Polymers Flashcards
What is a polymer drug conjugate?
chemically conjugate between a polymer and a drug
What is a Targeting moiety ?
target specific receptors/tissue. Can attach that to one of the chemical functions on the polymer chain.
What is a NEUTRAL polymer example?
Neutral: PEG, hydroxypropylmethacrylamide (HPMA), dextran
What is a CATIONIC polymer example?
Poy(lysine)
Cationic polymers are used to deliver nucleic acids such as plasma and DNA
What is a ANIONIC polymer example?
Poly(aspartic acid), Poly(glutamic acid)
What are the 2 main reasons to why nanomedicine can disappear from the blood circulation?
- It’s being degraded and eliminated by the kidney
2. Left the blood compartment and is accumulating in the tissue compartment
What is the EPR effect?
E = enhanced P = permeation “badly made blood vessels” R = retention “poor waste collection”
EPR: The basis to why nanomedicine is used for Tumours. Tumours develop quickly so they form new blood vessels, they will have larger pores so then nano-medicines, if the size is right, will be able to leave the blood circulation and be able to accumulate outside environment of the tumours. Once they are close to the tumour cells, lymphatic drainage – doesn’t work that well in tumours. When the nanomedicine gets to close to the tumour, it can stay very long there.
What is the main elimination route for polymer conjugates?
As polymer conjugates are water soluble, main elimination is through renal filtration.
What is the ideal size for a nanomedicine?
Ideal size for a nanomedicine is 60-100nm
What size will cause the polymer to be eliminated by the kisneys?
Glomerular filtration (limit 30-50 kDa) - Anything below 30-50, there is an increased chance the polymer will be eliminated by the kidney
What is the role of the MPS?
M = Mononuclear P = phagocyte S = system
Removal by the body’s defences (MPS) – Body can recognize it as something foreign so will be removed by phagocytes. More likely for large, hydrophobic or charged nanoparticles.
What size do you need to aim before to avoid accumulation in healthy tissue?
2-6 nm – minimum size (Need to target sizes above this to avoid accumulation in healthy tissues, large enough)
What is the mechanism of action of polymer-drug conjugates?
Once in tumour environment:
Take them up by pinocytosis (the ingestion of liquid into a cell by the budding of small vesicles from the cell membrane). – so take up anything in the aqueous environment.
Polymer drug conjugate will end up in an endosome which gets converted into a lisosome, and is enzymatically active. If they are degraded, then it can be released into the cytoplasm of the cell and exert its anticancer activity.
How does Polymer flexibility and morphology and orientation impact accumulation/elimination?
• Improved accumulation for rigid, tubular polymer chains
What are the different types of linkers?
- Non-biodegradable linkers - Should be avoided – as drug will be attached to polymer forever and never release the drug.
- Environment-sensitive linkers - pH-sensitive: esters and hydrazones – will tend to be degraded at acidic Ph. The outside environment around the tumor is slightly acidic in comparison to health tissues. pH can decrease to 5.5.-7.6. Risk that some of the drug will be released outside of the tumour.
• Sensitive to intracellular enzymatic degradation – to increase drug release
o Gly-Phe-Leu-Gly Ala–Leu-Ala-Leu (2 specific sequences of amino acids that the enzymes inside the liposomes will recognize
Dendrimers
Multiple surface functionalities
• Active targeting
• Drug binding
• Labelling – follow nanomedicine in the body
Spherical shape – good shape for nanomedicine.
Small size (<10 nm)
However difficult to synthesise
Commercially available
What are 3 examples of PAMAM Dendrimer Conjugates?
Synthesis of G4-NH2–ibuprofen conjugate with amide linkage
Synthesis of G4-OH–ibuprofen conjugate with ester linkage (pH-sensitive)
Synthesis of G4-OH–ibuprofen conjugate with linker (enzymatic release) – used one of the short amino acids
What can PEG do?
Improve stability and circulation times
Decrease immunogenicity and antigenicity
HPMA
• Doxorubicin conjugates (25-30,000 kDa)
Branched N-(2-hydroxypropyl)methacrylamide
• Drug conjugated through linker
o pH sensitive (hydrazone)
o Enzymatic degradation (release in lysosome)
• It is fluorescent – can follow
What are the advantages of polymer-drug conjugates?
Improved: Drug solubility Blood circulation time Stability Accumulation Tailored drug delivery
What are the disadvantages of polymer-drug conjugates?
Failed clinical trials
Modification may affect degradability
Release of drug may be prevented
What is a polymer?
Chain of repeating units each repeating unit is a monomer.
What is
Degree of polymerisation?
Number of monomer unit in a polymer
If the polymer is made from 100 monomers, then the degree of polymerisation is 100.
What is a Homopolymer?
chain composed of a single monomer – all the monomer units are the SAME
What is a co-polymer?
chain composed of two or more monomers
What type of polymers are dendrimers?
Star shaped polymer
They grow as a sphere, grow exponentially. Big advantage for drug delivery. Chemical function can be modified on the surface, allows attachment of drugs etc. As they are quite condensed, they can have a large MW, but size is quite small.
What is used to determine of Molecular weight of a polymer?
Using size exclusion/gel permeation chromatography (SEC or GPC)
Describe differential scanning calorimetry.
Glass transition temperature (Tg)
Transition from hard, brittle to soft and pliable materials
Property of semi-crystalline (zones which have crystalline areas and other zones) and amorphous polymers (will only have a Tg)
Crystallisation temperature (Tc)
Temperature at which polymer chains arrange in an ordered structure
Exothermic process
Tc > Tg as requires polymer chains to move around
Property of crystalline and semi-crystalline polymers
Melting temperature (Tm)
Temperature at which the crysatlline network is destroyed
Endothermic process
Tm > Tc
Property of semi-crystalline and crystalline polymer
Will not see this in an amorphous polymer
Give examples of Suspending agents (viscosity enhancers)
Polysaccharides: acacia, tragacanth, alginates (poly(D-mannuronic acid)), starch
Give examples of where Celluloses are used.
o Semi-solids (gels)
o Mucoadhesion (oro-buccal
formulations)
Modified release (matrix, coating)
Tablet manufacturing
Give examples of where Disintegrants and binders (starch, cellulose and derivatives, PEG, PVP)
Coating (cellulose, methacrylate derivatives) are used.
Plasticizers, solvents
Capsule shell (gelatin, potato starch,
HPMC) Emulsifiers
Polymers as therapeutic agents
Sodium Polystyrene Sulfonate (Resonium A)
Ion-exchange resin use in the treatment of hyperkalaemia
Oral or rectal administration
Poly(ethylene glycol) (Movicol®)
Treatment of constipation
High molecular weight poly(ethylene glycol)
Artificial tears
Polymers in nanomedicine
Water-soluble polymer-drug conjugates
Delivery of poorly water-soluble drugs
Polymeric micelles
Core-shell structures similar to surfactant micelles
Obtained from amphiphilic (typically block) copolymers or star-shaped
Polymer nanoparticles and nanocapsules (Canvas)
Polymer(ic) nanoparticles: solid matrix polymer particles
Hydrophobic polymer matrix for
Hydrophobic and hydrophilic drugs
Polymer nanocapsules
Monolayer membrane surrounding an aqueous liquid core
Polymeric nano-capsules
Polymersomes
Aqueous core surrounding by hydrophobic polymeric shell (bilayer)
The polymeric equivalent of liposomes, made using amphiphilic copolymers
