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SOM 3 > Nanomedicine for protein drug delivery > Flashcards

Nanomedicine for protein drug delivery Flashcards

1
Q

what are the main properties of protein?

A

high MW
highly water soluble
hydrolysable bonds
large SA 30-50

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2
Q

barriers to oral administration?

A

enzymatic degradation
acidic environments
transport across the intestinal epithelium

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3
Q

what are the instability problems associated with oral administration?

A
  1. chemical instability - incompatibility with excipients. hydrolysis and oxidation
  2. physical instability - proteins denature, heat/pH/organic solvents exposure
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4
Q

how are proteins administered?

A

parenteral routes - IV/IM/SC
mucosal - oral/nasal/pulmonary

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5
Q

name intranasal protein administration

A

flu vaccine
calcitonin

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6
Q

name sublingual protein administration

A

desmopressin

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7
Q

why is hydrolysable bonds important in proteins?

A

increase risk of enzymatic degradation and risk of hydrolysis

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8
Q

how are large proteins cleared?

A

liver
spleen
lung

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9
Q

how are small proteins cleared?

A

glomerular filtration

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10
Q

what are the immunogenicity risk factors of protein administration?

A

SC, IM >IV (half-life is low)
large size
protein aggregation (Provokes immune response)

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11
Q

what are the least immunogenic risk factors of protein administration?

A

neutral charged proteins

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12
Q

how do you improve bioavailability of protein administration?

A
  1. modify the chemical structure
  2. co-administration of enzyme inhibitors - proteolytic enzyme inhibitors = prevent hydrolysis of peptide/proteins
  3. polyethylene glycol PEG - mask surface charge properties
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13
Q

what does polyethylene glycol PEG do?

A
  1. increase molecular volume above glomerular filtration
  2. extends biological half life
  3. reduces immunogenicity effects (Stealth Effect)
  4. prevent premature degradation
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14
Q

whats the adv/disadv of nasal/pulmonary delivery of proteins?

A

adv-
1. low proteolytic activity compared to GI tract
2. strong immune responses
3. lower doses of drug required
4. nasal route - delivery to the brain

disadv-
1. epithelium is firmly closed by tight functions - transcellular
2. loose epithelium, no mucus barrier - paracellular only

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15
Q

what proteins are administered via transdermal route?

A

small hydrophobic drugs-due to low permeability through the stratum corneum

must
* i) penetrate through corneocytes and intervening lipids (intracellular transport) or
* ii) pass between corneocytes (intercellular transport) or
* iii) be transported across skin appendages such as hair follicles and sebaceous glands (skin appendageal transport) to reach target sites

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16
Q

what are the adv/barriers of therapeutic protein drugs?

A

Advantages:
* high specificity, great activity, and low toxicity

Barriers:
* vulnerable structure, susceptibility to enzymatic degradation, short circulation half-lives, and poor membrane permeability, stability issues, immunogenicity, inefficient membrane permeability and endosomal escape issues
* Development of effective protein delivery strategies is therefore essential to further enhance therapeutic outcomes to enable widespread medical applications

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17
Q

how are nanoparticle technologies used to deliver protein?

A

i) protect proteins from premature degradation or denaturation in biological environment
ii) enhance systemic circulation half-life of proteins with poor pharmacokinetic properties
iii) control sustained and/or tunable release which can maintain drug concentration in the therapeutic range
iv) target diseased tissues, cells, and subcellular organelles/ intracellular compartments, thus improving drug efficacy, mitigate adverse off-target effects and potentially lower the required dose for desired effect of biologic therapeutics

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18
Q

how does PEG have a longer half-life ?

A

increased systemic circulation due to evading mononuclear phagocytic system (MPS)

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19
Q

how does PEG evade mononuclear phagocytic system (MPS)?

A

neutral surface charge = avoids opsonisation

reduces non-specific adsorption of opsonin-stealth properties

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20
Q

what is active targeting used for in NPs?

A

facilitate drug transport

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21
Q

name active targeting agents used in NPs

A

cell-penetrating peptides (CPP)
- argine-rich peptides
- amphiphilic peptide carriers - Pep-1 = cell permeable sequence

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22
Q

how do cell-penetrating peptides work ? different methods

A
  1. direct penetration
  2. endocytosis-mediated uptake
  3. translocation via transitory structure formation
    = improve intracellular protein delivery
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23
Q

what are the barriers for creating NPs?

A
  1. organic solvents to make = denatures proteins/harm biological activity
  2. low loading efficiency -due to large lize and MW of these molecules
  3. drug release - controlled release needed
24
Q

name the types of proteins delivered?

A
  1. polymeric
  2. inorganic
  3. lipid-based
25
Q

name examples of polymeric proteins delivered?

A

polymersome
dendrimer
polymer micelle
nanosphere

26
Q

name examples of inorganic proteins delivered?

A

silica NP
quantum dot
iron oxide NP
gold NP

27
Q

name examples of lipid-based proteins delivered?

A

liposome
lipid NP
emulsion

28
Q

what must be added to inorganic proteins? and why?

A

a linker

attached to the surface - mask properties of the protein/peptide - surface charge
and linker must degrade at site of action

29
Q

name an example of polymeric NPs

A

poly(lactic-co-glycolic acid) PLGA

30
Q

why is poly(lactic-co-glycolic acid)/PLGA used?

A

biocompatible
biodegradable with favourable degradation rates

31
Q

what are the advantages of polymeric NPs?

A

Biodegradable, water soluble, biocompatible, stable, and surfaces modification

32
Q

what are the disadvantages of polymeric NPs?

A

particle aggregation, toxicity
Only a small number of polymeric nanomedicines are currently FDA approved and used in the clinic
Proteins release by both diffusion from the polymer matrix and the degradation/erosion of the polymer

33
Q

name an example of inorganic NPs

A

mesoporous silica NP

34
Q

describe mesoporous silica NP

A

inert
non-immunogenic
modifiable therapeutic agents

35
Q

name an example of lipid-based NPs

A

liposome

36
Q

what are the disadvantages of using lipid-based NPs

A

stability issues
encapsulation efficacy
release profiles

37
Q

what are virosomes

A

lipid-based NPs
drug delivery systems based on unilamellar phospholipid membrane which incorporate virus-derived proteins

38
Q

what are stimuli-responsive liposomes?

A

control drug release at site of action by lipid dissociation and simple diffusion

Examples:PH responsive and Thermosensitive Liposomes

39
Q

what stimuli activate stimuli-responsive liposomes?

A

temperature
pH
enzyme
redox
light

40
Q

how do thermosensitive liposomes work (TSL)?

A

contain phospholipids with phase transition temperature (Tm) slightly above the physiological temperature

41
Q

what are alternative nanocarriers for protein delivery?

A
  • polymer network
  • polymersomes
  • polymer micelles
  • nano/micro emulsions
  • solid lipid
  • exosomes
  • micelles
  • niosomes
42
Q

how do polymer network deliver proteins?

A

contains alot of H20
protein loading/release: swelling and degradability

43
Q

what are the adv/disadv of polymer networks?

A

Advantages
* stealth character- guarantee extended plasma half-life - due to hydrophilic polymers
* Enhanced targeting- control polymer composition Disadvantages
* the interference of the polymer with protein activity (4) - due to steric hinderance

44
Q

what are the adv/disadv of polymersomes?

A

Advantages
* higher membrane stability than liposomes
* Controlled size, shape, membrane thickness, mechanical strength, permeability and surface chemistry (2)
Disadvantages
* poor encapsulation efficiency (<5% for BSA and Hb) (3)
* membrane thickness - thermodynamic/kinetic barrier

45
Q

what are polymersomes made of?

A

block/graft of amphiphilic copolymers with low MW PEG = hydrophilic core

46
Q

name examples of polymer networks

A

insulin-loaded chitosan-based hydrogel nanoparticles

47
Q

name examples of polymersomes

A

poly ethylene glycol-poly propylene sulfide block copolymers and low MW PEG polymersomes (1)

48
Q

name examples of polymeric micelles

A

poly(ethylene glycol)-b-poly(l-glutamic acid) (PEG-PLE),

49
Q

what are polymeric micelles made of? and what does this mean?

A

amphiphilic block copolymers = hydrophobic core
low micellar composition = low drug dissolution when injected into the blood = increase stability

50
Q

what are the adv/disadv of polymeric micelles as a protein carriers?

A

Advantages
* more stable than surfactant-based micelles
* slow kinetics of dissociation: intravenous administration do not cause immediate dissolution (1)

Disadvantages
* Limited encapsulation- hydrophobic core (2)
* Ionic-hydrophilic block copolymers - polyionic complex micelles for proteins via electrostatic interactions (3)

51
Q

what are nanoemulsions made out of?

A

Colloidal dispersions composed of oil, water and surfactants (1, 2)
* Oil-in-water or water-in-oil microemulsion and nanoemulsions

52
Q

what are the adv/disadv of using nanoemulsions as a protein carriers?

A

Advantages
* high encapsulation efficiency
* Cheap process, can easily be scaled up

Disadvantages
* organic solvents, and high mechanical forces: pressure and temperatures (3)

53
Q

what are exosomes made out of?

A

lipid bilayer
neutral extracellular vesicles

54
Q

what are the adv/disadv of using exosomes as protein carriers?

A

Advantages
* Safe- minimal toxicity
* immunocompatibility
* High biocompatibility

Disadvantages
* Complex preparative and purification methods needed

55
Q

what are the adv/disadv of using niosomes as protein carriers?

A

Advantages
* ease preparation
* Biocompatibility
* low toxicity

Disadvantages
* physical instability- aggregate or fuse between themselves (3)

56
Q

what are niosomes made out of?

A

non-ionic surfactant vesicles
with non-ionic surfactants and cholesterol

57
Q

what are the adv/disadv of using protein based NPs as a protein carrier?

A

Advantages
* Optimally sized for endocytosis
* Nontoxic
* Biocompatible
* Biodegradable

Disadvantages
* Lack of reproducibility

SOM 3 (26 decks)

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