages and disadvantages of polymer conjugates
Advantages:
>great ability to extravasate
>ease of attaching homing devices
Disadvantages
>limited drug loading capacity
>drug covalently bond can mask active site
>carrier can only partially protect the drug
List some exaples of a polymer conjugate drugs
Doxorubicin and Poly(N-(2-hydroxypropyl)methacrylamide)
> reduced systemic toxicity
selective retention in tumour cells (EPR)- due to hydrophilicity
drug release by overexpressed thiol-dependent (cysteine) proteases in lysosomes
Neocarzinostatin (a peptide) that works by complexing a cromophore in it’s core
> polymer attached to 2 AA (position 1 and 20 of the peptide chain)
EPR effect used to avoid phagocytosis
Reduced the kidney clearance and reduced side effects
Design considerations for carriers
- Size
- <10nm cleared by kidney
- <100nm increase circulation time and reduce elimination form live
- > 400nm taken to the liver
- Shape:
- spherical shapes travel in the centre of vessels and reduced interaction with endothelial
- irregular particle tend to avoid elimination but the studies are few
- surface properties
- Hydrophobicity
- Zeta-potential
Types of particulate carriers
- Micelles
- Nano/micro-particles
- Lipidic particles
What are the advantages and disadvantage of particulate carriers
Advantages
- high drug loading capacity
- drug can be physically entrapped
- the system can confer protection to the drug
Disadvantages
- inability to cross the endothelial barrier
- subject to phagocytosis
What are the 2 types of micelles carriers available and it uses
The Di-block: Hydrophilic and hydrophobic
The tri block Hydrophilic and hydrophobic and hydrophilic /benefits
(Join in a chain)
Used to load hydrophobic drugs
Diameter of 20-40 nm to expolit EPR effect
- high loading dose
- LMW to favor glomerular eliminate
Which system so micelle carriers used
-EPR
Examples of micelle carrier medications
- doxorubicin
- Koniakon mixed-micelles: phytomenadione, prophylaxis and treatment of vitamin K deficiency bleeding (VKDB) in neonates and infants.
What are the different subclasses of polymer nanoparticulate
- Biodegradable polymers:
- Synthetic: PLGA/PLA/PCL
- Natural: Chitosan, alginate, other polysaccharides
what is the selection criteria for the polymeric nanoparticles
compatibility, functionalisation needed
What are the different types of nanoparticle medications available
- Plain nanoparticle
- Stealth
- Charge
- Targeting
- Stimuli
Properties of plain nanoparticulate
High aggregation
Low loading concentration
easily opsonised
Rapid clearance
Properties of stealth nanoparticulate
Steric stability
High drug protection
Slow opsonisation
biocompatibility
Properties of Charge nanoparticulate
High cellular uptake
high toxicity
Low specificity
Properties of Targeting nanoparticulate
High cellular uptake
High specificity
Properties of stimuli-responsiveness nanoparticulate
High selectivity
Example of protein nanoparticle
- Albumin
- Transports hydrophobic molecules and interacts with vitamin and hormone
- Reversible non-covalent bond
- Helps endothelial transcytosis- allows accumulation into tumours
Types lipidic particle
- conventional-phagocytosis
- Stealth- EPR
- Targeted: specific
- Cationic
What advantage do liposomes have over micelles
They can have hydrophilic drugs in their core and and hydrophobic drugs in their bilayers.
Exmple of liposome formulation
Ambisome: contains the drug Amphotericin B (antifungal)
-formed by phospholipids and cholesterol
-rapid uptake by MPS to the spleen and liver
》Abelcet: ribbon like particle (DMPC and DMPG)
》Amphotec: disk like (cholesteyl sulfate)
》Ambisome: Unilaminar (HSPC, DSPG,cholesterol)
Doxurubicin (caelyx): stealth liposomes which are not immunogenic
-EPR effect
Advantages of lipidic particle carrier
tissue targeting
reduced side effects
improved drug stability and solubility
possible intracellular drug delivery by addition of a ligand recognised by receptors on the cell membrane
Considerations that go into making a drug carrier:
- Purity of the carrier material: important to guarantee quality of the product
- Reproducibility: full physicochemical characterisation has to be carried out during the fist stages of development, later it will be included in the approval application documents
- Safety (i.e. immunological responses)
- Scaling-up possibility
- Shelf life
What are the general pharmaceutical considerations for development of a drug carries
- Purity of carries is guaranteed
- reproducibility
- Safety
- Scalling up probability
- shelf life
