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 nanomedicinewith the ability to producecombination 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 emulsificationtechnique to co-deliver both a photosensitizer, chlorin e6 (Ce6),and a chemotherapeutic drug, paclitaxel (PTX). The Ce6/PTX-H/P NPswere characterized for size, morphology, drug loading, entrapmentefficiencies, drug release, hemolytic tendency, and kinetic/storagestabilities by dynamic light scattering (DLS), scanning electron microscopy(SEM), ultraviolet (UV), infrared (IR), X-ray diffraction (XRD), X-rayphotoelectron spectroscopy (XPS), and differential scanning calorimetry(DSC) analysis. The protein integrity in NPs was verified by circulardichroism (CD) spectroscopy and sodium dodecyl-sulfate polyacrylamidegel electrophoresis (SDS-PAGE). The ability to generate reactive oxygenspecies (ROS) by Ce6 was monitored biochemically using DMA, RNO, andsinglet oxygen sensor green (SOSG). Next, cell studies using murinemelanoma (B16F10) and oral squamous cell carcinoma (FaDu) were performedto determine cellular uptake, laser irradiation-assisted cytotoxicity,combination drug effect, and cell death mechanisms. The invivo therapeutic efficacy was analyzed using tumor (B16F10)-bearingmice. The NPs released both PTX and Ce6 sustainably with the enhancementof drug release at a low pH of 4.6. The Ce6/PTX-H/P NPs exhibitedphotostimulated ROS production, resulting in enhanced cytotoxicitythan monotherapies and induced a synergistic therapeutic responsein FaDu cells (24 and 48 h of treatment). The Ce6/PTX-H/P NPs exhibitedextensive apoptotic induction, cell cycle arrest, DNA damage in theG2/M phase, and mitochondrial membrane perturbation compared to thefree Ce6 and PTX and Ce6- or PTX-loaded NPs. The Ce6/PTX-H/P NPs reducedthe tumor weight by 5.99% compared to the control and & SIM;2.66%compared to the free drugs, demonstrating the most effective treatmentmodality of all the tested formulations in the in vivo experiment using B16F10 tumor-bearing mice and in the immunohistochemistryanalysis. Ce6/PTX-H/P NPs could be a promising treatment option forsolid tumors.

Automated summary

In this study, PLGA nanoparticles modified with human serum albumin (HSA) were developed to co-deliver the photosensitizer Ce6 and chemotherapy drug PTX for combination chemo- and photodynamic therapeutic effects. The nanoparticles were characterized for size, morphology, drug loading, release, stability, and protein integrity. The ability of Ce6 to generate reactive oxygen species (ROS) was monitored biochemically. Cell studies and in vivo experiments were conducted to evaluate cellular uptake, cytotoxicity, combination drug effect, and therapeutic efficacy. The Ce6/PTX-H/P nanoparticles exhibited sustained drug release, enhanced cytotoxicity, and induced a synergistic therapeutic response.