PLGA nanoparticle encapsulation reduces toxicity while retaining the therapeutic efficacy of EtNBS-PDT in vitro
Hsin-I Hung1, Oliver J Klein1, Sam W Peterson1
1Wellman Center for Photomedicine, Harvard Medical School, Massachusetts General Hospital, 149 13th Street, Charlestown, Massachusetts 02129, United States.
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.
Insights
Nanoparticle encapsulation reduces dark toxicity of photosensitizers like EtNBS, enhancing photodynamic therapy effectiveness. This approach maintains cancer cell killing power, even in challenging tumor microenvironments.
Area of Science:
- Biochemistry
- Materials Science
- Oncology
Background:
- Photodynamic therapy (PDT) uses photosensitizers for targeted cancer treatment, effective against resistant tumors.
- Photosensitizers like EtNBS are potent in acidic, hypoxic tumor microenvironments but can cause light-independent 'dark toxicity' at higher doses.
Purpose of the Study:
- To evaluate nanoparticle encapsulation as a strategy to mitigate photosensitizer dark toxicity.
- To assess the efficacy of encapsulated photosensitizers in both normoxic and hypoxic conditions.
Main Methods:
- Encapsulation of EtNBS into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA-EtNBS).
- Assessment of dark toxicity and cytotoxicity of PLGA-EtNBS in cancer cells.
- Evaluation of nanoparticle penetration into 3D spheroid cultures.
Main Results:
- PLGA encapsulation significantly reduced EtNBS dark toxicity.
- Cytotoxicity was fully retained in both normoxic and hypoxic conditions.
- Light irradiation triggered an oxygen-independent release mechanism, degrading nanoparticles and releasing EtNBS.
Conclusions:
- PLGA-encapsulated EtNBS offers a dual benefit of reduced dark toxicity and preserved efficacy.
- The light-triggered release mechanism ensures targeted drug delivery.
- These nanoparticles show potential for treating resistant tumor regions inaccessible to conventional therapies.
