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#FME - Nanotechnology and Advanced Materials > 2.) Nanoparticle-based drug delivery > Flashcards

2.) Nanoparticle-based drug delivery Flashcards

1
Q

Rank the following drug types in size: sMW drugs, proteins, nucleic acids.

A
  1. ) sMW drugs (1 nm)
  2. ) Nucleic acids
  3. ) Proteins 10nm (mAb = 160 kDa)
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2
Q

What are some limitations with traditional drugs for drug delivery?

A

Limitations of sMW, proteins and nucleic acids:

  • Low cell uptake (if drug requires internalisation)
  • Short blood circulation time; 10 minutes for DNA (exception: mAbs)
  • Rapid degradation in physiological fluids
  • Lack of cell specificity (e.g. chemotherapy)
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3
Q

What are the two different types of nanoparticle delivery systems?

A
  • Viral vectors (majority of gene therapies)

- Non-viral vectors

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4
Q

Name some examples of viral vectors (for nanoparticle drug delivery).

A
  • Adenoviruses (nonenveloped, without outer lipid bilayer)
  • Adeno-associted viruses
  • Retroviruses
  • Lentiviruses (for non-dividing cells)
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5
Q

What are the advantages and disadvantages of using viral vectors for nanoparticle drug delivery?

A

Advantages:

  • Efficient cell uptake (see: gene therapies)
  • Endosomal escape

Disadvantages:

  • Immunogenicity (potential immune response)
  • Low cell specificty
  • Limited packaging capacity (genetic material able to be loaded into virus)
  • DIfficult to produce: purification, concentrated, storage requirements, small scale etc
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6
Q

Name some examples of non-viral vectors (for nanoparticle drug delivery).

A
  • Liposome
  • Polymerosomes
  • Cationic polymers
  • Cell penetrating peptides
  • Degradable polymer microparticles/nanoparticles
  • Magnetic nanoparticles
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7
Q

What advantages are associated with non-viral vectors for nanoparticle drug delivery?

A

See - disadvantages of viral vectors:

  • Lower immunogenicity
  • Patients do not have pre-existing immunity (patient may have immune response to viral vector w/pre-existing immunity)
  • Larger payloads (more genetic material)
  • Easier to synthethise
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8
Q

What is a liposome? What are they commonly made of?

A
  • Amphiphilic molecule mimicking cell membrane: hydrophilic head (facing out to water) and hydrophobic fatty tails
  • Self assembly to bilayer structure (driven thermodynamically)
    »> Commonly made up of DOTMA (, N-[1-(2,3-
    dioleyloxy)propyl)-N,N,N-trimethylammonium chloride)
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9
Q

What are polymersomes?

A
  • Polymeric versions of liposomes
  • Made up of amphiphilic polymers
  • Similar to liposomes (amphiphilic nature)
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10
Q

What are cationic polymers?

A

Example:
- Polyethylenimine (PEI) for delivering nucleic acids
- Positively charged (cationic) PEI can condense negatively charged nucleic acids (negative phosphate backbone) to form polyplexes [spherical/doughnut-shaped nanoparticulate complexes)
- Positive charge also helps binding of polyplexes to cell membrane (which is negatively charged)
»> It is an electrostatic interaction between polymer and nucleic acid

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11
Q

What are cell-penetrating peptides?

A

CPPs are similar to cationic polymers:

  • Utilises macropinocytosis: a v. efficient variant of endocytosis as mechanism of entering cells
  • Origin: shown that the TAT protein (transactivator of transcription) protein from HIV virus could directly enter cells
  • Examples of CPP: octa-arginine (8R) and poly(L-lysine) [PLL]
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12
Q

What are degradable polymer micro/nanoparticles?

A
  • Solid, hydrolytically degradable particles
  • Degradation rate controls release rate of drug: days/months timescale of delivery (M/R profile)
  • Examples: PLGA (poly lactic-co-glycolic acid)
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13
Q

What are the advantages of using degradable micro/nanoparticles?

A
  • Long-term delivery (days or longer)

- Can alter and control drug PK by enabling sustained release

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14
Q

Describe a method of making drug-loaded nanoparticles from polymers?

A

Double emulsion method (W/O/W):
E.g.
- PLGA polymer is dissolved in organic solvent (dichloroethane, CH2Cl2) to form oil phase
- This is added to a cisplatin solution (dissolved in water) which is the water phase
- Sonification/mechanical agitation of the two allows dispersion of water phase in oil (W/O phase)
- W/O phase is poured into more water, with a surfactant added (PVA - polyvinyl alcohol) to stabilise dispersion
- End result = drug in water phase is encapsulated in oil phase which is in water phase solution
»> Evaporation of organic solvent (CH2Cl2) = exposes solid drug (cisplatin)

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15
Q

What are magnetic nanoparticles? How can they be applied therapeutically?

A
  • Nanoparticles made of iron (II, III) oxide commonly (made via chemical coprecipitation)
  • Drug loaded surface coating can then be applied onto magnetic particles (e.g. PEG polymer, such as Doxorubicin)
  • Can then respond to external magnetic field = magnetic field-guided delivery of drug to target, as well as allowing tracking of where drug is going (e.g. to tumour?)
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16
Q

What are the advantages of magnetic field-guided delivery in tumour targeting?

A
  • Nanoparticles larger than 10nM usually cannot diffuse through normal/healthy endothelium (via small vascular pores)
  • Leaky vasculature of tumours allow nanoparticles of up to 700nM to penetrate the endothelium
    »> External magnetic field facilitates delivery of magnetic nanoparticle to tumour site, increasing amount of drug delivered/less wastage elsewhere and off-target effects
17
Q

What strategies are availible to increase serum half-life?

A
  • Fc fusion proteins

- PEGylation

18
Q

How do Fc fusion proteins increase serum half-life?

A

Fragment crystallisable fusion proteins:

  • Made via DNA recombinant proteins
  • Conjugate with peptide/protein drug molecules to endow with immunoglobulin-like property of long serum half-life (days-weeks)
  • Does this by utilising the neonatal Fc receptor recycling pathway
19
Q

How does PEGylation increase serum half-life?

A

Polyethylene glycol:

  • Conjugation with v. hydrophilic (oxygen backbone) to drug (e.g. protein) = high hydration (water solvation layer) which increases hydrodynamic radius of the conjugate, reducing renal filtration
  • PEG layer is 5-10x size of the protein itself
  • Prevents uptake and clearance by mononuclear phagocytes (e.g. macrophages)
  • Decreases formation of neutralising Ab against a protein by masking antigen sites
  • Protection from proteolytic enzymes e.g. trypsin, chymotrypsin, proteases
20
Q

What are the drawbacks/disadvantages of using PEGylation to increase serum half-life?

A
  • Steric interference can reduce activity and binding affinity
  • Protein is shielded from target as well as enzymes/Abs/phagocytes etc
21
Q

How can we increase cell specificity?

A

Via antibody-drug conjugates:

  • Antibody is linked to drug via linker
  • Antibody conveys specificity to particular cell
22
Q

How can antibody-drug conjugates be optimised for cell specificity?

A
  • Better choices of target antigen and antibody
  • Development of more potent drugs
  • Development of linkers with greater stability
23
Q

What are the three types of endocytosis, and their distinguishing features?

A

Phagocytosis:

  • Big particles > 500nM
  • Engulfed to form phagosome (internal compartment)
  • E.g. bacteria
  • Major endocytosis pathway

Pinocytosis:

  • Smaller molecules suspended in extracellular fluid surrounding cells brought into the cell
  • Via budding off of vesicle from the plasma membrane

Receptor-mediated endocytosis:

  • Inward budding similar to pinocytosis but involving protein receptor sites on the plasma membrane (to metabolites, hormones etc)
  • E.g. steroid receptors
24
Q

What is endosomal escape, and why is it beneficial?

What if it does not occur?

A
  • Once drug is internalised (endocytosis) it is encapsulated in the endosome
  • Escape from endosome desired so drug can reach intracellular target sites e.g. in the cytosol, or the nucleus for DNA
    »> Viruses can either fuse their viral envelope with the phospholipid bilayer, or lyse the lipid membrane or generate a pore through it
  • The endosome will eventually be degraded by the lysosome (degradative enzymes enclosed within)
25
Q

What are the two parameters/formulas that dictate drug loading into nanoparticles?

A

Drug loading efficiency =
(Drug added - free un-encapsultated drug)/drug added

Loading capacity =
(Encapsulated drug/nanoparticle mass) x 100

#FME - Nanotechnology and Advanced Materials (3 decks)

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