BMS40 – Nanomedicine
BMS40 – NANOMEDICINE
Opleiding: Master Biomedical Sciences
Onderwijsinstelling: Radboudumc
1
, BMS40 – Nanomedicine
Content
Current drug delivery nano systems..................................................................................................4
General concepts in drug delivery.........................................................................................................................4
Barriers in drug delivery........................................................................................................................................4
Advanced drug delivery.........................................................................................................................................5
Liposomes........................................................................................................................................................5
Antibody drug conjugates (ADC).....................................................................................................................6
Oligonucleotides..............................................................................................................................................7
Conjugation strategies.......................................................................................................................8
Lysine – reactions with amines.............................................................................................................................8
Cysteine – reactions with thiols............................................................................................................................9
Maleimide chemistry (side chains)..................................................................................................................9
Disulfide exchange (reversible).......................................................................................................................9
Native chemical ligation..................................................................................................................................9
Regioselective coupling at the C-terminus – Sortase A......................................................................................10
Bio-orthogonal chemistry....................................................................................................................................10
Click reaction between azides and alkynes...................................................................................................10
Cu-free click chemistry with strained alkynes...............................................................................................10
Non-covalent strategies......................................................................................................................................10
Biotin-streptavidin binding............................................................................................................................11
Chelate formation.........................................................................................................................................11
Crosslinkers.........................................................................................................................................................11
Organs-on-chip................................................................................................................................11
Why do we want to use organs-on-chips?..........................................................................................................11
Fabrication and function.....................................................................................................................................13
Applications.........................................................................................................................................................13
Tumor-on-a-chip............................................................................................................................................13
Receptor nanodomains as drug targets...........................................................................................14
Theranostic approaches...................................................................................................................16
Theranostics........................................................................................................................................................16
Fluorescence imaging..........................................................................................................................................17
Photodynamic therapy........................................................................................................................................17
Brachytherapy with radioactive microspheres................................................................................18
2
, BMS40 – Nanomedicine
Radioembolization...............................................................................................................................................18
Intratumoral injections........................................................................................................................................18
3
, BMS40 – Nanomedicine
Current drug delivery nano systems
General concepts in drug delivery
A nanoparticle consists of certain aspects. It always consists of a matrix,
which is typically a bilayer of cell membrane. Within this matrix, or within
the bilayer, the drug is placed for safe delivery. The ratio between drug
and matrix should be as high as possible.
Drug targeting is about enhancing the concentration of a drug at the site of action, so only at the place in the
body where you actually want the drug to have an effect. It is important to enhance the concentration of a drug
at its site of action:
To avoid side effects
To use expensive drugs more effectively
Less total dose
Higher concentration for a longer period of time
Protection from degradation and excretion
For an established drug molecule (e.g. doxorubicin)
For a molecule that otherwise could not be a drug (e.g. siRNA) → drug delivery
Drug delivery means getting the drug through the body to the site of action, so all the technology utilized to
present a drug to the desired body site where it can be released, absorbed and target the correct molecules.
Drug delivery in nanoparticle-based systems is limited by the amount of drug that can be loaded on a single
particle. In determining the best drug delivery strategy, there are certain things you need to consider for
optimal working. A minimal design to implement main functionalities (like targeting, uptake and release) is
useful, as this can move around the body much easier. No toxicity, stability in the body, and low production
costs are needed. Elimination of the targeting vehicle is a must, as you do not want the delivery system to
accumulate in the body (possible through secretion or break down). Lastly, compatibility with drug to be
targeted, so the delivery system can actually safely hold the drug until the site of action.
Barriers in drug delivery
The characteristics of each cell layer/membrane are organ-specific and depending on the route of
application/localization of the target different numbers of barriers have to be crossed. Most drugs start in the
GI and have to cross the epithelia to the blood. From there, another endothelia layer has to be crossed to enter
the cell and the cell membrane itself. Therefore, an important driver for nanomedicine development is the
more barriers can be crossed the more comfortable the route of application.
Types of capillary endothelia:
Continuous → skeletal muscle (containing many transport vesicles) and blood-brain-barrier
(containing few vesicles)
Fenestrated → endocrine glands, intestines, pancreas, glomeruli (diffusion of small proteins, 60 – 80
nm)
Sinusoid → bone marrow, lymph nodes, liver, spleen (30 – 40 μm)
For non-destructive transport, activation of intracellular processes is needed for permeation enhancement.
Paracellular transport can be enhanced through permeation enhancers for small molecules, but this is not an
option for nanomedicines. The classical approach is transcellular transport in which a drug is conjugated to a
metabolic cargo, like a vitamin, so the cell takes it in through a vesicle.
Drug delivery of nanomedicines across the blood-brain-barrier involves
transcytosis. Transcytosis is a form of specialized transport through which
an extracellular cargo is endocytosed, shuttled across the cytoplasm in
membrane‐bound vesicles, and secreted at a different plasma membrane
surface. Receptors to target are transferrin receptor (TfR), human insulin
4
BMS40 – NANOMEDICINE
Opleiding: Master Biomedical Sciences
Onderwijsinstelling: Radboudumc
1
, BMS40 – Nanomedicine
Content
Current drug delivery nano systems..................................................................................................4
General concepts in drug delivery.........................................................................................................................4
Barriers in drug delivery........................................................................................................................................4
Advanced drug delivery.........................................................................................................................................5
Liposomes........................................................................................................................................................5
Antibody drug conjugates (ADC).....................................................................................................................6
Oligonucleotides..............................................................................................................................................7
Conjugation strategies.......................................................................................................................8
Lysine – reactions with amines.............................................................................................................................8
Cysteine – reactions with thiols............................................................................................................................9
Maleimide chemistry (side chains)..................................................................................................................9
Disulfide exchange (reversible).......................................................................................................................9
Native chemical ligation..................................................................................................................................9
Regioselective coupling at the C-terminus – Sortase A......................................................................................10
Bio-orthogonal chemistry....................................................................................................................................10
Click reaction between azides and alkynes...................................................................................................10
Cu-free click chemistry with strained alkynes...............................................................................................10
Non-covalent strategies......................................................................................................................................10
Biotin-streptavidin binding............................................................................................................................11
Chelate formation.........................................................................................................................................11
Crosslinkers.........................................................................................................................................................11
Organs-on-chip................................................................................................................................11
Why do we want to use organs-on-chips?..........................................................................................................11
Fabrication and function.....................................................................................................................................13
Applications.........................................................................................................................................................13
Tumor-on-a-chip............................................................................................................................................13
Receptor nanodomains as drug targets...........................................................................................14
Theranostic approaches...................................................................................................................16
Theranostics........................................................................................................................................................16
Fluorescence imaging..........................................................................................................................................17
Photodynamic therapy........................................................................................................................................17
Brachytherapy with radioactive microspheres................................................................................18
2
, BMS40 – Nanomedicine
Radioembolization...............................................................................................................................................18
Intratumoral injections........................................................................................................................................18
3
, BMS40 – Nanomedicine
Current drug delivery nano systems
General concepts in drug delivery
A nanoparticle consists of certain aspects. It always consists of a matrix,
which is typically a bilayer of cell membrane. Within this matrix, or within
the bilayer, the drug is placed for safe delivery. The ratio between drug
and matrix should be as high as possible.
Drug targeting is about enhancing the concentration of a drug at the site of action, so only at the place in the
body where you actually want the drug to have an effect. It is important to enhance the concentration of a drug
at its site of action:
To avoid side effects
To use expensive drugs more effectively
Less total dose
Higher concentration for a longer period of time
Protection from degradation and excretion
For an established drug molecule (e.g. doxorubicin)
For a molecule that otherwise could not be a drug (e.g. siRNA) → drug delivery
Drug delivery means getting the drug through the body to the site of action, so all the technology utilized to
present a drug to the desired body site where it can be released, absorbed and target the correct molecules.
Drug delivery in nanoparticle-based systems is limited by the amount of drug that can be loaded on a single
particle. In determining the best drug delivery strategy, there are certain things you need to consider for
optimal working. A minimal design to implement main functionalities (like targeting, uptake and release) is
useful, as this can move around the body much easier. No toxicity, stability in the body, and low production
costs are needed. Elimination of the targeting vehicle is a must, as you do not want the delivery system to
accumulate in the body (possible through secretion or break down). Lastly, compatibility with drug to be
targeted, so the delivery system can actually safely hold the drug until the site of action.
Barriers in drug delivery
The characteristics of each cell layer/membrane are organ-specific and depending on the route of
application/localization of the target different numbers of barriers have to be crossed. Most drugs start in the
GI and have to cross the epithelia to the blood. From there, another endothelia layer has to be crossed to enter
the cell and the cell membrane itself. Therefore, an important driver for nanomedicine development is the
more barriers can be crossed the more comfortable the route of application.
Types of capillary endothelia:
Continuous → skeletal muscle (containing many transport vesicles) and blood-brain-barrier
(containing few vesicles)
Fenestrated → endocrine glands, intestines, pancreas, glomeruli (diffusion of small proteins, 60 – 80
nm)
Sinusoid → bone marrow, lymph nodes, liver, spleen (30 – 40 μm)
For non-destructive transport, activation of intracellular processes is needed for permeation enhancement.
Paracellular transport can be enhanced through permeation enhancers for small molecules, but this is not an
option for nanomedicines. The classical approach is transcellular transport in which a drug is conjugated to a
metabolic cargo, like a vitamin, so the cell takes it in through a vesicle.
Drug delivery of nanomedicines across the blood-brain-barrier involves
transcytosis. Transcytosis is a form of specialized transport through which
an extracellular cargo is endocytosed, shuttled across the cytoplasm in
membrane‐bound vesicles, and secreted at a different plasma membrane
surface. Receptors to target are transferrin receptor (TfR), human insulin
4
