Lecture 1: Drug Delivery & Targeting
Why Drug Targeting?
- Reduce Adverse Effects: Minimize side effects on healthy tissues.
- Protect Drugs from Degradation: Ensure stability of drugs while circulating in the bloodstream.
- Enhance Therapeutic Effects: Increase the effectiveness of drugs in target cells.
- Improve Multidrug Approaches: Enable combination therapies with better outcomes.
- Allow Personalized Medicine: Tailor treatments to individual patient needs.
Drug Carriers (optimal size: 7-100 nm):
1. Micelles
> Function: Encapsulate hydrophobic drugs.
> Benefit: Enhance solubility and stability of drugs
2. Liposomes
> Description: Spherical vesicles with a phospholipid bilayer.
> PEGylation: Addition of PEG layer enhances circulation time and reduces immune recognition.
> Example: Doxil.
3. Polymers
> Example: PLGA nanoparticles.
> Function: Form nanoparticles for drug delivery.
4. Antibodies
>Importance of Size: Optimal size for drug carriers is 7-100 nm.
A) 7 nm: Prevents renal clearance.
B) 100 nm: Avoids uptake by macrophages.
5. Proteins: Utilized in drug delivery for their specific targeting abilities
6. Viruses: Engineered as carries targeted drug delivery
Specific Drug Delivery Using Carriers:
1. Passive Targeting:
Mechanism: Prevents uptake by cells and degradation and prevents excretion by organ (mostly
kidney), prolongs circulation time in blood, by increase in size and PEGylation due to enhanced passive
inflow.
The Enhanced Permeability and Retention (EPR) effect is a phenomenon where molecules, such as
liposomes, nanoparticles, and macromolecular drugs, tend to gather more in tumor tissue compared to
normal tissue. This happens because tumors need a lot of nutrients and oxygen to grow quickly, so they
stimulate the production of new blood vessels, a process called angiogenesis. The new blood vessels
formed in tumors are often leaky and abnormal in structure, which allows molecules to easily pass
through them.
How?
1.Tumor Blood Vessels: Tumors induce the formation of new blood vessels through angiogenesis to
support their rapid growth.
2. Leaky Vasculature: The new blood vessels in tumors have gaps between endothelial cells, making
them leaky and allowing molecules to pass through more easily.
3. Poor Lymphatic Drainage: Tumors usually have inefficient lymphatic drainage, so molecules that
enter the tumor tissue tend to accumulate there instead of being cleared away.
, Benefits:
1. Selective Accumulation: Molecules preferentially accumulate in tumors or inflamed
tissues due to the leaky blood vessels and poor drainage, increasing the concentration
of the drug in the target area.
2. Reduced Side Effects: Concentrating the drug in the tumor helps minimize exposure of
healthy tissues to the drug, reducing side effects.
3. Increased delivery of nanomedicines to tumors and inflamed tissue is possible due to the
EPR effect.
Purpose of PEGylation:
PEGylation is a process where molecules are coated with polyethylene glycol (PEG) chains.
This serves several purposes:
● Increase in Size: Prevents kidney filtration and enhances circulation time. (Renal filter)
● Increase in Charge: Makes particles more negative, preventing opsonization (immune
recognition and clearance).
● Increase in Hydrophilicity: Creates a protective water shield around the molecule.
● Prevention of Clearance: Increases half-life, enhancing uptake in tumors via the EPR
effect.
Mechanism of PEGylation:
> Formation of PEG Layer:
- PEG is a hydrophilic polymer that forms a protective layer around the drug or carrier. This
layer provides a shield against the immune system.
> Increased Size:
- PEGylation increases the size of the nanoparticle, which helps to prevent rapid clearance by
the kidneys (renal filtration).
> Immune System Evasion:
- The hydrophilic and neutral nature of PEG reduces the recognition and uptake by
macrophages and the mononuclear phagocyte system (MPS). This prolongs the circulation
time of the drug in the bloodstream.
, Benefits of PEGylation:
> Prolonged Circulation Time:
- By evading the immune system and reducing renal clearance, PEGylated nanoparticles
remain in the bloodstream longer, allowing more time for the drug to reach and accumulate
in the target tissue.
> Enhanced Stability:
- PEGylation enhances the stability of the drug or carrier in the bloodstream, protecting it from
degradation.
> Increased Drug Accumulation:
- The combination of prolonged circulation time and the EPR effect results in higher drug
accumulation in the target area, such as tumors or inflamed tissues.
> Immune System Evasion:
- Prevents recognition and clearance by macrophages and MPS.
> Reduced Renal Clearance:
- Prevents rapid filtration by kidneys.
PEG-Dilemma:
- Increased Size: Prolonged circulation but reduced tissue penetration (loss of EPR effect).
- Increased Size = increased uptake by macrophages (--> reduced circulation time → loss of
EPR effect) → rapid removal and induction of immune response.
So, Increased in size = longer circulation time, but too large = reduced inflow in tumor.
EPR CANNOT BE USED IN TUMORS THAT HAVE INCREASED INTERSTITIAL PRESSURE AND
IN LOSS OF FENESTRAE IN THE LIVER DURING FIBROSIS/SCAR FORMATION → leads to loss
in EPR effect (liver fibrosis), also in brain diseases due to BBB
How EPR Effect and PEGylation Work Together to Enhance Drug Delivery:
> Prolonged Presence in Bloodstream:
- PEGylation ensures that the nanoparticles circulate for an extended period, increasing the
likelihood of encountering the leaky vasculature in tumors or inflamed tissues.
> Enhanced Accumulation in Target Area:
- The EPR effect allows these circulating nanoparticles to pass through the leaky blood
vessels and accumulate in the target area.
> Synergistic Effect:
- The combined effect of PEGylation and the EPR effect maximizes the therapeutic
concentration of the drug in the diseased tissue while minimizing exposure to healthy
tissues.
Biological Barriers for Nanoparticles:
1. Endothelial Barriers: Barriers formed by the endothelial cells lining blood vessels.
2. Cellular Barriers: Barriers posed by cells in tissues.
3. The Vascular wall and BBB
4. Clearance by MPS System:
○ Large particles (>100 nm) are taken up by macrophages in the liver and spleen. (RES)
○ Renal Clearance: Small particles (<7 nm (67kD)) are filtered out by kidneys.
Elimination of nanoparticles by:
Immune System: The immune system recognizes and produces antibodies against nanoparticles,
leading to their clearance by immune cells.
Macrophages: Macrophages engulf and degrade nanoparticles through phagocytosis, particularly in
the liver and spleen (for red blood cells) as part of the MPS and RES (liver and spleen)
Why Drug Targeting?
- Reduce Adverse Effects: Minimize side effects on healthy tissues.
- Protect Drugs from Degradation: Ensure stability of drugs while circulating in the bloodstream.
- Enhance Therapeutic Effects: Increase the effectiveness of drugs in target cells.
- Improve Multidrug Approaches: Enable combination therapies with better outcomes.
- Allow Personalized Medicine: Tailor treatments to individual patient needs.
Drug Carriers (optimal size: 7-100 nm):
1. Micelles
> Function: Encapsulate hydrophobic drugs.
> Benefit: Enhance solubility and stability of drugs
2. Liposomes
> Description: Spherical vesicles with a phospholipid bilayer.
> PEGylation: Addition of PEG layer enhances circulation time and reduces immune recognition.
> Example: Doxil.
3. Polymers
> Example: PLGA nanoparticles.
> Function: Form nanoparticles for drug delivery.
4. Antibodies
>Importance of Size: Optimal size for drug carriers is 7-100 nm.
A) 7 nm: Prevents renal clearance.
B) 100 nm: Avoids uptake by macrophages.
5. Proteins: Utilized in drug delivery for their specific targeting abilities
6. Viruses: Engineered as carries targeted drug delivery
Specific Drug Delivery Using Carriers:
1. Passive Targeting:
Mechanism: Prevents uptake by cells and degradation and prevents excretion by organ (mostly
kidney), prolongs circulation time in blood, by increase in size and PEGylation due to enhanced passive
inflow.
The Enhanced Permeability and Retention (EPR) effect is a phenomenon where molecules, such as
liposomes, nanoparticles, and macromolecular drugs, tend to gather more in tumor tissue compared to
normal tissue. This happens because tumors need a lot of nutrients and oxygen to grow quickly, so they
stimulate the production of new blood vessels, a process called angiogenesis. The new blood vessels
formed in tumors are often leaky and abnormal in structure, which allows molecules to easily pass
through them.
How?
1.Tumor Blood Vessels: Tumors induce the formation of new blood vessels through angiogenesis to
support their rapid growth.
2. Leaky Vasculature: The new blood vessels in tumors have gaps between endothelial cells, making
them leaky and allowing molecules to pass through more easily.
3. Poor Lymphatic Drainage: Tumors usually have inefficient lymphatic drainage, so molecules that
enter the tumor tissue tend to accumulate there instead of being cleared away.
, Benefits:
1. Selective Accumulation: Molecules preferentially accumulate in tumors or inflamed
tissues due to the leaky blood vessels and poor drainage, increasing the concentration
of the drug in the target area.
2. Reduced Side Effects: Concentrating the drug in the tumor helps minimize exposure of
healthy tissues to the drug, reducing side effects.
3. Increased delivery of nanomedicines to tumors and inflamed tissue is possible due to the
EPR effect.
Purpose of PEGylation:
PEGylation is a process where molecules are coated with polyethylene glycol (PEG) chains.
This serves several purposes:
● Increase in Size: Prevents kidney filtration and enhances circulation time. (Renal filter)
● Increase in Charge: Makes particles more negative, preventing opsonization (immune
recognition and clearance).
● Increase in Hydrophilicity: Creates a protective water shield around the molecule.
● Prevention of Clearance: Increases half-life, enhancing uptake in tumors via the EPR
effect.
Mechanism of PEGylation:
> Formation of PEG Layer:
- PEG is a hydrophilic polymer that forms a protective layer around the drug or carrier. This
layer provides a shield against the immune system.
> Increased Size:
- PEGylation increases the size of the nanoparticle, which helps to prevent rapid clearance by
the kidneys (renal filtration).
> Immune System Evasion:
- The hydrophilic and neutral nature of PEG reduces the recognition and uptake by
macrophages and the mononuclear phagocyte system (MPS). This prolongs the circulation
time of the drug in the bloodstream.
, Benefits of PEGylation:
> Prolonged Circulation Time:
- By evading the immune system and reducing renal clearance, PEGylated nanoparticles
remain in the bloodstream longer, allowing more time for the drug to reach and accumulate
in the target tissue.
> Enhanced Stability:
- PEGylation enhances the stability of the drug or carrier in the bloodstream, protecting it from
degradation.
> Increased Drug Accumulation:
- The combination of prolonged circulation time and the EPR effect results in higher drug
accumulation in the target area, such as tumors or inflamed tissues.
> Immune System Evasion:
- Prevents recognition and clearance by macrophages and MPS.
> Reduced Renal Clearance:
- Prevents rapid filtration by kidneys.
PEG-Dilemma:
- Increased Size: Prolonged circulation but reduced tissue penetration (loss of EPR effect).
- Increased Size = increased uptake by macrophages (--> reduced circulation time → loss of
EPR effect) → rapid removal and induction of immune response.
So, Increased in size = longer circulation time, but too large = reduced inflow in tumor.
EPR CANNOT BE USED IN TUMORS THAT HAVE INCREASED INTERSTITIAL PRESSURE AND
IN LOSS OF FENESTRAE IN THE LIVER DURING FIBROSIS/SCAR FORMATION → leads to loss
in EPR effect (liver fibrosis), also in brain diseases due to BBB
How EPR Effect and PEGylation Work Together to Enhance Drug Delivery:
> Prolonged Presence in Bloodstream:
- PEGylation ensures that the nanoparticles circulate for an extended period, increasing the
likelihood of encountering the leaky vasculature in tumors or inflamed tissues.
> Enhanced Accumulation in Target Area:
- The EPR effect allows these circulating nanoparticles to pass through the leaky blood
vessels and accumulate in the target area.
> Synergistic Effect:
- The combined effect of PEGylation and the EPR effect maximizes the therapeutic
concentration of the drug in the diseased tissue while minimizing exposure to healthy
tissues.
Biological Barriers for Nanoparticles:
1. Endothelial Barriers: Barriers formed by the endothelial cells lining blood vessels.
2. Cellular Barriers: Barriers posed by cells in tissues.
3. The Vascular wall and BBB
4. Clearance by MPS System:
○ Large particles (>100 nm) are taken up by macrophages in the liver and spleen. (RES)
○ Renal Clearance: Small particles (<7 nm (67kD)) are filtered out by kidneys.
Elimination of nanoparticles by:
Immune System: The immune system recognizes and produces antibodies against nanoparticles,
leading to their clearance by immune cells.
Macrophages: Macrophages engulf and degrade nanoparticles through phagocytosis, particularly in
the liver and spleen (for red blood cells) as part of the MPS and RES (liver and spleen)
