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Lab 3 > Nanomedicines for Protein Delivery > Flashcards

Nanomedicines for Protein Delivery Flashcards

1
Q

What are biopharmaceuticals?

A

drugs made by living cells or organisms to treat diseases, such as monoclonal antibodies and recombinant proteins.

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2
Q

what are the main properties of biopharm/ proteins?

A

high MW >5000 Da
highly water soluble
hydrolysable bonds
large SA 30-50

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3
Q

diff types?

A

proteins
enz
peptides
nucleic acids
carbs
cell based therapies
vaccines

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4
Q

barriers to oral administration?

A

enzymatic degradation
acidic environments
transport across the intestinal epithelium

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5
Q

Is oral administration possible for proteins? Why?

A

no:

  • need to overcome 3 barriers that limits their bioavailabulity
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6
Q

What are the instability problems for biopharmaceutical proteins? 2 types

A

chemical instability: Incompatibility with excipients: hydrolysis, Oxidation

physical instability: proteins are prone to denature, alter their native structure on exposure to heat, extremes of pH or organic solvents

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7
Q

difference between transcellular and paracellular transport?

A

T: though memb (lipophilic mols)

P: mols pass through tight junctions between cells (hydrophilic)

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8
Q

how are proteins administered?

A

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

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9
Q

name intranasal protein administration

A

flu vaccine
calcitonin

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10
Q

name sublingual protein administration

A

desmopressin

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11
Q

how are small proteins cleared?

A

glom filtration

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12
Q

how are large proteins cleared? >200nm

A

liver
spleen
lung

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13
Q

what are the immunogenicity risk factors of protein administration?

A

SC, IM >IV
large size
protein aggregation

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14
Q

what are the least immunogenic risk factors of protein administration?

A

neutral charged proteins

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15
Q

protein aggregates provoke what, compromising efficacy of drug?

A

immune response

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16
Q

How can you improve the bioavailability of protein drugs?

A

modify chemical structure
co-administer enzyme inhibitors
PEGylation

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17
Q

How does PEG affect the characteristics of protein drugs?

A
  • increases proteins M volume abive glom filtration threshold
  • Extends half-life
  • Reduces immunogenicity- stealth effect!!
  • Prevents premature degradation.
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18
Q

Advantanges of using protein nanodrugs for nasal and pulmonary delivery?

A
  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
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19
Q

Disadvantanges of using protein nanodrugs for nasal and pulmonary delivery?

A
  1. epithelium is firmly closed by tight functions - transcellular
  2. loose epithelium, no mucus barrier - paracellular only
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20
Q

What is the main barrier to nasal and pulmonary delivery?

A

airway epithelium is firmly closes by tight junctions.

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21
Q

What drugs are suitable for transdermal route?

A

Small hydrophobic drugs

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22
Q

what must proteins administered via transdermal route do?

A

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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23
Q

what are the adv/disadv 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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24
Q

2 types of targeting w NPs?

A

passive: EPR effect

active: receptor-ligand ints

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25
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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26
Q

main issue w NPs: aggregates, why?

A

minimise surface charge + energy
triger opsonisation
MPS clears them after recognising :(

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27
Q

why do you get increase NP aggregation in blood?

A

complex, highly ionic nature

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28
Q

T/F: smaller liposomes <200nm are clared more slowly that larger?

A

true

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29
Q

what surface charge allows slower clearance/ better ability to avoid opsonisation and MPS?

A

neutral!

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30
Q

how does PEG have a longer half-life ?

A

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

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31
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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32
Q

what is active targeting used for in NPs?

A

facilitate drug transport

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33
Q

name active targeting agents used in NPs

A

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

34
Q

how do cell-penetrating peptides work ? different methods

A

direct penetration

endocytosis-mediated uptake

translocation via transitory structure formation
= improve intracellular protein delivery

35
Q

what are the 3 barriers for creating NPs?

A

organic solvents to make = denatures proteins/harm biological activity

low loading efficiency

drug release - controlled release needed

36
Q

name the types of proteins delivered?

A

polymeric
inorganic
lipid-based

37
Q

name examples of polymeric proteins delivered?

A

polymersome
dendrimer
polymer micelle
nanosphere

38
Q

name examples of inorganic proteins delivered?

A

silica NP
quantum dot
iron oxide NP
gold NP

39
Q

name examples of lipid-based proteins delivered?

A

liposome
lipid NP
emulsion

40
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

41
Q

name an example of polymeric NPs

A

poly(lactic-co-glycolic acid) P

42
Q

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

A

biocompatible
biodegradable with favourable degradation rates

43
Q

what are the advantages of polymeric NPs?

A

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

44
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

45
Q

how are polymeric NPs released?

A

by both diffusion from the polymer matrix and the degradation/erosion of the polymer

46
Q

name an example of inorganic NPs

A

mesoporous silica NP

47
Q

describe mesoporous silica NP (inorganic NPs)

A

inert
non-immunogenic
modifiable therapeutic agents

48
Q

what are the disadvantages of using lipid-based NPs

A

stability issues
encapsulation efficacy
release profiles

49
Q

classical eg of lipid based NPs?

A

liposomes

50
Q

what are virosomes

A

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

51
Q

disadvantages of lipid based NPs?

A

have to use organic solvents in prep = not ideal for proteins
low loading efficacy esp smaller liposomes

52
Q

how does drug release for lipid based NPs occur?

A

through diffusion - membrane
or by dissociation of lipid

53
Q

what are stimuli-responsive liposomes?

A

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

54
Q

what stimuli activate stimuli-responsive liposomes?

A

temperature
pH
enzyme
redox
light

55
Q

2 types of stimuli responsive liposomes?

A

pH responsive
thermosensitive TSL

56
Q

how do thermosensitive liposomes work (TSL)?

A

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

eg DPPC - Tm 41degrees

57
Q

what are alternative nanocarriers for protein delivery?

A

polymer network
polymersomes
polymer micelles
nano/micro emulsions
solid lipid
exosomes
micelles
niosomes

58
Q

how do polymer network deliver proteins?

A

contains alot of H2O
protein loading/release: swelling and degradability

59
Q

example of polymer network?

A

insulin loaded chitosan-based hydrogel NPs

60
Q

Advantages of polymer networks as protein DDS?

A
  • stealth character- guarantee extended plasma half-life - due to hydrophilic polymers
  • Enhanced targeting- control polymer composition
61
Q

Disadvantages of polymer networks as protein DDS?

A

the interference of the polymer with protein activity - due to steric hinderance

62
Q

how are polymersomes made?

A

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

have similar properties to those of liposomes

63
Q

Advantages of polymersomes?

A

higher membrane stability than liposomes.

controlled size, shape and membrane thickness, mechanical strength, surface chemistry

64
Q

Disadvantages of polymersomes?

A
  • poor encapsulation efficiency (<5% for BSA and Hb) (3)
  • membrane thickness - thermodynamic/kinetic barrier
65
Q

name examples of polymersomes

A

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

66
Q

how are polymeric micelles made?

A

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

low CMCs

67
Q

Advantages of polymeric micelles ?

A
  • more stable than surfactant-based micelles
  • slow kinetics of dissociation: IV administration do not cause immediate dissolution
68
Q

Disadvantages of polymeric micelles ?

A
  • Limited encapsulation due to hydrophobic core
  • Ionic-hydrophilic block copolymers - polyionic complex micelles for proteins via electrostatic interactions
69
Q

what are nanoemulsions made out of?

A

Colloidal dispersions composed of oil, water and surfactants (1, 2)

o/w OR w/o microemulsion and nanoemulsions

70
Q

Advantages of protein delivery by nanoemulsion?

A
  • high encapsulation efficiency
  • Cheap process, can easily be scaled up
71
Q

Disadvantages of protein delivery by nanoemulsion?

A

use organic solvents, and high mechanical forces: pressure and temperatures

71
Q

SLNs (term 1)

A
72
Q

what are exosomes made out of?

A

lipid bilayer
neutral extracellular vesicles w native membrane composition

73
Q

Advantages of using exosomes for protein drug delivery?

A
  • Safe- minimal toxicity
  • immunocompatibility
  • High biocompatibility
74
Q

disadvantages of using exosomes for protein drug delivery?

A
  • Complex preparative and purification methods needed
75
Q

what are niosomes made out of?

A

non-ionic surfactant vesicles (10-20um)
with non-ionic surfactants and cholesterol

76
Q

Advantages of niosomes for protein drug delivery?

A

Biocompatibility
Low toxicity
Ease of preparation

77
Q

Disdvantages of niosomes for protein drug delivery?

A

Physical instability as they can aggregate or fuse between themselves.

78
Q

what are protein-based nanomaterials made of?

A

hollow protein NPs comprised of virus capsids, virus-like particles, ferritin, heat shock proteins, chaperonins….

formed by self assembly of protein subunits

79
Q

carrier and drug in protein based nanomaterial made of..

A

same aa building blocks

80
Q

advantages of protein based NPs as protein carrier?

A

Optimally sized for endocytosis
Nontoxic
Biocompatible
Biodegradable

81
Q

disadvantages of protein based NPs as protein carrier?

A

Lack of reproducibility

Lab 3 (21 decks)

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