lec 8: nanotoxicity

toxicology

• the dose make the poison

• reports a lethal dose or inhibitory conc. at which 50% of the population dies for experiences effect

• related to

  • dosage

  • route of exposure

  • duration of exposure

  • stability → degradability

abestos

• 3-20um long, 10nm in diameter

• used in building insulation, etc.

• causes mesothelioma or asbestosis following long exposure

  • mechanical damage → fibers tangle with choromosomes and interlocking lung tissue

  • activate unwanted signaling channels

  • inflammation due to foreign body response

concern about nanomaterials

• several diseases have been found to be promoted by nanoparticles

• important to understand mechanism of toxicity and how to design and engineer biomaterials to eliminate toxicity and side effects

mechanism of nanotoxicity

• production of excess reaction oxygen species (ROS) → highly reactive molecules derived from O2

• ROS play a significant role in cell signalling and hemostasis, but in excess, they contribute to cellular damage

ROS damaging cells

• peroxidizing lipids → free radicals ‘steal’ electrons from the lipids in cell membranes, resulting in cell damage

• disrupting DNA

• interfering with signaling functions

• activating pro-cell death factors (could be good for cancer applications)

unfolding of proteins/enzymes to modify function

• NPs unfold fibrinogen (clotting cascade) and up-regulation of an inflammatory pathway

accessibility of NPs to typically non-accessible regions

• BBB

• permeation through skin not facilitated by chemical alone

rheological modifications in blood

• potential for shearing blood cells, activating platelets → initiating clotting cascade

nanotoxicity: effect of size

smaller particles:

• higher reactivity → enhanced ROS generation

• increased potential to cross epithelial junctions

• increases surface area:volume ratio (specific surface area) → more molecules to bind to the SA, resulting in increased toxic effect

administration of np

• side effects can be significant depending on the mechanism it is administered/exposure

• difficult to decouple size effects with those related to surface chemistry when comparing surface materials

effect of shape

• in-vitro results are very different from in-vivo because the nps have much more completed in-vivo fate in the procedure from administration to metabolism and excretion

• particles with higher aspect rations (length:width/diameter)

  • enhance potential for clotting/aggregation

  • enhance capacity for blocking membrane pores

  • prolonged retention, increase oxidative stress, and cytotoxicity

  • macrophage response: trigger chronic imflammation as macrophages struggle to engulf them, releasing harmful oxidants and cytokines