Polymers Flashcards
what’s a polymer? poly + mer
Chain of repeating units: each repeating unit is a monomer (natural/synthetic)
what is meant by degree of polymerisation?
number of monomer units in a polymer
whats a dimer?
2 monomer long polymer
whats an oligomer?
(in between region. Have long chain but not sure hm units): tetramer < oligomer < polymer
how is polymer written, with degree of polymerisation?
(monomer)n degree of polymerisation as subscript. Brackets important
name a natural polymer produced in body, therapeutic agent
heparin
whats the monomer of polymers DNA, RNA?
nucleic acid
proteins are polymer sof…
amino acids.
Don’t always know hm. Removing one doesn’t affect whole behaviour but 3D structure: have size and shape and colloidal structure
polymers: application in formulation
suspending agents
semi solids
mucoadhesion
MR
tablet manufacture
plasticisers, solvents
capsule shell
emulsifiers
polymers used in formulation as suspending agents… what do they enhance?
and give examples of some used
viscosity enhancers
- polysaccharides: acacia, tragacanth, alginates, starch
- celluloses
when may polymers be used in tablet manufacture?
o Disintegrants and binders (starch, cellulose and derivatives, PEG, PVP)
o Coating (cellulose, methacrylate derivatives)
other than in formualtion, what else are polymers used for?3
packaging (plastics, rubber, apper cellulose)
adhesives (transdermal patches)
tubing
and more!
polymers as therapeutic agents: name 3 applications
sodium polystyrene sulfonate (Resonium A)
poly(ethylene glycol) (Movicol)
artifical tears
what is sodium polystyrene sulfonte (resonium A), an ion exchange resin, used in the treatment of?
hyperkalaemia
sodium polystyrene sulfonte (resonium A) administration route?
oral/ rectal
what can the high molecular weight polymer known as polyethylene glycol/ movicol be used to treat?
constipation as hydrophilic polymer, attract water, soften stool 😊
what is meant by linear polymer in terms of morphology?
no branching, straight line of Cs with no modifications along the line
what is meant by homopolymer?
chain composed of a single monomer
give one example of a polymer that is both a linear polymer and a homopolymer?
polyethylene glycol
what is meant by copolymer?
chain composed of 2+ monomers
3 types of copolymers?
statistic: poly(A-co-B)
alternating: (A-alt-B)
block: poly(A)-block-poly(B)
what is meant statistic poly (A CO b)?
random arrangement, 2 monomers have the same reactivity
(co: copolymer)
what is meant by poly (a alt b)?
organised in particular alternating order
not random. ababababababab
what is meant by poly (A) block poly (B)?
polymer a attached to polymer b such as in the case of polymeric micelles
as want hydrophobic region attached to hydrophilic
clear regions/blocks
Non-linear/ branched morphologies of polymers?
Graft
comb
Star-shaped
graft copolymers or comb polymers are an example of non linear or branched morphologies and follows rhe backbone of a comb structure. whats the difference?
graft: polymers diff sides
comb: polymer branching same side
what type of polymer would a poly (A) graft poly (B) be?
graft
how do star shaped polymers (star poly (A) or star poly (A co B) or star poly (A) block poly (B) look?
one centre (initiator) with many arms coming from it
dendrimers are a specific type of polymer that have a naturally spherical shape due to the shape of the branches and is hard to get perfect without any structural defects. the MORE you expand are you MORE/ LESS likely to introduce defects?
more
sometimes the functions on a dendrimer may not all react, when/why?
when too close together, not accessible
dendrimers are similar to what type of polymer and how?
Same as star, start with max functions initiator. E.g. 3 then monomer, each functions modified. From 3 -> 6 functions. 1st generation (grown out of initiator)
dendrimers are attractive for drug delivery because?
every functional group on surface can be used to conjugate drugs- chemically attract to dendrimer structure
why might drug loading be hard in a dendrimer?
not much space and not every function may be able to accomodate a drug if it interacts with water or is ionised
the risk of dendrimers not having many available chemical functions or breaking down during synthesis means it is challenging to use as?
DDS
elemental analysis and NMR can be used to confirm what about a polymer?
composition/structure
would the addition of PEG in a polymer make it part of the hydrophilic or hydrophobic portion?
hydrophilic, as it hides the hydrophobic matrix
Same for liposomes… (PEG) put on surface to hide lipids and body doesn’t see hydrophobic stuff as doesn’t like it and tries to remove it as bacteria and viruses have it… signals saying its dangerous and attack.
- Most nanomeds are hydrophobic so if want to inject in body, have to mask hydrophobicity, usually with PEG
- Attaching/ coating with PEG (PEGylation) decrease risk of
…
immune system recognising particle
what type of chromatography can be used for molecular weight determination for polymers ?
size exclusion/ gel permeation (SEC or GPC)
For SEC/GPC what considerations must be made for solvent selection?
must dissolve sample, no incompatibilities, no interference with sample, not corrosive
for SEC/GPC what does the column depend on?
solvent, sample and adequate for mw range
outline how SEC/GPC works?
sample injected, size separation, large solutes, small solutes eluted as they go into all nooks etc
star shaped polymers are constrained and cannot expand or contract as much. if using linear standards to study a star shaped polymer what effects might this have on your results?
results invalid as GPC wont account for this
in SEC/GPC, which polymer chain sizes go furthest and which stay behind?
Smaller polymer chains stay behind as theyre exploring and going into nooks and crannies
Larger polymer chains: elute faster. Detected first in GPC spectrograms (first, big curve C)
MW data analysis of polymers, how is this done/ results obtained?
Calibration relative to monodisperse standards of known MW
* Elution times compared to a standard curve
* Standard curve used to analyse similar polymers with known MW then look at signal and retention times get for unknown sample and compare to known curve
* Separation based on dimensions not affinity
star shaped polymers are essentially constrained and cannot expand or contract as much. if using linear standards to study a star shaped polymer what effects might this have on your results?
results invalid as GPC wont account for this
why must you select mobile phase carefully when characterising?
- Conditions really important could be looking at same polymer but different results depending on morphology of polymer OR mobile phase used
wrong solvent may –> no results
Polymers MW determination….
polymers are rarely monodisperse meaning that there will be mixture of molecular weights due to different chain lengths.
how is MW therefore given?
as an average
what is meant by Mn?
number average molecular weight
what is meant by Mw?
weight average molecular weight
As well as Nm, MW can be given in terms of weight average (Mw). What does this account for?
increased contribution of larger molecules to the overall total weight
formula for PI? polydispersity index
Pi= Mw / Mn
what is meant by polydispersity index?
width of MW distribution
if the gap between mw and mn is narrow, will polydispersity be higher or lower?
difference is smaller, values closer to each other, Pi smaller
what will higher Pi look like on the MW distribution graph?
narrower peak, to the right
Polymer characterisation- thermal properties…
how are they measured?
using Differential scanning calorimetry (DSC)
what does DSC tell us?
crystallinity of polymers
3 types of crystallisation a polymer can be/have?
amorphous
semi crystalline
crystalline
what is meant by amorphous?
lack of rigid organised network
what is meant by crystalline?
very structured network
most polymer chains are either amorphous or semi crystalline, true or false?
true
what is meant by differential?
comparison between sample and reference
what is meant by scanning?
study at a range of temperatures cooling and heating
what is meant by calorimetry?
measuring the amount of heat required to keep reference and sample at the same temperature
in DSC, when Reference going through different transitions: some will be….
- no change in heat capacity
- exothermic
- endothermic
what type of diagram shows heat flow on the y axis and temperature on the x axis that can show different transitions that can be observed?
thermogram
polymer characterisation: DSC output of method of analysis- results shown on a?
thermogram
how many different transitions are there on a thermogram? name them
3:
Tg
Tc
Tm
what is the first transition on the thermogram?
Tg glass transition temperature
which transition has no change in heat capacity but instead a change in the baseline? There is no exchange of heat therefore it cannot be said to be exo or endothermic.
phase 1 : Tg
In Tg polymer chains are reorganised, what effect does this have in the polymers?
polymer goes from hard brittle material to soft and pliable material so increase in flexibility of chains
TRUE OR FALSE: Tg can be detected for amorphous and semi crystalline polymers? only
true
would a perfectly crystalline structure show Tg in its thermogram?
no
once chains have regained flexibility they can organise themselves into an organised network. What transition is this?
2: Tc
what parameter must be present in order to see Tc on a thermogram?
some degree of crystallinity
Tc can be observed for which 2 types of polymers?
semi crystalline and crystalline
crystallisation is exothermic so it will release heat, therefore it the amount of heat that the sample requires to keep it the same as the reference higher or lower?
lower
why there is a trough around Tc in a thermogram?
sample releases heat during crystallisation to amount of heat supplied to sample must be lower to be kept at the same temperature as the reference
Tm (melting) is the destruction of the crystalline network which happens at a temperature above the temperature for crystallisation. This can be observed for which types of polymers?
crystalline and semi crystalline
melting is an endothermic process which means that it absorbs heat therefore will more or less heat need to be provided to the sample to ensure that it is kept at the same temperature as the reference?
more
why is a peak seen around Tm on thermogram?
providing extra heat to sample to keep it at the same temperature as the reference
Polymers as DDS (polymer drug conjugates)…
4 diff polymers in nanomedicine?
water soluble polymer drug conjugates
polymeric micelles
polymer nanoparticles + nanocapsules
polymeric vesicles
what type of polymer drug conjugate may be used to deliver poorly water soluble drugs?
water soluble polymer drug conjugates
i.e. just attach drugs to hydrophilic water soluble backbone
Polymeric micelles: Core-shell structures similar to surfactant micelles, obtained from what?
amphiphilic (typically block) copolymers or star-shaped
Polymeric nanoparticles: solid matrix polymer particles made up of…
- Hydrophobic polymer matrix for hydrophobic AND hydrophilic drugs
what are polymer nanocapusles?
mono layer membrane surrounding aq liquid core
Polymeric vesicles are similar to with liposomes how?
Like liposome where liquid core. Can be oil or water (with liposomes. restricted)
But here depends on properties of polymer using
wha tdo polymersomes (polymeric equivalent of liposomes) consist of and made of?
Aqueous core surrounding by hydrophobic polymeric shell (bilayer)
made using amphiphilic copolymers
with DDS, drug is hidden in nanoparticle then after admin, what happens depends fully on?
DDS. Control kinetics of dosage form
give some properties of an ideal drug carrier/ DDS?
inert,
non toxic,
slow clearance,
high loading,
targeted,
active,
stable,
release
why do we do nanomedicine?
want to make pk such as elimination abs etc independent of physio chemical properties of the drug
polymer drug conjugates have a water soluble backbone. if a linear one is used it is limited to the addition of only x drugs?
2
why do we need the backbone to be water soluble?
improve aq solubility for drugs like anti cancer drugs that are poorly water soluble
what type of polymer often used as main backbone w chains in case of polymer drug conjugates?
GRAFT
main backbone with chains. Can each be used to attach drug/ attach probe for imagine (diagnostic purposes)
what type of polymer often used as main backbone w chains in case of polymer drug conjugates?
GRAFT
main backbone with chains. Can each be used to attach drug/ attach probe for imagine (diagnostic purposes)
what does drug conjugation on polymers/ water soluble backbone allow?
controlled (site specific) delivery
why is it important to have a backbone with modifiable chemical functions?
cooh and amino functions allow modification to allow a new bond with a drug or imaging agent
why is it important to have a backbone with modifiable chemical functions?
cooh and amino functions allow modification to allow a new bond with a drug or imaging agent
the backbone can have a targeting moiety, waht is the rationale behind this?
goes to specific cell or tissue, increased specificity, reduced adverse effects
the backbone can have a targeting moiety, waht is the rationale behind this?
goes to specific cell or tissue, increased specificity, reduced adverse effects
do polymer drug conjugates have high or low mw ?
high
do polymer drug conjugates have high or low mw ?
high
why do we need high enough MW of chain of polymer drug conjugates?
so its not eliminated fast by kidney filtration. Limit to what kidney can eliminate (that’s why no albumin in urine large molecules unless problem)
the polymers (water soluble backbone) for drug conjugation can be…
neutral
cationic
anionic
neutral polymers such as PEG can be used for backbones but what is the setback?
linear so limits drug loading
HPMA and dextran better
name a cationic polymer that can be used as a carrier?
polylysine
name 2 anionic polymers that can be used as carriers?
polyaspartic and polyglutamic acid
what to think about when choosing a polymeric carrier for drug conj?
charge of polymer, electrostatic reactions…
ideal properties for some polymers for polymer carriers?
biodegradable,
biocompatible,
large enough to avoid kidney excretions
have sufficient number of modifiable functions
why do we want polymer carriers to be biocompatible?
so they don’t have problem that theyre in body or stay in body for a long time
why are star shaped polymers and dendrimers better than linear for polymer drug conjugates?
more functions for more drug loading
only true requirement for polymeric carriers?
is water solubility: PEG is able to get away with it!
are hmpc and peg biocompatible or biodegradable?
biocompatible
most polymer drug conjugates are given by what route of admin?
IV
directly in blood compartment form which they will distribute… can be to tissues/ site of action/ non specific site.
what is meant by passive targeting
relies on properties of nanomedicine and effect of disease??
what is meant by enhanced permeation vessels and how can this aid nanomedicine for cancer?
tumours make poor blood vessels with large pores that can encourage nanomedicine to accumulate in tumour area
why is nanomed retained to tumour for a long period of time?
lymphatic drainage not working well so takes a while for it to be removed in cancer patients
epR (retention)
micelles injected in the blood can enter tumors passively due to what effect?
EPR
kidney pore size?
5nm
when you inject a polymer drug conjugate into blood circn IV, what 2 things might happen?
elimination (renal filtration/ metabolised and degraded by enzyme. Lose polymer)
OR accumulation in the tumour: EPR effect. Gets rid of it too. Want 😊
why is the size of polymer we use for conjugation therefore important?
NOT MW, but hydrodynamic size
as we want EPR effect: polymer to tumour not just renal excretion and elim
if polymer drug conj is SMALLer than pore size what happens?
can distribute in tissues we don’t want it in ☹
why cant we only rely on passive targeting or EPR effect for all cancers?
EPR effect not found/strong in all cancers
why are polymer drug conjugates internalised by cells when they take in water?
water soluble
glomerular filtration of PDC from blood, whats the limit in size?
30-50 kDa
removal of PDC by body’s defences (by MPS) more likely for what nanoparticles?
large
hydrophobic (not PDC)
or charged.
3 types of elimination possible for PDC?
glom filt
removal by bodys defences: MPS
polymer degradation (enzyme)
whats MPS and RES?
M = Mononuclear
P = phagocyte
S = system
R = Reticulo
E = Endothelial
S = system
MPS/RES
Responsible for pattern seen for…
DDSs administered IV
Macrophages main component of MPS. Part of innate immune system so don’t differentiate.Looking for what mols/patterns?
very specific patterns… big, positive, hydrophobic = will be recognised by MPS and removed.
With nanomedicine, that interaction (with MPS) leads to what?
accumulation in liver and spleen. Be careful about properties of nanocarriers and size to miinimise accumulation in organs
from the blood, PDC may be accumulated within …(2)
-healthy tissue
-tumour vicinity
how may PDC be eliminated form blood, and accumulated into healthy tissue?
through capillary fenestrations/ discontinuous capillaries (2-6nm pore size) just be bigger
then removed by lymphatic system, returned to blood circ
how may PDC be eliminated from blood, and accumulated into tumour vicinity?
EPR effect!
inc sizes of pores in tumour caps
bad lymphatic drainage
efficiency depends on vascularisation and blood flow
MoA for PDC to become internalised by cell?…..
healthy tissue stay in drug circulation, once come close to tumour, come out and taken up by cancer cells. Released and have pharmacological activity
PDC are water soluble so will get into cell, unless put something on surface that binds to a receptor… will be taken up at same time cell shrinks.
So when theyre taking fluids water, PDC will just be solubilised in that water and will be internalised by cell.
If polymer not degraded, it can accumulate for long time in cells.
Other factors affecting accumulation/elimination?
- Polymer flexibility and morphology
- Decreased renal filtration and increases circulation times
how does Polymer flexibility and morphology affect accumulation/elim of PDC?
Improved accumulation for rigid, tubular polymer chains
-These pass through larger tumour pores more efficiently (smaller than size of polymer)
-Easier to shrink all, not just one strand and pull rest through. Harder to get half through at first but then easy to get rest in.
how does Decreased renal filtration and increases circulation times affect accumulation/elim of PDC?
Spherical, rigid polymers vs. elongated flexible polymers
-Harder for arborescent, rigid polymers to deform
Summary
Efficacy as a cancer nanomedicine will depend on its ability to:
-avoid X,Y,Z
-accumulate in…
-and importantly….?
- Avoid renal filtration and degradation
- Avoid accumulation in healthy tissue
- Avoid removal by immune defences
- Accumulate in the tumour tissue
…AND OF COURSE RELEASE THE DRUG IN AN ACTIVE FORM!!!!!
Polymeric micelles…..
polymeric micelles are core-shell nanostructures formed by what?
amphiphilic polymer chains above a minimum polymer conc, in a solvent selective for either moiety
2 types of polymer micelles?
Conventional micelles: water-soluble type Reverse micelles: oil-soluble type
conventional micelles are the water soluble type. What can they used in the delivery of?
hydrophobic drugs! and polyionic therapeutic macromolecules
reverse micelles are oil soluble and can be used to deliver?
water soluble macromolecules
what type of micelles have a
- hydrophobic core
- hydrophilic core
- conventional
- reverse
reverse micelles have a hydrophilic core and can solubilise peptides in oil. useful why?
useful as peptides unstable molecules. Dissolve in oil to increase stability and control release
what are conventional micelles used for?
delivering hydrophobic drugs in their hydrophobic core, mainly for
- gene therapy and DNA uses
micelles can be further classified into what 2 types?
multimolecular
unimolecular
polymeric MULTImolecular micelles have a hydrophobic core for drug encapsulation.
they can be biodeg or not,
ionisable or neutral.
are they semi crystalline or amorphous?
can be both
depend son nature of polymer used
multimolecular micelle hydrophilic shell is often made of PEG why?
as it needs to be quite dense and rlly good at fully hiding the hydrophobic core
??
what type of polymers form a micelle?
If you have block copolymers coming together
Lot of different polymer chains coming to form micelle
unimolecular micelles: doesnt take minimum conc to make, why?
as have readymade micelle?
(Hydrophobic centre and modify and attach hydrophilic chains so outside in hydrophilic
Single molecule)
hydrophilic shells for polymeric micelles are generally made of?
PEG
Core forming polymers - Core forming block should be…
-biodegradable but at least biocompatible/inert
-hydrophobic enough to interact w drug (affinity)
how may a core forming polymer be made hydrophobic enough to interact w drug-affinity?
though interaction w drug
to load into micelle core
core forming polymers can be arranged as….
-Attached at end of chain… block copolymer
-Distributed along the chain… graft copolymer
As long as you have distinct regions.
main difference w core forming polymers?
= density of shell (hydrophilic region). Can pack more micelles but other can bend etc.
name the 3 biodegradable polyesters moieties?
PLGA
PCL
PDLLA
(check structures!p104)
name the other common hydrophobic moieties that may be used?
DSPE: long chain lipid
PPO
Vit E derivatives (not technically a polymer)
can attach PEG chain
shell forming block: Common hydrophilic moieties?
PEG!!
HO /[O \/\ ] OH
n
properties of PEG?
flexible hydrophilic barrier
steric stabilisation
stealth properties
active targeting
PEG has stealth properties …meaning?
dec interaction w blood proteins
inc circulation times
what is meant by stealth of peg?
well hydrated so buffer zone created between NP and physiological env, ensuring nothing interacts with nanomedicine hydrophobic part
advantages of polymeric micelles?
solubilisation of hydrophobic drugs,
protection of loaded drug,
solubilisation via complexes,
small size,
colloidal solution so easy to detect precipitates
why is it easy to detect precipitates of polymeric micelles?
as not soluble in water. All others: cloudy. With micelles: can get clear… detect issues quickly
how does sterilisation of micelles occur?
due to small size, ster. by filtration
EPR effect
long circn times
disadvantages of polymeric micelles?
unstable
prep needs organic solvents
what types of instability do polymeric micelles display?
thermodynamic and kinetic
if micelles diluted below critical micelle conc that we have it will fall apart meaing drug is released straight away and pk depends on properties of drug now, is this concept kinetic or thermodynamic?
* Dissociation at C < CMC
thermodynamic
amorphous polymers are super flexible and can be formed easily, if there is some crystalline character that means some parts are rigid that form a network and cause polymeric micelle instability. is this concept thermodynamic or kinetic?
kinetic
whats is (polymeric) micellisation driven by? 3 possible forces
Hydrophobic
Electrostatic
Metal coordination
describe micellisation through hydrophobic forces
Between core + insoluble drug (not happy to be in water, wants to be in core) protection from water. Naturally more stable for amphiphilic polymer chain and happy
o Solubilisation of the drug inside the core
o Physical/chemical drug loading
describe micellisation through electrostatic forces e.g. polyion complex micelles
o Separately, polymer doesn’t look hydrophobic. E.g. PEG with a polylysine (water soluble). As a whole will be water soluble
o Polylysine +. If bring – drug, +- go together, now hiding whats making polylysine water soluble. Losing charge. Solubility of the polylysine will decrease. Also: now attached big chunk of water insoluble molecule. Will make polylysine block more hydrophobic = after attached drug, will want to form micelle and go inside micelle core
o Block copolymers where one block is ionisable
describe micellisation through metal coordination e.g. platinum drug micelles
same as with electrostatic…
Start with polymer with lots of COOH functions, water soluble 😊 once coordinate platinum, lose some water solubility, convinces polymer to assemble into micelles
2 types/ methods of drug encapsulation?
chemical conjugation
!! physical methods eg direct encap
chemical conjugation of drug encapsulation involves what type of binding of drug to core-forming polymer?
covalent
drug encap- chemical conjugation, what is release of drug form core-forming polymer controlled by ad what to remember?
Release controlled by degradation rate of the bond
Basically create new chemical function and attach drug to hydrophobic segment so it will be inside core
!do want drug to be released. Needs to be a chemical function that can be degraded eventually
2 methods of preparation of polymeric micelles?
dialysis method
emulsion method
which method of preparing polymeric micelles:
no chemical bond more about affinity.
start with ethanol/ acetone and put into dialysis bag. water comes in and replaces the solvent coming out- drives micelle formation and neither hydrophobic segment or drug want to be in contact with water
dialysis
which method of preparing polymeric micelles:
similar to other. have polymer in water w organic solvent- core happy to expand and swell a bit, letting drug diffuse in.
remove organic solvent and core collapses with drug inside micelle.
(just understand: balance of affinity and how to use that to load drug)
emulsion
how is a film formed after micellisation?
polymer dissolved with a volatile organic solvent, this evaporates and film rehydrates
what can sonication: drug encapsulated using ultrasonic probe, do?
increase drug loading or force chains to create more spaces for drug
what causes electrostatic interactions between PEG and DNA?
the opposite charges:
PEG +
DNA -
when PEG and DNA interact and neutralise, they will become more hydrophobic and self assemble into micelles and same for:
coordination micelles with Pt.
need COOH funcitons!
Polyion-complex micelles: PEG +
ionisable moiety
coordination micelles
with platinum, you need COOH functions specifically + that can coordinate Pt but once interacting with it, becomes hydrophobic and form core of micelle.
Polyaspartic acid and polyglutamic acid used why?
have COOH on side chain rather than other aas that have one on end.
polymeric micelles are characterised on what 3 things?
aggregation number
particle size
surface charge
why are neutral micelles preferred?
immune system and charge can create stability issues in blood with electrolytes
+ is good if conjugating DNA to it else avoid as sticks everywhere… toxicity
- Fine as long as stability not too much of issue…with some liposomes, can use – to target them to macrophages if these cells you want targeted for specific disease
how do you find aggregation number of polymeric micelles?
from determination of MW of the micelles
to find particle size of polymeric micelles?
light scattering microscopy LSM
but low amount of light is scattered if small
whats used to find surface charge of polymeric micelles?
zeta potential
Polymeric micelles classification:
Micellisation is the Transition from unimeres to micelles and occurs at?
minimal polymer conc (must be known!)
the micellisation transition not as clear cut as surfactant why?
low surface active properties.
the micellisation transition not as clear cut as surfactant why?
low surface active properties.
micellisation linked to…
stability
polymeric micelles classified on drug loading and entrapment efficiency. whats the difference?
drug loading = amoutn of drug encap inside micelles
entrapment efficiency = how effective the loading method was
drug loading DL =
amount of drug/ amount of formulation
drug loading DL =
amount of drug/ amount of formulation
entrapment efficiency EE% =
final amount drug in nanocarrier /initial amount drug added
polymeric micelles have a PK similar to?
PDC
micelles hydrophilic and behaves like hydrophilic fluid.
shouldnt have many issues w immune reaction as long as?
core hidden well
what do polymeric micelles benefit from (system) and when are they taken in?
EPR effect
in at same time as cells taking water and fluids
the 2 types of stability w polymeric micelles = CAC (critical aggregation conc) and kinetic.
what are each related to?
CAC: depends on properties of core. how long hydrophobic segment is etc. can be affected by drug loading as introducing hydrophobic and poorly water soluble thing
kinetic: fluidity and flexibility of core. core viscosity, how easily it flows. more visous core = more struc, more slowly micelle will break apart
what type of stability:
Not relly looking at nature of environment (if hydrophobic/ philic)
Looking how viscous core is… some molecules can interact and form dimers… easier to do if next to each toher/ close by
kinetic
can measure kinetic stability of polymeric micelles using FRET or fluorescence quenching.
what does FRET depend on to work?
distance between probes
If close enough, will excite CFP, which will excite venus and emit light and able to detect signal at 528
Where signal coming out will tell if micelle still in one piece or fallen apart
Kinetic stability of micelles: Fluorescence quenching
Quenching of the signal inside the micelles, Signal differs based on what?
if in high or diluted conc
Dissociation detection (micelle come apart) through an increase in the signal or local conc just high
micelles have other stabiliity issues too. they are only as good as their…
shell.
micelles need a dense shell to really hide the hydrophobic core. If not hidden well, anything can happen usually in blood because of serum proteins. Come in, go to core, remove dr and cause what?
Destabilisation by serum proteins
3 different possible stability/ destabilistaion of polymeric micelles?
- Drug extraction (A)
- Protein adsorption (B)
- Protein entering the core (c)
o System is recognised by immune system… can completely destabilise micelle, break apart and release drug prematurely, so need good dense shell so well hydrated and core completely hidden
o Opsonisation and complement activation
= what type of micelle destabilisation?
protein adsorption (B)
destabilisation of polymeric micelles * Can be influenced by the HLB: Efficacy of hydrated shell
or?
Destabilisation in presence of salts
-If core not hidden, will behave as hydrophobic colloid and will have salting out? Micelles will end up precipitating, if happens in blood hugely problematic
3 ways drug can be released from micelles?
- Diffusion… impact of affinity for core-forming block
- Degradation
- Dissociation
drug release from micelles at site of action: 2 diff emthods?
- Endocytosis
- Extracellular/ intracellular release (triggered or no) - Possible pharmacological activity of unimers???
Internalisation/ release?
p109
do want drug to come out, example
Micelles circulate in blood vessel, come close to tumour, comes out of circulation, taken up by cell, inside cell will release drug.
Can control so happens at specific pH and location inside cell
PDC: selection of a linker….
selecting a linker is the final element of design for PDC.
why is it used?
Initially: would use chemical functions along water soluble backbone to attach drug or targeting moiety
Often drug not attached directly to polymer backbone.
Linker used to act as a bridge between drug and backbone
en selecting a linker to attach drug to polymer backbone, what should it ideally prevent, and enable?
prevent premature release in blood (be stable)
enable specific drug release at site
Non-biodegradable linkers should be avoided because?
they make drug release step harder
give 2 examples of environment-sensitive linkers
(pH-sensitive)
esters and hydrazones
pH-sensitive linkers will degrade under what conditions?
acidic
what causes degradation of pH-sensitive linkers? and where?
acidic conditions
PDC enters cell + will be trapped in endosome that will mature -> lysosome + get decrease in pH.
This could breakdown ester/ hydrazone linker and release drug. But environment outside tumours also more acidic than extracellular environment in normal healthy tissues = risk: if pH low enough, get some degradation of pH sensitive linkers outside cell. Then if anything affects ability of drug to accumulate inside cell, this can impact pharmacological activity of drug. If want to avoid drug release outside cell, go for linker….
linkers are also senstive to intracellular enzymatic degradation. what does this exploit?
Again exploiting transition from endosome to lysosome where you have increase in enzymatic activity and these can break down linkers obtained from specific combination of aas.
- Gly-Phe-Leu-Gly
- Ala–Leu-Ala-Leu
on amino acid chain (linker), attach drug at one end and other to polymer backbone.
completely stable in blood circn, when will it get broken down to release drug?
only when PDC gets into cell
hydrazone linker structure?
NH2
/
N
II
C
/ \
R1 R2
dendrimers have multiple surface functionalities and allow…3
o Active targeting
o Drug binding
o Labelling to follow in body
due to the way generations grow, whats the shape of dendrimers?
spherical
dendrimers: small size of <10nm.
whats the problem if structure is too small?
get elimination by kidney OR AND accumulation in healthy tissue as dendrimer may be smaller than pores in blood vessels
dendrimers are difficult to synthesis as increasing generation num above certain limit introduces defects in structure.
what makes this easier?
Commercially available – can buy
PAMAM dendrimer conjugates are an example of what?
dendrimer used as PDC
what 2 types of linkage can you get for synthesis of G4-NH2–ibuprofen conjugate?
amide (amino function)
ester (pH sensitive)
for synthesis of G4-NH2–ibuprofen conjugate with amide linkage, what can you attach the drug (ibuprofen) directly to?
amino function (the modifiable bit)
COOH reacts with amino –> amide bond made between drug and dendrimer
for synthesis of G4-NH2–ibuprofen conjugate with ester linkage, what can you attach the drug (ibuprofen) directly to?
OH functions on periphery instead
Conjugate OH with COOH, under right conditions get ester bond between drug and dendrimer
when you make G4-NH2–ibuprofen conjugate with a linker, whats the method followed for drug release inside cell?
ibu - linker - dendrimer
= got bridge between drug and dendrimer (not drug directly attached)
linker has specific property and only degraded in cell by: enzymatic degradation
which will have the highest drug release and why:
PEG or linkers: OH, NH2, GFLG?
PEG
(end group will be an hydroxyl). -OH. Reacts with COOH of ibuprofen to make ester
Reason: when you have a dendrimer, the accessibility of ester function (where dendrimer links to drug) limited compared to accessibility of ester on linear chain.
compact structure, harder to reach ester on dendrimer vs linear polymer, existing in extended conformation, so easier for ester to be hydrolysed.
at what sort of pHs will a PDC with ester linkage show high drug release?
very high/low pHs. (not in middle) as esters sensitive to hydrolysis
how will % drug release look for drug on ester linkage to dendrimer at pHs 7.4 and 5?
release bit faster at neutral pH compared to acidic pH, meaning will have bit of drug released in blood circulation and into tumour, will have more sustained release.
Here, barely reaching 10% drug release in blood in 10 days. Not talking about burst effect, just the longer the dendrimer stays at pH7.4, then we eventually start to see hydrolysis of the ester function and drug release.
slowest w pH5
which linker in PDC will show highest enzymatic release: proteases (GFLG) / NH2 / OH?
GFLG protease
with enzyme, get faster drug release rate for dendrimers prepared with linker vs amide bond or ester bond.
with linker: longer distance between dendrimer + drug = enough to allow enzymes access to linker which they can then degrade to release drug
hat about a linker and PDC is key for fast degradation for ester linker on linear polymer?
accessibiilty!!
3 PDC examples?
PEG
PEG-L-asparaginase
HPMA
PEG is Biocompatible, though not biodegradale and has Potential issues with?
immunogenecity
PEG is:
* Highly hydrated and flexible
* Low polydispersity index
* Easily modified for….?
further chemical conjugation
what is meant by PEGylation?
Conjugation of PEG to proteins
what 2 things to PEGylation improve?
stability and circulation times
what 2 things does PEGylation decrease?
immunogenicity and antigenicity
give examples of pegylation?
L-asparaginase
Interferon
Interferon beta-1a
rGCSF
rHGH
whats PEG- L-asparaginase?
PEG5000-enzyme conjugate
FDA approved in the 1990s
for Acute lymphoblastic leukaemia
Increased half-life of the enzyme: Steric hindrance from the PEG chains
Decreased immunogenicity: Ironically…anti-PEG antibodies are now an issue
One of the most studied polymer drug conjugates
- Doxorubicin conjugates (25-30,000 kDa) ?
HPMA
HPMA = drug conjugated through linker. describe 2 things about it?
- pH sensitive (hydrazone)
- Enzymatic degradation (release in lysosome)
advantages of PDC? (PEG)
IMPROVED
* Drug solubility
* Blood circulation times
* Stability
* Accumulation
TAILORED DRUG DELIVERY
* Composition
* Targeting
* Environment responsive drug release
disadvantages of PDC? (PEG)
History of failed clinical trials
* Immunogenicity
* Inadequate drug loading
* Unsuitable linkers
Modification may affect degradability
Release of drug may be prevented
Polymer-drug conjugates behave as nanomedicines and are manufactured by
covalently attaching a drug to a polymer backbone
(which must be carefully selected along with method of conjugation to optimise the formulation)
pharmacokinetics of polymer-drug conjugate will be affected by what?
polymer properties
How can polymer architecture impact elimination by renal filtration?
size shape and charge
too big: cant be filtered by kidneys and instead undergo metab and excretion -> bile
too small: can be filtered by kidneys but may accumulate in renal tubules -> renal tox
linear: more efficient learance than branched
+charge bind to -ve proteins –> reduced renal clearance
-ve may be more efficiently cleared by kidneys
What are the differences between an actively and passively targeted polymer-drug conjugate?
actively targeted: have specific ligand attached = allows for taregted delivery to certain cells/tissues
ligand binds to receptor = more drug reaching target and less drug to healthy cells
passively targeting: rley on characteristics of target tissue to acummulate there
advantages of actievly taregting PDC?
greater efficacy of drug and lower doses needed to get therapeutic effect and less SEs.
but passive may be easier to make although not as effective as targeting specific tissues
What is the main disadvantage of using a linear polymer to prepare a polymer-drug conjugate?
limited loading capacity as limited func groups available for chemical conjugation w drugs
= lower therapeutic effect of drug
lack of struc diversity
What is required for a polymer-drug conjugate (or any DDS) to take advantage of the EPR effect?
- drug must be small enough to pass through leaky tumor vasculature (pores in blood vessels) and get into tumour tissues
- drug needs high MW nad size so its restrained in tumor tissue and doesnt easily diffuse out
also size charge solubility stability…
