Cross-Correlative Single-Cell Analysis Reveals Biological Mechanisms of Nanoparticle Radiosensitization.
ACS Nano
; 13(5): 5077-5090, 2019 05 28.
Article
in En
| MEDLINE
| ID: mdl-31009200
ABSTRACT
Nanoparticle radiosensitization has been demonstrated well to enhance the effects of radiotherapy, motivate the improvement of therapeutic ratios, and decrease morbidity in cancer treatment. A significant challenge exists in optimizing formulations and translation due to insufficient knowledge of the associated mechanisms, which have historically been limited to physical concepts. Here, we investigated a concept for the role of biological mechanisms. The mere presence of gold nanoparticles led to a down-regulation of thymidylate synthase, important for DNA damage repair in the radioresistant S-phase cells. By developing a cross-correlative methodology to reveal probabilistic gold nanoparticle uptake by cell sub-populations and the associated sensitization as a function of the uptake, a number of revealing observations have been achieved. Surprisingly, for low numbers of nanoparticles, a desensitization action was observed. Sensitization was discovered to preferentially impact S-phase cells, in which impairment of the DNA damage response by the homologous recombination pathway dominates. This small but radioresistant cell population correlates with much greater proliferative ability. Thus, a paradigm is presented whereby enhanced DNA damage is not necessarily due to an increase in the number of DNA double-strand breaks (DSBs) created but can be from a nanoparticle-induced impairment of the damage response by down-regulating repair proteins such as thymidylate synthase.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Radiation-Sensitizing Agents
/
Nanoparticles
/
Single-Cell Analysis
Limits:
Humans
Language:
En
Journal:
ACS Nano
Year:
2019
Document type:
Article
Affiliation country:
Australia