2.) Nanoparticle-based drug delivery Flashcards
Rank the following drug types in size: sMW drugs, proteins, nucleic acids.
- ) sMW drugs (1 nm)
- ) Nucleic acids
- ) Proteins 10nm (mAb = 160 kDa)
What are some limitations with traditional drugs for drug delivery?
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)
What are the two different types of nanoparticle delivery systems?
- Viral vectors (majority of gene therapies)
- Non-viral vectors
Name some examples of viral vectors (for nanoparticle drug delivery).
- Adenoviruses (nonenveloped, without outer lipid bilayer)
- Adeno-associted viruses
- Retroviruses
- Lentiviruses (for non-dividing cells)
What are the advantages and disadvantages of using viral vectors for nanoparticle drug delivery?
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
Name some examples of non-viral vectors (for nanoparticle drug delivery).
- Liposome
- Polymerosomes
- Cationic polymers
- Cell penetrating peptides
- Degradable polymer microparticles/nanoparticles
- Magnetic nanoparticles
What advantages are associated with non-viral vectors for nanoparticle drug delivery?
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
What is a liposome? What are they commonly made of?
- 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)
What are polymersomes?
- Polymeric versions of liposomes
- Made up of amphiphilic polymers
- Similar to liposomes (amphiphilic nature)
What are cationic polymers?
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
What are cell-penetrating peptides?
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]
What are degradable polymer micro/nanoparticles?
- 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)
What are the advantages of using degradable micro/nanoparticles?
- Long-term delivery (days or longer)
- Can alter and control drug PK by enabling sustained release
Describe a method of making drug-loaded nanoparticles from polymers?
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)
What are magnetic nanoparticles? How can they be applied therapeutically?
- 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?)
