Concurrent Delivery of Paclitaxel and Chlorin e6 to Tumors Using Albumin/PLGA Nanoparticles for NIR Light-Triggered Chemo/Photodynamic Therapy

In an attempt to develop a nanomedicine with the ability to produce combination chemo- and photodynamic therapeutic effects in cancer, herein, we fabricated poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) using human serum albumin (HSA) as the surface modifier via the emulsification technique to co-deliver both a photosensitizer, chlorin e6 (Ce6), and a chemotherapeutic drug, paclitaxel (PTX). The Ce6/PTX-H/P NPs were characterized for size, morphology, drug loading, entrapment efficiencies, drug release, hemolytic tendency, and kinetic/storage stabilities by dynamic light scattering (DLS), scanning electron microscopy (SEM), ultraviolet (UV), infrared (IR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and differential scanning calorimetry (DSC) analysis. The protein integrity in NPs was verified by circular dichroism (CD) spectroscopy and sodium dodecyl–sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The ability to generate reactive oxygen species (ROS) by Ce6 was monitored biochemically using DMA, RNO, and singlet oxygen sensor green (SOSG). Next, cell studies using murine melanoma (B16F10) and oral squamous cell carcinoma (FaDu) were performed to determine cellular uptake, laser irradiation-assisted cytotoxicity, combination drug effect, and cell death mechanisms. The in vivo therapeutic efficacy was analyzed using tumor (B16F10)-bearing mice. The NPs released both PTX and Ce6 sustainably with the enhancement of drug release at a low pH of 4.6. The Ce6/PTX-H/P NPs exhibited photostimulated ROS production, resulting in enhanced cytotoxicity than monotherapies and induced a synergistic therapeutic response in FaDu cells (24 and 48 h of treatment). The Ce6/PTX-H/P NPs exhibited extensive apoptotic induction, cell cycle arrest, DNA damage in the G2/M phase, and mitochondrial membrane perturbation compared to the free Ce6 and PTX and Ce6- or PTX-loaded NPs. The Ce6/PTX-H/P NPs reduced the tumor weight by 5.99% compared to the control and ∼2.66% compared to the free drugs, demonstrating the most effective treatment modality of all the tested formulations in the in vivo experiment using B16F10 tumor-bearing mice and in the immunohistochemistry analysis. Ce6/PTX-H/P NPs could be a promising treatment option for solid tumors.