Download The dreams of targeted drug delivery

The dreams of targeted drug
delivery
Drug delivery
Drug (pharmaceutical agent, API)
chemical substances applied to body where they are metabolized and are
expected to have beneficial effect (in treatment, mitigation or prevention of
disease or facilitating repair of injury etc.)
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Conventional drug delivery
Problem:
lack of selectivity and missing control of the release
Targeting
efficiency: 0.01%
Non cotrolled delivery process. OK for low cost
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safe drugs and short term treatment.
Targeted drug delivery and controlled
release – ideal course
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Way to tissue/cells – carrier – targeting
Goal tissue/cells, way of the transport into
Goal tissue
or cells
Carrier
Biocompatibility?
How carrier recognises
the target
Kind of carrier
Biodegradability?
Targeting
Tools of transport
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Way to tissue/cells – obstacles
After the application into the bloodstream carrier is exposed
to quite a number of pitfalls:
Phagocytosis:
 the first step of phagocytosis is particles opsonization – binding of blood
serum proteins on the surface of particles
 the elimination (clearance) of so stained particles is very quick (liver 80-90%,
spleen 5-8%, bone marrow 1-2%)
 opsonization depends on: size, shape, surface charge and
hydrophilic/hydrophobic character of surface – small, uncharged and
hydrophilic particles are eliminated slowly
 protection of carriers: hydrophilization of surface – stealth carriers are used
(PEG, dextrans, liposoms, hydrophilic polymeric micelles)
 positive: up to 100x lower clearance
 negative: in some cases changes in interaction with receptors
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Way to tissue/cells – obstacles
Trapping by cell receptors:
typical mainly for carriers having on the surface biopolymers or other biological
active substances (liver, spleen)
hyaluronan interacts with HARE receptors in liver, very effective clearance
protection of carriers: probably saturation of liver receptors by hyaluronan
fragments
Elimination from bloodstream by kidney:
carriers having diameter ≤ 5 nm are removed into urine by filtration
protection of carriers: carrier diameter ≥ 5 nm
Recommended carrier diameter (hydrodynamic diameter) 5 (6) – 100 (200) nm
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Way to tissue/cells – obstacles
 Organ/tissue barriers:
 majority of organs/tissues protect their internal environment by various barriers
(exception – liver parenchym and several other tissues)
 barriers could be overcome directly by small lipophilic (steroid hormones) or
hydrophilic (glucose) substances if their concentration is high enough
(diffusion)
 blood-brain barrier (BBB) is one of the
most effective barriers
 for overcoming BBB – intranasal carrier
application is used, more effective is
combination of carrier with penetrating
peptides
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Way to tissue – EPR effect
 inflammed tissue – capillary fenestration: gaps
among endothelial cells (coats of capillaries)
 using these gaps, macromolecules, carriers and
immune cells can penetrate into the tissue
 it is possible to use this effect for carriers
transported into pathological tissue
 EPR effect could be amplified by the application
of inflammation eliciting/supporting substances
(TNFα)
 in solid tumours EPR effect is endorsed by
minimal lymphatic system – extension of acting
time of cytostatics in tumour
 despite the EPR effect, only roughly slightly less
than 1% of applied cytostaticum reaches tumour
EPR effect = enhanced
permeability and retention
effect
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Way to tissue/cells – carrier – targeting
Goal tissue/cells, way of the transport into
Goal tissue
or cells
Carrier
Biocompatibility?
How carrier recognises
the target
Kind of carriers
Biodegradability?
Targeting
Tools of transport
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Carriers
Carriers with effect on the whole system
 liposomes, polymersomes
 polymeric micelles
 microbubbles
 dendrimers
 synthetic/peptidic nanotubes
 pro-drugs
Carriers with local effect
 nano-fibres and micro-fibres
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Carriers
Liposomes, polymersomes:
 liposomes: most often spheroidal vesicles having a hydrophilic
core surrounded by lipidic bilayer similar to the cell membrane
which separates the inner part from its surroundings
 liposomes are made namely from natural or synthetic
phospholipids or their derivatives (self – assembling system)
 they are used namely for the transport
of hydrophilic substances,
hydrophobic could be transported
embeded into lipidic bilayer
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Carriers
Liposomes, polymersomes:
 polymersomes: amphiphilic diblock copolymers is used for the
formation of monolayers at the oil-water interface. After
evaporation polymer bilayers are formed
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Carriers
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Carriers
Polymeric micelles:
 polymers with one part being hydrophilic and second part being
hydrophobic (amphiphilic polymers) form in water polymeric micelles,
where hydrophobic parts form a core and hydrophilic shell
 hydrophobic drugs can be solubilized in the hydrophobic core while the
hydrophilic shell stabilizes carriers in water solution
 block copolymer or grafted polymers could be used for the formation of
polymeric micelles
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Carriers
Microbubbles:
 microbubbles are small (1-5 microns in diameter), lipid or albumin shelled
gas bubbles which are strong reflectors of sound
 due to the influence of ultrasound waves, collapse of the bubbles occurs
which leads to:
1. generation of high temperature in the core of bubbles
2. shock waves are generated able to
mechanically destroyed surrounding
tissue (support for better drug
penetration into tissue)
3. fragments of bubble wall carrying
active substances are, in principal,
micro-projectiles (shrapnel) able to
transport drugs into surrounding tissue
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Carriers
Dendrimers:
 polymeric substance prepared by chemical synthesis
 they are effective namely in nucleic acid (genes) and special substances
delivery
 active substances are incorporated/encapsulated into the structure where
they are stabilized by ionic interaction or by van der Waals forces
 size in tens of nanometres
 some of them show the problem with biocompatibility
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Way to tissue/cells – carrier – targeting
Goal tissue/cells, way of the transport into
Goal tissue
or cells
Carrier
Biocompatibility?
How carrier recognises
the target
Kind of carrier
Biodegradability?
Targeting
Tools of transport
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Carrier targeting via specific structures
on the cell surface
 for the „real“ targeting of drug, each carrier has to be furnished with specific
molecules able to recognise and bind to typical structures on the cell surface
Most common molecules are:
ligands for receptors
antibody against surface antigens
Drug
lectins
peptides
aptamers
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Carrier targeting via specific structures
on the cell surface
 cell receptors specific for certain molecules (hyaluronan – CD 44, mannose –
mannose receptor on macrophages, galactose –galactose receptor on
hepatocytes)
 monoclonal antibodies against cell surface antigens
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Carrier targeting via specific structures
on the cell surface
Lectins:
 groups of glycoproteins that bind specifically and reversibly to sugar moiety
 can interact with glycoconjugates present on the cell surface. The unique
carbohydrate specificities of lectins can facilitate carrier targeting.
Peptides:
 RGDXY peptide for interaction with integrins (specific integrin of cancer cells
αVβ3)
 binding sites on the surface of some cells pro specific peptide sequences
(NPNWGPR at melanoma)
Aptamers:
 synthetic oligonucleotides that bind to a specific targets such as small
molecules, proteins, nucleic acids, cells and carriers
 they reveal high specificity, affinity and thermal stability and low
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immunogenicity
Non-specific carrier internalization
Phagocytosis: non-specific internalization of largest particles (2 – 3 μm),
macrophages, dendritic cells
Pinocytosis: mechanism by which cells ingest extracellular fluid and its contents
(solubilized molecules, not particles)
Macropinocytosis: nonspecific internalization of smaller particles ~ 1 μm
Cell penetrating peptides: CPP (next page)
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Non-specific carrier internalization - CPP
Cell penetrating peptides:






group of peptides derived from peptides of viruses
peptides having as far as 30 amino acids
their primary structure is rich in arginine
non-immunogenic, low cytotoxicity
penetrates through cell membrane of different cells, do not invade their
structure and stability
they can transfer across cell membrane small molecules, biopolymers
and nanoparticles (carriers)
Penetratin: RQIKIWFQNRRMKWKK, Tat peptide: YGRKKRRQRRR, short CPP
peptide VPMLK,
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Biocompatibility and biodegradability
Biodegradability
 enzymatically or hydrolytically fully degradable material used for carrier
preparation
 fragments after degradation are metabolized or excluded from the organism
Biocompatibility
 it is the ability of material not to negatively influences processes running in the
tissue (not to initiate pathological processes)
 it is specific interaction between this tissue and that material (and its standard
impurities) and its exact form. It is very difficult to say that this material is
biocompatible without specification of tissue or cells
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Controlled drug release from carrier
External impulses
λNIR
Redox
Internal impulses
pH in cells compartments:
• physiological conditions
about 7.3-7.4
• cancer tissue about 6.5
• endosome about 5.5
• lysosome 4.6-5,5
Carrier contains enzyme
Carrier contains substrate
for enzyme
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„Classical carriers“ and theranostics
„Classical carrier“
Theranostics
 carrier is targeted into selected
tissue/cells
 carrier is able to release drug
by controlled manner
 drug release is controlled by
internal and external impulses
 carrier is targeted into selected
tissue/cells
 carrier is able to release drug by
controlled manner
 drug release is controlled mainly
by external impulses
 carrier is furnished by the system
for localization of its position in
the body and allowing to quantify
amount of theranostics in focused
tissue
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Theranostics
For someone a diagnostic agent
really informs about illness
development for others it is
system giving us the information
about carrier position and its
quantity in the body/tissue
 magnetic nanoparticles could
be used mainly for localization
and quantification of carriers in
tissue
 fluorescent substrate for
caspase 3 could be used
primarily for quantification of
apoptosis in the tumour tissue
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Theranostics
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Carrier from Contipro
C6+NR
Water
C6em
C18+NR
C18em
Oil
Carrier from Contipro
Thank you for your attention
NF-CZ07-ICP-1-040-2014: Formation of research surrounding
for young researchers in the field of advanced materials
for catalysis and bioapplications
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