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Week 2 Drug delivery & developmentSMDs/biologics
LE Drug Targeting and Delivery (Part I) (Rik Oude Egberink)
Classical drugs (like paracetamol) are small organic molecules that are usually lipophilic enough to
cross membranes (distribute well throughout body). They act by inhibiting enzymes/receptors. If you
want to use (m)RNA as drugs (they are not drugs by themselves), they need a transport vehicle or
you make a nanoparticle of the RNA.
SiRNA is negatively charged and large thus it cannot get into the cell, but if it can enter the cell via a
transport way it can act as a drug.
Risk of side effects by
- Insufficient specificity (cross reactivity with other targets) because it can distribute well
thoughout the body
- Inhibition of important metabolic routes in non-target organs
Classical drugs are poor inhibitors of protein-protein interactions due to large surface area and weak
binding of the proteins. Classical drugs need deep pockets for binding. So bigger proteins are needed
(like antibodies). Oligonucleotides (such as mRNA)offer a very straightforward way to inhibit/change
protein expression.
Drug targeting goal is to enhance concentration of a drug at site-of-action (avoid side effects,
minimize costs, minimize dose, and increase t1/2).
Drug targeting = how do we accumulate drugs at a target site
Drug delivery = how do we get the drug at the site
- Minimal design
- No toxicity
- Elimination of vehicle (secretion vs break-down)
- Compatibility with drug to be targeted (hydrophobic or hydrophilic)
- Costs
- Stability (therapeutics and storage)
We want the drug to remain undetected from the immune system, but you want it to specifically find
and hit the target.
Nanomedicine consists of a matrix containing the drug (both matrix and drug should be hydrophobic
OR hydrophilic), with a surface modification and a receptor for targeting ligand = all biodegradable
Esther: C with double bonded O, is what you degrade by hydrolysis (biodegradable by metabolism)
, PLGA breaks down in minutes but is adjustable so it breaks down over years (used for prestethic and
slow releasing medicine (like insulin)
Delivery routes
- Peroral = oral
- Pulmonal = lungs
- Ophthalmic = eyes
- Percutane = through skin (don’t need doctor)
- Intravenous = into bloodstream
- Intrathecal = injection in spine (passing blood-brain barrier)
Delivery route dictated which barriers the drugs will encounter. There are 3 barriers: epithelial,
endothelial and plasma membrane. Number and nature of barriers are organ-dependent = important
for exam
There are 3 types of capillary endothelia:
- Continuous: endothelial layer with intercellular clefts. Skeletal muscle contains many
transport vesicles, and BBB contains few vesicles.
- Fenestrated: endothelial layer with fenestrations (60-80 nm). Small proteins can pass.
Present in endocrine glands, intestines, pancreas, and glomeruli.
- Sinusoid: endothelial layer with intercellular gaps (30-40 microns) and an incomplete
basement membrane. Entire cells can pass. Present in the bone marrow, lymph nodes, liver,
and spleen.
A cell is 10-20 microns
- Transcellular transport = transport via endocytosed and exocytosis. Cargo should be
recognized. You can conjugation a drug to a metabolic cargo (e.g. vitamin can be conjugated
to insulin) = conjugation strategy (also used in BBB).
- Paracellular transport = transport between cells. Tight junction proteins can tighten or loosen
via calcium signaling, to let proteins diffuse. Too small for nanomedicines. Small proteins
max.
- Nanomedicine: for non-destructive transport, there is no permeation enhancement without
activation of intracellular processes.
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