PHAR 303 – Nanomedicine Lecture 3: Pharmacokinetics and Biodistribution of Nanoparticles

What is the purpose of labelling nanoparticles?

To see how ADME processes are occurring

How are nanoparticles selective?

They are selective of tissue type

Reticuloendothelial system (RES)

Provides a passageway within and between tissues and organs

Fenestrae

Holes in endothelial walls

What uptakes nanoparticles in the RES?

Macrophages

How do macrophages uptake nanoparticles?

LNPs babe opsin which bind to scavenger receptors

Why can cancer tissue take up more particles?

Fenestrae and gap junctions are much wider

Phase I LNP Biodistribution

Systemic biodistribution, LNP goes through kidney and liver

Phase II LNP Biodistribution

Tumour penetration

Phase III LNP Biodistribution

Intra-tumoral biodistribution (LNP goes deep into tumour)

What phase I (systemic biodistribution) factors affect the PK of NPs?

Size, PEGylation, charge

Renal filtration size cut off for NPs

5.5 nm

Renal filtration MW cut off for NPs

40 kDa

How does PEGylation affect a NPs interaction with macrophages?

It reduces macrophage uptake, prolonging circulation half-life (reduces RES uptake)

How does PEGylation affect the PK of NPs?

Increases steric hindrance and reduces protein binding

What would have a greater effect at increasing the circulation half life for a LNP?

A. Polyglycerol (PG), PC, Cholesterol

B. PEG, PG, PC, Cholesterol

B

1 multiple choice option

What does PEGylation do to the PK of encapsulated drugs?

Improves the PK

Positively charged NPs are eliminated by the...

Lung

Negatively charged NPs are eliminated by the...

Liver

PEG-750

Good for positively charged NPs

PEG-5000

Good for negatively and positively charged NPs

Extravasion

Going from circulation to tissue

Phase II factors affecting extravasion

Size, blood vessel modulation

_________ sized NPs extravasate into tumours more efficiently

Small

2 multiple choice options

How does nitroglycerin impact tumour blood flow and polymer delivery?

Increases blood flow and delivery

What is TNF-α

A chemical messenger produced by the immune system that induces inflammation

What does TNF-α do?

Increases tumour vascular permeability and liposome extravasation

What does radiation do?

Increases tumour vascular permeability and liposome extravasation

Phase III factors affecting tumour penetration

Size, targeting ligand, charge

For phase III (intratumour) NP delivery, how would a large NP and targeting ligand impact tumour penetration?

It would reduce tumour penetration

2 multiple choice options

What molecules exhibit increased tumour penetration?

Small and neutral

3 multiple choice options

K1

Penetration rate constant