Lec 10- drug delivery and targeting (part 2) Flashcards
1
Q
Drug delivery
A
- To derive maximum benefit, a drug should be delivered to its target site at a rate and concentration that permits it’s optimal therapeutic activity whilst minimising undesirable side effects
2
Q
General principles of drug targeting
A
- The biodistribution of a drug may be controlled using a drug targeting system that can control the localisation and release of a drug thereby enhancing its potency and reducing toxicity
- This can also help to protect the drug from inactivation before it reaches its target
3
Q
Why do we want to target drugs
A
- For example, drug targeting can improve the outcome of chemotherapy by:
- Promoting the distribution of a chemotherapeutic drug to cancer cells, thus enhancing potency
- Enhancing the amount of drug that acts solely in cancer cells, thus reducing toxicity to non-cancerous cells
- Prolonging the retention of the chemotherapeutic drug at the tumour site
4
Q
Access to targets
A
- The route by which a drug formulation is administered can have a strong impact on the rate of drug delivery and its site of action
- Targeting ‘external organs’ is easy
- Skin, lung, eye, GIT
- Targeting internal organs are more difficult
- Brain, liver, kidneys, tumours
5
Q
Requirements for a targeting system
(definition of drug targeting)
A
- There must be no non-specific interactions with biological components- such as mucus
- The targeting system should be non-toxic/therapeutically acceptable
- It should specifically target the drug to the physiological target
- It should retain the drug during transit to the site
- The drug must be able to access the target site
- The drug should be retained at the site
- And the drug must be in released from its targeting system
6
Q
To achieve this
A
- Schematic representation of a drug-carrier-targeting device
- DRUG: the physic-chemical nature of a drug carrier system can dictate the fate and distribution of the drug
- Movement out of the systemic circulation is required for drugs to reach many target sites
7
Q
TARGET: there are various sites and levels, to which we can target a drug including
A
- Specific organs: Examples include targeting the brain to treat Alzheimer’s, Parkinson’s and Creutzfeldt-Jakob disease or targeting the lung in the treatment of CF
- Tissues: Tumours or sites of inflammation
- Invading organisms: targeting bacteria, viruses, parasites
- Specific cells: for example targeting of trastuzumab to HER2+ cancer cells
- Cytosolic targets: many drugs require delivery across the cell membrane since their specific target is inside the cell. For example within the cytoplasm, proteins or receptors (e.g. glucocorticoid receptors) may be a target
- Subcellular compartments: additional compartments within in the cell, such as the nucleus, or organelles such as mitochondria, may also contain the target (DNA intercalating agents such as doxorubicin, or for gene therapy)
8
Q
Carrier: options for carrier systems
Soluble carrier systems
A
- Includes natural and synthetic water solublepolymers and antibodies
- With these systems the drug is conjugated to the carrier
9
Q
Carrier: options for carrier systems
Particulate carrier system
A
- Includes nanoparticles, liposomes, microspheres
- Here the drug is either surface-bound or entrapped within the carrier
10
Q
Pro-drugs and drug carrier conjugates
A
- In principle, there is little difference between pro-drugs and drug carrier conjugates
- Both have the active drug administered as part of a larger molecule that has PK and Pharmacodynamic properties that are generally different from that of the active drug
- However, basically drug carrier conjugates are larger and as such can be considered as macromolecular/colloidal drug delivery systems
11
Q
Barriers to drug targeting
A
*
12
Q
Barriers to drug targeting
A
- The body’s natural defence system has a range of methods to remove particulate drug delivery systems and drug-conjugates
- Molecules within the blood can bind to particulates and mark them for recognition and destruction by phagocytic cells within the immune system
13
Q
Elimination of the drug carrier
A
- A major barrier that drug delivery systems must be able to overcome in the systemic circulation is the removal of particulates by phagocytic cells of the mononuclear phagocyte system (MPS)
- The MPS consists of cells including
- Bone marrow monoblasts
- Blood monocytes
- Mobile tissue macrophages and fixed tissue macrophages
- E.g. In the liver (Kupffer cells)
- The lung (Alveolar macrophages)
- The spleen, bone marrow and lymph nodes
14
Q
Recognition of carriers
A
- The main function of these phagocytic cells is to eliminate and remove foreign material, including bacteria and proteins
- But how do they know what to remove?
- Opsonisation of foreign particles (Bacteria and particular drug carriers)
- A method of marking the particulates for easier recognition and destruction by phagocytes
15
Q
Blood oposonins
A
- Fibronectin
- Complement proteins
- Antibodies
- In particular IgG, by binding to carrier through their Fab region leaving the Fc region free
- Phagocytes have Fc receptors and therefore bind to the coated molecule or particulate and internalise and destroy it
21
Q
Endothelial lining
A
- Continuous most difficult- e.g. the brain
- Fenestrated easier- e.g. kidneys/GIT
- Sinusoidal- e.g. liver
27
Q
EPR effect
(Enhanced Permeation and Retention)
A
- The EPR effect can be used to passively target a drug-carrier to a site where the vasculature is leaky and gaps in the endothelium are present
- E.g. sites of inflammation or certain tumour sites (angiogenesis)
- Angiogenesis- vessels rapidly form which makes mistakes (gaps= leaky), lymphatic drainage is very bad for the same reason
- A delivery system must be designed to avoid recognition and clearance of the particulates by the MPS
- Allows the carrier to reach and cross the endothelium
28
Q
Active targeting
A
- Active targeting is based on ligand-receptor complementary binding and takes advantage of elevated levels of such receptors at a target site
- Anything that can bind to a receptor
