ALA/Ag2S/MnO2 hybrid nanoparticles for near-infrared image-guided long-wavelength phototherapy of breast cancer

Abstract

Thecombination of photothermal therapy (PTT) and photodynamictherapy (PDT) based on temperature increase and the formation of reactiveoxygen species (ROS), respectively, is an exciting avenue to providelocal and improved therapy of tumors with minimal off-site toxicity.5-Aminolevulinic acid (ALA) is one of the most popular PDT pro-drugs,and its efficiency improves significantly when delivered to tumorswith nanoparticles (NPs). But the tumor site's hypoxic environmentis a handicap for the oxygen-consuming PDT process. In this work,highly stable, small, theranostic NPs composed of Ag(2)Squantum dots and MnO2, electrostatically loaded with ALA,were developed for enhanced PDT/PTT combination of tumors. MnO2 catalyzes endogenous H2O2 to O-2 conversion and glutathione depletion, enhancing ROS generationand ALA-PDT efficiency. Ag2S quantum dots (AS QDs) conjugatedwith bovine serum albumin (BSA) support MnO2 formationand stabilization around Ag2S. AS-BSA-MnO2 provideda strong intracellular near-infrared (NIR) signal and increased thesolution temperature by 15 degrees C upon laser irradiation at 808 nm(215 mW, 10 mg/mL), proving the hybrid NP as an optically trackable,long-wavelength PTT agent. In the in vitro studies, no significantcytotoxicity was observed in the absence of laser irradiation in healthy(C2C12) or breast cancer cell lines (SKBR3 and MDA-MB-231). The mosteffective phototoxicity was observed when AS-BSA-MnO2-ALA-treatedcells were co-irradiated for 5 min with 640 nm (300 mW) and 808 nm(700 mW) due to enhanced ALA-PDT combined with PTT. The viabilityof cancer cells decreased to approximately 5-10% at 50 mu g/mL[Ag], corresponding to 1.6 mM [ALA], whereas at the same concentration,individual PTT and PDT treatments decreased the viability to 55-35%,respectively. The late apoptotic death of the treated cells was mostlycorrelated with high ROS levels and lactate dehydrogenase. Overall,these hybrid NPs overcome tumor hypoxia, deliver ALA to tumor cells,and provide both NIR tracking and enhanced PDT + PTT combination therapyupon short, low-dose co-irradiation at long wavelengths. These agentsthat may be utilized for treating other cancer types are also highlysuitable for in vivo investigations.