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formulation roldo and cox and karen ball > drug targeting > Flashcards

drug targeting Flashcards

1
Q

what is passive drug targeting?

A

Passive mechanism of targeting means the strategies that employ the natural response of the body to the administration of a foreign molecule

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2
Q

state one way passive drug targeting achieved?

A

Tweaking the size of the particle administered; when a drug is administered intravenously depending on the particle size the drug would affect a specific area of the body.

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3
Q

How do drug particles move depending on site of administration and particle size

A

If a drug is administered intravenously and the particle size is greater than 7microns it would accumulate in the lungs, but if it is less than 7microns it would accumulate in the liver and spleen.

Strategy of tweaking the particle size and administering either intra-arterial or intravenously is best for targeting tumours in a particular organ.

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4
Q

what is the aim of making particles size up to 10nm-250 nm and particles between 380-780nm.

A

The size range of particles that can get to solid tumours are particles that are 10-250 nm and particles between 380-780nm get to tumour vessels

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5
Q

With respect to passive targeting How are particles less than 7microns (especially between 0.4-2 microns) accumulated in the liver and spleen?

A

this is because they are recognised by macrophages as a foreign body there for the are opsonized by antibodies and phagocytosed by the macrophages which takes the drug particles to the liver for elimination, but upon getting to the liver the drug is released therefore targeting the liver.

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6
Q

What is the full meaning of MPS and RES drug targeting and what is the best particle size for it and what is it used to treat?

A

MPS: Mononuclear phagocyte system

RES: Reticuloendothelial system

Particles 0.4-2 µm

Treatment of:

macrophage associated microbial diseases

deficiencies of lysosomal enzymes

immunopotentiation of vaccines

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7
Q

What is extravasate?

A

Drug particle going from blood vessel to the tissue that is being targeted (damaged tissue or tumour tissue)

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8
Q

Explain the EPR strategy?

A

This is when hydrophilic polymers are attached around the surface of the drug particle causing water adsorption on the particle surface making the particle bigger and more biocompatible, therefore it would not be recognised as a foreign body by opsonin and there would be no phagocytosis.

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9
Q

What is the result and the aim of the EPR strategy? 5

A

Does not reach the liver

Prolonged circulation time

Can move from circulation to tissue (EXTRAVASATE) only in damaged tissue

PASSIVE TARGETING TO TUMOUR OR INFLAMMED TISSUE BY ENHANCED PERMEABILITY

Accumulates in damaged tissue due to poor lymphatic drainage ENHANCED RETENTION

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10
Q

What is enhanced permeability?

A

It is a characteristic of tumor tissue, where the capillaries present in the tumours are developing very fast meaning that they are not developed correctly and they are leaky, so they have gaps between their endothelial cells that allow molecules to go through. (especially molecules between 380-780 nm, meaning that the particle size should be within this range to work for EPR strategy)

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11
Q

Why does the EPR strategy allow enhanced retention?

A

the drug accumulates in damaged tissue due to poor lymphatic drainage ENHANCED RETENTION

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12
Q

what is EPR strategy full meaning?

A

enhanced permeability and retention strategy

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13
Q

Solid tumours can be targeted exploiting the enhanced permeability and retention (EPR) effect. Which of the following options best describes the requirements for a particulate system to exploit the EPR?

A

It has a diameter between 50-400nm, its surface is coated with a hydrophilic polymer to avoid opsonisation.

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14
Q

What are the requirements for effective drug targeting, how can these requirements be met?

Evasion from opsonisation and clearance (kidney and liver)

Retention within the intended site of action achieved

Specific interaction carrier/receptor

Release of carried drug

A

Evasion from opsonisation and clearance (kidney and liver) achieved by: thinking of the Size of the carrier ( we need particles between 50nm - 400nm) and Surface chemistry (adding a hydrophilic polymer or positive charges)

Retention within the intended site of action achieved by Hindrance and Defective drainage (EPR)

Specific interaction carrier/receptor achieved by using of specific homing devices

Release of carried drug achieved by triggered controlled release.

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15
Q

list 4 homing devices?

A

Antibodies and antibodies fragments

Oligonucleotides (APTAMERS)

Carbohydrates
(lactose, galactose, mannose, galactosamine)
Recognised by Lectins overexpressed on certain tumour cell surfaces

Other small molecules
e.g. FOLIC ACID (folate or vitamin B6)
Recognised by folate receptor overexpressed on certain tumour cell surfaces

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16
Q

what are the advantages and disadvantages of antibodies and antibody fragments as homing device??

A

advantage
high degree of specificity

disadvantage
complex and large molecules

expensive production

immunogenic (can trigger immune response)

it can limit tumour penetration due to big size

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17
Q

what are the advantages and disadvantages of oligonucleotides (aptamers) as homing device

A

advantages
small size

low immunogenicity

good penetration (TAT)

ease of production

disadvantage
rapid blood clearance ( SPIGELMERS, L-oligonucleotides are less cleared)

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18
Q

what are the advantages and disadvantages of carbohydrates as homing device?

A

advantages
small molecule
cheap

disadvantage
low specificity
low binding affinity (needs high density surface modification (have a lot of them on the surface) to have good efficacy.

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19
Q

what is the most appropriate strategy for each of the following requirement:

A- Evasion from opsonisation

B- Avoidance of renal clearance

C- Specific interaction with the target site

D- Targeted release of carried drug

A

A- Use hydrophilic coating for enhanced hindrance

B- Use particles bigger than 50 nm

C- Use of specific homing device

D- Use stimuli responsive polymeric carriers

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20
Q

which homing devices match with the properties listed below:

A-This is expensive to produce but has a high affinity even though its ability to penetrate the tumour is poor.

B- This is a small molecule that binds specifically to the overexpressed folate receptor.

C- This molecule undergoes very fast blood clearance due to enzymatic degradation, the latter can be avoided by creating the mirror image of this molecule.

D- It must be used in high density on the surface of delivery systems due to low specificity and low binding affinity.

A

A- Antibodies and antibodies fragments

B- (other molecules)FOLIC ACID (folate or vitamin B6)

C- Oligonucleotides (APTAMERS)

D- Carbohydrates
(lactose, galactose, mannose, galactosamine)

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21
Q

Which type of targeting is being referred to below:

A- A moiety that is recognised specifically by a cell or tissue is added to the drug delivery system

B- Targeting can be achieved by intra-arterial injection

C- Targeting can exploit the natural processes in the body such as macrophages uptake to target the liver

D- The drug is retained on the tumour site by defective lymphatic drainage

A

A- active

B- passive

C- passive

D- EPR

22
Q

three essential component for polymer conjugates and explain their function

A

Molecular weight of the polymer ensures access to the target tissue

Targeting moiety can be pendant or included in the backbone

Spacer between drug and polymer can avoid shielding the active site and facilitate release or control release, spaces can be made to degrade under certain conditions in order to release a drug under those conditions, can protect the drug, increase drug solubility.

23
Q

what is the function of a spacer on a polymer conjugate?

A

control release

spacers can be made to degrade under certain conditions in order to release a drug under those conditions

Drugs can be conjugated to a polymeric carrier with an enzyme sensitive spacer. If the enzyme is overexpressed by tumour cells, the drug will be preferentially released at the site of the tumour

can protect the drug

increase drug solubility.

24
Q

what are the advantages and disadvantages of using polymer conjugates?

A

advantages

great ability to extravasate
ease of attaching homing devices
flexibility

disadvantages

limited drug loading capacity

drug covalently bond can mask active site

carrier can only partially protect the drug

25
Q

what is doxorubicin used for? how does it work

A

it is an anticancer drug, it works as an inhibitor of topoisomerase II, it works by intercalating into the DNA inducing then the alkylation and inhibiting the attachment of the topoisomerase that should be re-tying the DNA strands.

26
Q

(regarding polymer conjugation) why is doxorubicin conjugated.

A

because of the mechanism of action doxorubicin is extremely cytotoxic, so the alkylation effect can take place also in non cancer cells, therefore it is important to try and target the drug specifically. otherwise there would be side effects like severe nausea, vomiting, ulcers in the mouth, and also depression of bone marrow and platelets.

27
Q

how does the polymer conjugate to doxorubicin avoid the extreme cytotoxic effect of the drug ?

A

it increase the size of the drug

selective accumulation of the drug in the tumour:
it is a hydrophilic polymer, so it can interact with water and create a sort of a cloud of water around the molecule, this allows the construct between the polymer and the drug to exploit the EPR effect. and in this way the drug is selectively accumulated in the tumour.

selective release of the drug in the tumour:
there is a specific linker between the drug and the polymer. and this specific linker is degraded by an over expressed thiol-dependant protease. because this is over expressed in the lysosomes in the tumour, this means that the release of the drug is more likely to occur in the tumour.

28
Q

what polymer conjugate is used for improving doxorubicin and what is the resulting drug?

A

HPMA - Poly(N-(2-hydroxypropyl)methacrylamide)

adriamycin

29
Q

summarize the aim of putting a polymer conjugate on doxorubicin

A

reduced systemic toxicity

selective retention in tumour cells (EPR)

drug release by overexpressed thiol- dependent (cysteine) proteases in lysosomes

30
Q

summarize the aim of polymer conjugation in neocarzinostatin by (SMA: poly(styrene maleic acid))

A 
limit side effects and system toxicity
Have EPR
avoid clearance by kidney or macrophages
longer circulation
retains the original activity
increases tumour localisation
31
Q

which polymer conjugate is used for neocarzinostatin

A

SMA: poly(styrene maleic acid)

32
Q

how does drug particle carrier size affect drug efficacy and effect?

A

less than 10nm kidney clearance

less than 100nm reduced hepatic filtration, increase circulation time

greater than 400nm clearance by macrophages and RES, liver and spleen accumulation

33
Q

how does drug particle carrier shape affect drug efficacy and effect?

A

spherical drug particles tend to travel in the centre of the vessels, and they have reduced interaction with the endothelial surfaces. making it not ideal because we want interaction with the endothelium for “extravasation”.

irregular particles seem to be better at avoiding elimination. there are very few studies around irregular particles therefore they are not in use.

34
Q

how does drug particle carrier surface properties affect drug efficacy and effect?

A

hydrophobicity: hydrophobic particles tend to induce agglutination (clumping of particles) making the particles subjected to opsonization and complement activation. making hydrophilic particles better because they would have an EPR effect.

zeta potential: charge is very important, a positive charge improves “extravasation” making it able to be release in a cell which is important in tumour targetting.

35
Q

list three type of particulate carries.

A

Micelles
Nano/micro- particles
Lipidic particles

36
Q

what are advantages and disadvantages of particulate drug carriers?

A

Advantages:

high drug loading capacity

drug can be physically entrapped

the system can confer protection to the drug

Disadvantages:

inability to cross the endothelial barrier

subject to phagocytosis

37
Q

explain micelles as a particulate carrier?

it is formed by surfactant, when we have water and we introduce a surfactant that has a hydrophilic head and a lipophilic tail, the tail would point away from the water and if we continue to increase the concentration of the surfactant we would reach the critical micellular concentration (CMC). hydrophilic head on the outside and lipophilic tail on the inside of a ball like structure.

the same principle can be applied where a micelle is formed from a hydrophilic block (PEG) and a hydrophobic block ___________or ____________. this would produce a Di-block or a Tri-block with a hydrophobic core.

A

it is formed by surfactant, when we have water and we introduce a surfactant that has a hydrophilic head and a lipophilic tail, the tail would point away from the water and if we continue to increase the concentration of the surfactant we would reach the critical micellular concentration (CMC). hydrophilic head on the outside and lipophilic tail on the inside of a ball like structure.

the same principle can be applied where a micelle is formed from a hydrophilic block (PEG) and a hydrophobic block poly(aspatic acid) or poly(β−benzyl-L-aspartate). this would produce a Di-block or a Tri-block with a hydrophobic core.

38
Q

the hydrophilic block and hydrophobic block micelle can be used to upload what type of drugs

A

hydrophobic drugs like doxorubicin

39
Q

what effect do micelles use to reach the tumour?

A

they use the EPR effect to accumulate in the tumour

they are also a lot smaller than other particulate system. so they can have diameters between 20 and 40 nm and they are very hydrophilic on the outside so they avoid elimination by macrophages.

40
Q

state a live application of the use of micelles as a particle carrier

A

Koniakon mixed-micelles: phytomenadione, prophylaxis and treatment of vitamin K deficiency bleeding (VKDB) in neonates and infants. which is formed by phospholipids like glycocholic acid and lecithin.

41
Q

list the biodegradable synthetic and natural polymers that can be used in nano particles for particulate carriers

A

Synthetic:

Poly lactic co glycolic acid
Poly lactic acid
Poly caprolactone

Natural: degradation by enzymes

Chitosan (polysaccharide from crab shells)
alginate ( polysaccharides from algae)
other polysaccharides

42
Q

state different types of nano particles and how they affect the drug effectiveness?

A 
stealth nano particles:
steric stability
high drug protection
slow opsonization
biocompatibility
nano particles with charge (ionized):
eg cationic
high cellular uptake
high toxicity 
low specificity
targeting nano particles: by attaching a homing device
high cellular uptake 
high specificity
immunogenic
high clearance

stimuli responsive nano particles: (changing solubility in response to stimuli like pH or temperature)

high selectivity
questioning stability.

43
Q

which protein can form nano particles

A

albumin

44
Q

list facts about albumin as a particulate carrier

A

Albumin is a natural carrier of hydrophobic molecules

Albumin is actively transported through endothelium to tumours

it is an endogenous carrier, it is used to transport hydrophobic molecules in the body which is very good for drug delivery

albumin interacts with different molecules like vitamins and hormones by forming an irreversible non covalent bond on the surface.

some albumin particles have been developed for the delivery for paclitaxel.

45
Q

how was albumin used in the delivery of paclitaxel.

A

it was done by preparing particles that were about 130 nm in size which were loaded with paclitaxel, which was then delivered using the EPR effect.

46
Q

what are the advantages of using albumin as a drug carrier?

A

it helps the endothelial transcytosis, so it allows the drug to exit circulation and accumulate into the tumour.

47
Q

what are the different targeting mechanism for liposomes as a particulate drug carrier?

A

conventional liposomes (not ideal): easily phagocytosed

stealth liposomes: uses EPR

targeted liposomes: attaching specific antibodies to the liposome

cationic liposomes: using charge

48
Q

why do liposomes have an advantage over micelles?

A

because micelles can only load hydrophobic drugs in their core but liposomes can both have hydrophilic drugs in their core and hydrophobic drugs in their phospholipid bilayer.

49
Q

which formulation uses liposome as drug carrier?

A

ambisome: liposomal amphotericin B

CAELYX (DOXORUBICIN ENCAPSULATED IN PEGylated liposomes (100 nm in size)

50
Q

what are the advantages of using stealth liposomes?

A

tissue targeting

reduced side effects

improved drug stability and solubility

possible intracellular drug delivery by addition of a ligand recognised by receptors on the cell membrane

51
Q

what are the General Pharmaceutical considerations
for the development of a drug carrier

5

A

Purity of the carrier material: important to guarantee quality of the product

Reproducibility: full physicochemical characterisation has to be carried out during the fist stages of development, later it will be included in the approval application documents

Safety (i.e. immunological responses)

Scaling-up possibility

Shelf life

formulation roldo and cox and karen ball (11 decks)

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