PLGA nanoparticle encapsulation reduces toxicity while retaining the therapeutic efficacy of EtNBS-PDT in vitro

Abstract

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.

Photodynamic therapy in 3D cancer models and the utilisation of nanodelivery systems

“…In an attempt to minimise the dark toxicity of EtNBS and examine its potential as a PDT photosensitser, Hung et al (2016) 122 encapsulated EtNBS in PLGA NPs and tested this formulation in OVCAR5 monolayer and spheroid models. In monolayer culture, EtNBS loaded nanoparticles showed reduced dark toxicity compared to cells treated with free EtNBS.…”

An Integrin-Targeted, Highly Diffusive Construct for Photodynamic Therapy

“…However, EtNBS is known to have so-called “dark toxicity”, a light-independent toxicity that can manifest when high concentrations of the small cationic photosensitizer are present. It was recently shown that encapsulation of EtNBS within nanoparticles can partially alleviate this toxicity, yet it is unclear if this delivery mechanism will be successful for systemic administration 23 . A mechanism to target EtNBS to cells of interest could avoid this dark toxicity when systemically administered and improve PDT outcome even within hypoxic environments.…”

Sensing, monitoring, and release of therapeutics: the translational journey of next generation bandages

“…Prior studies in the Evans team led to the development of proof-of-concept PLGA nanoparticles whose degradation could be triggered with light using photosensitizers. 24 Recent research efforts have been focused on embedding such particles into hydrogels, 25,26 to build oxygen sensing, drug-releasing materials. By incorporating oxygen-sensing phosphors into a hydrogel burn dressing developed by the Grinstaff lab at Boston University, [27][28][29] oxygenation measurements can now be performed on complex wound topologies in transudating/ exudating wound beds.…”