Photodynamic therapy regimens, which use light-activated molecules known as
photosensitizers, are highly selective against many
malignancies and can bypass certain challenging therapeutic resistance mechanisms.
Photosensitizers such as the small cationic molecule
EtNBS (5-ethylamino-9-diethyl-aminobenzo[a]phenothiazinium
chloride) have proven potent against
cancer cells that reside within acidic and hypoxic tumour microenvironments. At higher doses, however, these
photosensitizers induce "dark toxicity" through light-independent mechanisms. In this study, we evaluated the use of nanoparticle encapsulation to overcome this limitation. Interestingly, encapsulation of the compound within
poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA-
EtNBS) was found to significantly reduce
EtNBS dark toxicity while completely retaining the molecule's cytotoxicity in both normoxic and hypoxic conditions. This dual effect can be attributed to the mechanism of release:
EtNBS remains encapsulated until external light irradiation, which stimulates an
oxygen-independent, radical-mediated process that degrades the PLGA nanoparticles and releases the molecule. As these PLGA-encapsulated
EtNBS nanoparticles are capable of penetrating deeply into the hypoxic and acidic cores of 3D spheroid cultures, they may enable the safe and efficacious treatment of otherwise unresponsive tumour regions.