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drug design > drug formualtuion > Flashcards

drug formualtuion Flashcards

1
Q

what does hypoxia do

A

helps the tumour to grow and esacpe treatembts

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2
Q

what are the advantages of liposomes

A

they are easy and cheap to produce

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3
Q

what are the quailites of tumour vessles

A
  • far apart
  • serpertine formation
  • variable blood flow
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4
Q

what are the factors in the microenviroment that affect the drug uptake and effectiveness in tumours

A
  • angiogensis
    -nutrients and oxygen uptake
    -heterogeneicity of tumours
    -cell prolifertaion rate
    -intersistail fluid poressure
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5
Q

what factor is induced in low o2 levels

A

HIF-1, hypoxia inducible factor 1

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6
Q

what are the levels of O2 in hypoxic tumours

A

around 0.3%

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7
Q

what does hypoxa selecetd pressures increase

A

intrinsic resistance to antitumour immunity, or immunosupression and can increase therapuetic reistance

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8
Q

what is shunting

A

the blocking of the atrial part of into the venous part of the blood system without feeding the tissue properluy

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9
Q

what are the qualities of hypoxic cancer cells

A
  • high HIF-1
    -increased genetic instabilty
    -influence ECM remodellinh
    -altered angiogensis
    -less suspectible to chemo and radiation
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10
Q

what biological marker is red and what does it do

A

Pimondazole - exogenous hypoxia marker

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11
Q

what biological marker is brown and what does it

A

BrdU- marker of DNA proliferation incorporates itslef into the DNA

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12
Q

What biological marker is blue and what does it do

A

Hoechst - blood perfusion marker, diffuses out of blood cells

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13
Q

how is HIF activated

A

through the stabilisation of the alpha subunit

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14
Q

how does HIF normally work

A

HIFa-> proline hydrolysis -> VHL mediated degradation

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15
Q

what is the startergy to expolit tumour hypoxia

A

exlpoit the reductuve enviorment by using drugs that are reduced to cytoxic speices in the hypoxic regions if tumours

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16
Q

what are the three main classes of hypoxia drugs

A

quinone antiboitics
nitroaramtics
di-N-oxides

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17
Q

what is an examamnple of a di-N-oxide drug and how dies it work

A

AQ4N
in healthy cells just stays in the cytoplasm and has a low tocixity
if hypoxic cells then AQ4N is taken up and converted to AQ4 which is highly toxic and has stroing binding to DNA

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18
Q

what does the upregualtion of EMT do

A

allows the tumour cells to be more plastic

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19
Q

how do you create hypoxic cells

A

leave them for 24-48 hrs in low o2 anymore and they will die

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20
Q

what cell culture can be used to look at hypoxia gradiatnets

A

spheirical

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21
Q

what do carbinaic anhydrases 9 and 12 do

A

upregulated by hypoxia
- involved in intracellular pH regualtion
-indirect cells extracellular acidification

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22
Q

what were the disadvatges of small molecule inhibitors for carbonic anhydrases

A
  • weren’t specific enough
  • had off target affects
23
Q

what features do carbonic anhydrases inhibitors have

A
  • zinc binding group- binds to the enzymatic domain
  • tail creates more elctivity
  • linker which spaces the zinc deep into the enzyamtic cleft
24
Q

what is an example of a carbonic anhydrase inhibitor and what is its disadvangte

A

s4 and the disadvatge is it has a low uptake into the cells

25
Q

how do you make CAi more affective for the isotopes

A

by changing the variable region

26
Q

what are exmaples of nanoaprticles

A

liposomes

27
Q

what are the advatges of liposomes

A
  • increased stability via encapsulation
  • can trap lipophilic and hydrophilic drugs
  • less toxic to snesnitive tissues
    -increased effficacy and theraputic affect
  • have flexibilty to couple with site spefic ligands to achieve active binding
  • tehy are non toxic, biodegradeable, biocompatible and non immunogenic
28
Q

what are the disadvantages of liposomes

A
  • cost
  • not all will be stable
  • short half life
  • somtimes lipids undergo oxidation or hydrolysis like reactions
  • leakage and fusion of encapsulated drug
29
Q

what are lipsomes made out of

A

cholestrol and phosphloplids

30
Q

what is pahse transition tempertaure

A

the temperature required to change from a ordered gel phase to the disordered cystatline phase

31
Q

what isthe major draw back from using liposomes more often

A

their instabilty

32
Q

what are the stabilty asepcts of liposomes

A
  • polar head
  • chain length
  • cholsterol: phospho lipid ratio
  • PEGlated
  • fatty acid chains
  • degree of unsaturation
33
Q

what does fatty acid chains do to help stabilty of lipsomes

A

reduces compactness

34
Q

what does PEGlation do for liposome stabilty

A

stops recognition from the immune system

35
Q

how does the chol: phospho lipid ratio help liposome stabilty

A

higher chol to phoso stabilises

36
Q

how does the degree of saturation help with liposome stabilty

A

lipids with unsaturated acyls are suspectebible to degradation

37
Q

what is passive intergration of drug to liposome

A

drug and liposomes are mixed together to get passive intergration and then gel filtration to get rid of the unbound inhibitor

38
Q

how does the drug get intregrated into liposome with hydration

A

this is passive
- test the levels of chol:phopho
- mix them togetehr and let the solvent evaporate
- then hydrate with buffer for intergration
- extrude
- filtration chromotograhy

39
Q

what size do you want the liposomes

A

between large unilamer vesicles and small unilamer

40
Q

what is extrusion

A

when the lipsome suspension is passed through a membrane filter with a defined pore size. mikes liposomes smaller and more uniform

41
Q

what extruder would you use in a lab

A

high pressure commerical extruder

42
Q

what is active loading of the drugs

A
  • liposomes are added to citrate buffer
  • then Na2Co3 added and exchanged for the buffer this creates a proton gradinet
  • then drig is added and exchanged into the liposome
43
Q

what is the differnce between active and passive loading

A

passive laoding is during the fomration of the vesicle
passive loading is for hydrophlic or lipophilic drugs
active is a after the formation of the vesicle
active is for weakly acidic or wekaly alkaline drugs

44
Q

what features are looked at with liposome characterissation

A
  • size
  • surface charge
  • drug encapsulation percentage
  • phase transition tempreature
  • lipid phase transisiton
45
Q

how is the size of liposome measured

A

static and dynamic light scattering

46
Q

how is the drug encapsulation percentage measured

A

spectrophometry or flourecsnt spectroscopy

47
Q

how is the surface charge measured

A

photon correlalation spectrascopy

48
Q

how is phase transition tenmpreatyre measured

A

diiferential scanning calorimetry

49
Q

how is lipid pahse transiiton measured

A

x-ray diffraction

50
Q

factors affecting the passive uptake of liposmes

A
  • vascualr permabilty
  • level of angiogensis
  • size of the nanoparticle
  • physsiochemical properties
  • intersistal fluid pressure
  • lymphatic drainage
51
Q

what does active uptake of nanoparticle increase

A
  • accumulation
  • specificty
  • drug uptake
52
Q

waht drug is 10 fld higher conc in liposome

A

daunoXone -> daunorubicin

53
Q

what liposome incorporates doxicrubin

A

doxcil and myocet allows greater accumulationof doxirubicn with reduced cardiomyopathy

54
Q

what is an example of a fucntionaliseed nanoparticle

A

liposome with retinoic acid loaded in them there is a greater uptake

drug design (12 decks)

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