Nanoparticles

What is doxorubicin?

- An anthracycline antibiotic used in cancer chemotherapy.

- Intercalates into DNA strands.

Describe a myocet

- A liposomal formulation of doxorubicin used in breast cancer treatment.

- An LUV composed of egg PC and cholesterol

Describe the mechanism of action of a myocet when injected IV.

- Myocet liposomes are recognised by opsonins in the blood which mark them for phagocytosis.

- This leads to accumulation of liposomes in the mononuclear phagocyte system (MPS) where they are broken down.

- This releases doxorubicin over time.

What are the advantages of the MOA of myocet?

Maintains therapeutic drug levels over an extended period of time due to slow release from MPS.

What are issues with myocets?

They are large and lack PEGylation which make them more likely to be recognised and cleared by the immune system which limits their circulation time in bloodstream.

What is the enhanced permeation and retention (EPR) effect of tumours?

- Tumour blood vessels are poorly formed which leads to leak vasculature and compromised lymphatic drainage.

- This allows nanoparticles to pass through blood vessel walls and accumulate in tumour tissue.

- Also prevents efficient removal of nanoparticles from tumour site allowing prolonged drug release.

What is Doxil (caelyx)?

- Another liposomal formulation of doxorubicin used to treat ovarian and breast cancer.

- Cimprised of a lipid bilayer with a PEGylated surface forming SUVs.

Why is Doxil (caelyx) more likely to reach the tumour in circulation?

- The PEGylation prevents recognition and clearance by opsonins and immune system cells.

- This allows them to circulate in blood stream for longer periods increasing likelihood of reaching tumour

What are the advantages of Doxil (caelyx)?

- They are small and are PEGylated which enhance stability and circulation time.

- They can also exploit EPR effect of tumours.

What are issues with Doxil (Caelyx)?

- PEGylation reduces rate of drug release

- This may require additional strategies to ensure effective drug delivery.

What is abraxane?

- A hydrophobic nanoparticle formulation used to treat breast and lung cancer.

- Consists of paclitaxel and is bound to albumin to form nanoparticles.

Describe the MOA of albumin-bound nanoparticles e.g., Abraxane.

- The albumin-bound nanoparticles enhance the solubility of paclitaxel which allow its delivery to tumour cells.

- This also ensures that nanoparticles are non-antigenic and can circulate in the blood stream.

What are the advantages of albumin-bound nanoparticles (abraxane)?

- Albumin nanoparticles are uptaken via transcytosis and GP60 glycoprotein.

- Doesn't require PEGylation to avoid clearance.

Why are lipid nanoparticles used to encapsulate mRNA e.g., COVID-19 vaccine?

- Acts as a reservoir for the vaccine.

- Protects fragile drugs/vaccines from breakdown in the blood or tissue facilitating their delivery.

- Also can solubilise poorly-soluble drugs (NOT mRNA)

Describe the MOA of lipid nanoparticles e.g., Covid-19 vaccine

- They are PEGylated which avoid opsonisation and clearance by immune system.

- This allows them to be circulate in the bloodstream and taken up by cells.

- mRNA in lipid nanoparticles can be translated into proteins which can trigger antibody production

What are adenovirus vectors?

Adenovirus vectors are modified viruses used to deliver genetic material into cells safely, without causing disease.

What are advantages of adenovirus vectors?

- More stable than lipid nanoparticles.

- Can be stored at lower temperatures.

What are advantages of nanoparticle formulations?

- They offer enhanced stability by encapsulating fragile molecules such as mRNA.

- Improved delivery as they exploit natural uptake mechanisms

- Reduced toxicity

What are issues with nanoparticle formulations?

- Require ultra low temperature storage.

- Expensive due to storage and testing.

What are the types of clearance?

- Renal

- Hepatic

- MPS

Describe renal clearance mechanisms.

- Only small molecules are filtered in the kidney (

Describe Hepatic clearance.

- Larger particles are processed by the liver then accumulated into bile and excreted in faeces.

- Slower clearance which can increase toxicity

Describe mononuclear phagocytic system (MPS) as a type of clearance.

- Larger particles can be recognised by opsonins, which attach to the particles, targeting them for processing by the (MPS).

- These particles can remain in the system for years.

Eventually, they are engulfed and cleared from the body.

What factors can affect clearance?

- Size

- Surface properties e.g., PEG, can prevent opsonisation and uptake by the MPS affecting clearance rates.