DRUG DELIVERY STRATEGIES
NANOMEDICINE
− enhance the concentration of the drug molecule at its place of action:
o to avoid side effects
o to use expensive drugs more effectively → less total dose and higher concentration for a
longer period of time (protection from degradation and excretion)
o for an established drug molecule (e. g. doxorubicin)
o for a molecule that otherwise could not be a drug (e. g. siRNA)
− requirements:
o ability to synthesize and manipulate molecules → (bio-)chemistry
o structural and functional understanding of biology at nanoscales → microscopy/structure
analysis
o control of localization → delivery/targeting strategies
o generation of small structures → semiconductor technology/principles of molecular self-
organisation
− size:
o 80 - 200 nm
o too small → problems with endocytosis
o too big → only phagocytosis possible which not all cells are capable of
DRUG DELIVERY
− classical drugs:
o small organic molecules
o lipophilic enough to cross membranes (compatible with oral delivery)
o distribute mostly freely throughout the body
o act by inhibiting enzymes/receptors
− what is needed:
o protection from degradation,
o modifying pharmacokinetics → long circulation time
o tissue/cell targeting → decrease of side-effects, avoidance of drug resistance
− requirements:
o minimal design to implement main functionalities → as simple as possible to make it in large
scale)
o toxicity
o stability → secretion vs. break-down
o compatibility with drugs → hydrophilicity
o protective matrix
o production costs
o intracellular trafficking (in only a few cases)
o targeting functionality
,− delivery routes:
BARRIERS
− the more barriers can be
crossed the more
comfortable route of
application → pill vs.
injection
− organ-dependent:
o continuous capillaries – skeletal muscle vs. blood-brain barrier → many vs. few transport
vesicles
o fenestrated capillaries – endocrine glands, intestines, pancreas, kidneys
o sinusoid capillaries – bone marrow, lymph nodes, liver, spleen
− cellular barriers:
o for non-destructive transport, there is no permeation enhancement without activation of
intracellular processes
o paracellular:
o tight junction proteins interacting with each other → controlling the tightness of the
junction
o Ca2+ signals induced → change in the protein conformation → less sticky proteins
o permeation enhancers → not an option for nanomedicine (too large)
o transcellular:
o cell surface receptors
, o conjugation of a drug to a metabolic cargo (vitamin B12) which binds to the receptor
o hijacking a transport system
− blood-brain-barrier:
o coupling the medicine to a
liposome which binds to the
transferrin receptor (TfR), human
insulin receptor (HIR) or LRP →
transcytosis
o can lead to less transferrin
import → side effects
o the affinity of the targeting
ligand must not be too high →
otherwise no release and no
transcytosis
TARGETING STRATEGIES
− tissue/cell-specific ligands: antibodies, Fab, single chain antibodies, peptides, small molecule ligands
− environment-dependent enrichment – pH, enzymatic activities
− tissue structure – EPR effect
− EPR effect
o enhanced permeation and retention in tumours
o molecules tend to accumulate more in tumour tissue rather than normal tissue
o result of rapid vascularization
o absence of lymphatic drainage does not promote extravasation (fluid leakage) → only
transport through diffusion (inefficient)
− active targeting:
o a receptor binding the drug
o antibody targeting the drug to the tumour
o randomly diffusing through the tumour, but higher retention
− drug delivery vehicles:
o nanoparticles – lipid and polymer based
o conjugates – antibodies and receptor ligands
− liposomes:
o aqueous core with a membrane bilayer coat
o passive targeting
o doxorubicin: used for chemotherapy, greatly enhanced plasma half-life, high peak
concentrations can be avoided reducing cardiotoxicity, however, it can’t reach tumour cells
while in a liposome (almost nothing is released into the cell)
o advantages:
o increased efficacy, therapeutic index, and stability of the encapsulated drug
o avoidance of side effects/toxicity
o improved pharmacokinetics due to slower release
o high flexibility
NANOMEDICINE
− enhance the concentration of the drug molecule at its place of action:
o to avoid side effects
o to use expensive drugs more effectively → less total dose and higher concentration for a
longer period of time (protection from degradation and excretion)
o for an established drug molecule (e. g. doxorubicin)
o for a molecule that otherwise could not be a drug (e. g. siRNA)
− requirements:
o ability to synthesize and manipulate molecules → (bio-)chemistry
o structural and functional understanding of biology at nanoscales → microscopy/structure
analysis
o control of localization → delivery/targeting strategies
o generation of small structures → semiconductor technology/principles of molecular self-
organisation
− size:
o 80 - 200 nm
o too small → problems with endocytosis
o too big → only phagocytosis possible which not all cells are capable of
DRUG DELIVERY
− classical drugs:
o small organic molecules
o lipophilic enough to cross membranes (compatible with oral delivery)
o distribute mostly freely throughout the body
o act by inhibiting enzymes/receptors
− what is needed:
o protection from degradation,
o modifying pharmacokinetics → long circulation time
o tissue/cell targeting → decrease of side-effects, avoidance of drug resistance
− requirements:
o minimal design to implement main functionalities → as simple as possible to make it in large
scale)
o toxicity
o stability → secretion vs. break-down
o compatibility with drugs → hydrophilicity
o protective matrix
o production costs
o intracellular trafficking (in only a few cases)
o targeting functionality
,− delivery routes:
BARRIERS
− the more barriers can be
crossed the more
comfortable route of
application → pill vs.
injection
− organ-dependent:
o continuous capillaries – skeletal muscle vs. blood-brain barrier → many vs. few transport
vesicles
o fenestrated capillaries – endocrine glands, intestines, pancreas, kidneys
o sinusoid capillaries – bone marrow, lymph nodes, liver, spleen
− cellular barriers:
o for non-destructive transport, there is no permeation enhancement without activation of
intracellular processes
o paracellular:
o tight junction proteins interacting with each other → controlling the tightness of the
junction
o Ca2+ signals induced → change in the protein conformation → less sticky proteins
o permeation enhancers → not an option for nanomedicine (too large)
o transcellular:
o cell surface receptors
, o conjugation of a drug to a metabolic cargo (vitamin B12) which binds to the receptor
o hijacking a transport system
− blood-brain-barrier:
o coupling the medicine to a
liposome which binds to the
transferrin receptor (TfR), human
insulin receptor (HIR) or LRP →
transcytosis
o can lead to less transferrin
import → side effects
o the affinity of the targeting
ligand must not be too high →
otherwise no release and no
transcytosis
TARGETING STRATEGIES
− tissue/cell-specific ligands: antibodies, Fab, single chain antibodies, peptides, small molecule ligands
− environment-dependent enrichment – pH, enzymatic activities
− tissue structure – EPR effect
− EPR effect
o enhanced permeation and retention in tumours
o molecules tend to accumulate more in tumour tissue rather than normal tissue
o result of rapid vascularization
o absence of lymphatic drainage does not promote extravasation (fluid leakage) → only
transport through diffusion (inefficient)
− active targeting:
o a receptor binding the drug
o antibody targeting the drug to the tumour
o randomly diffusing through the tumour, but higher retention
− drug delivery vehicles:
o nanoparticles – lipid and polymer based
o conjugates – antibodies and receptor ligands
− liposomes:
o aqueous core with a membrane bilayer coat
o passive targeting
o doxorubicin: used for chemotherapy, greatly enhanced plasma half-life, high peak
concentrations can be avoided reducing cardiotoxicity, however, it can’t reach tumour cells
while in a liposome (almost nothing is released into the cell)
o advantages:
o increased efficacy, therapeutic index, and stability of the encapsulated drug
o avoidance of side effects/toxicity
o improved pharmacokinetics due to slower release
o high flexibility
