NIR-responsive cisplatin nanoparticles for synergistic chemo-photothermal therapy of oral squamous cell carcinoma

Abstract

The typically occurring malignant tumor in the head and neck is oral squamous cell carcinoma (OSCC), which is highly aggressive and invasive. Despite surgical advancements, radiation, and chemotherapy, the prognosis for OSCC is still poor. Chemotherapy's effectiveness is frequently restricted by its serious side effects and the development of resistance. In this study, a cisplatin (CDDP)-loaded magnetic targeting nanoplatform (CDDP@PPy@Fe₃O₄) has been designed for synergistic chemo-photothermal therapy. PPy with carboxyl groups was first prepared by chemical oxidative polymerization. Then, Fe₃O₄ nanoparticles were synthesized in situ on its surface and loaded with CDDP through a reaction with the carboxyl groups. The CDDP@PPy@Fe₃O₄ nanocomposite serves not only as a nanocarrier for the targeted delivery of CDDP to alleviate the systemic toxicity of chemotherapy but also possesses excellent photothermal conversion properties, generating localized heat upon near-infrared laser irradiation that enables photothermal therapy. Contrary to using only chemotherapy or photothermal therapy, CDDP@PPy@Fe₃O₄ nanoparticles combined with NIR exposure exert superior anticancer effects against OSCC both in vivo and in vitro while exhibiting minimal side effects. Therefore, CDDP@PPy@Fe₃O₄ nanoparticles could be a promising candidate for nanomedicine in OSCC combination therapy.

Fig. 1. CDDP@PPy@Fe₃O₄ nanoparticle synthesis along with combined chemo-photothermal therapy in the tumor microenvironment.

Fig. 2. (A–C) Transmission electron microscopy images showing (A) PPy, (B) PPy@Fe₃O₄, and (C) CDDP@PPy@Fe₃O₄. (D) Particle-size distribution of PPy, PPy@Fe₃O₄, and CDDP@PPy@Fe₃O₄. (E) Fourier transform infrared spectroscopy of PPy and PPy@Fe₃O₄. (F) Zeta potential of PPy@Fe₃O₄ and CDDP@PPy@Fe₃O₄.

Fig. 3. (A) X-ray diffraction pattern showing PPy@Fe₃O₄. The standard Fe₃O₄ (JCPDS No. 65-3107) pattern is provided at the bottom for reference. (B) High-resolution X-ray photoelectron spectroscopy (XPS) spectrum of the Fe 2p region. (C) Comparative XPS spectra of (a) PPy@Fe₃O₄ and (b) CDDP@PPy@Fe₃O₄ in the wide-scan range. (D) Room-temperature magnetic hysteresis loop of CDDP@PPy@Fe₃O₄.

Fig. 4. Photothermal properties of CDDP@PPy@Fe₃O₄ nanoparticles (NPs). (A) Thermographic images and (B) corresponding heating curves of varying CDDP@PPy@Fe₃O₄ NP concentrations (808 nm, 1 W cm⁻²). (C) Heating curves of 200 μg mL⁻¹ CDDP@PPy@Fe₃O₄ NPs under varying power densities. (D) Heating-cooling curves of 200 μg mL⁻¹ CDDP@PPy@Fe₃O₄ NPs under repeated cycles at 1 W cm⁻². (E) Calculation of photothermal conversion efficiency (PCE).

Fig. 5. PPy@Fe₃O₄ NP cytotoxicity (A and B) Cell Counting Kit-8 assay results showing human umbilical vein endothelial cells (HUVEC) and human oral keratinocytes survival rates after exposure to varying PPy@Fe₃O₄ NPs concentrations for 24 h. (C) Calcein-acetoxymethyl/propidium iodide staining showing fluorescent HUVEC. Scale bar: 200 μm.

Fig. 6. In vitro release and anticancer effect. (A) Cumulative release of CDDP from CDDP@PPy@Fe₃O₄. (B and C) CAL27 cell viability after treatment, receiving or not receiving an 808 nm laser for 10 min at 1 W cm⁻². (D) Calcein-acetoxymethyl/propidium iodide staining showing fluorescent CAL27 cells. Scale bar: 200 μm. (L: laser).

Fig. 7. In vivo photothermal properties of CDDP@PPy@Fe₃O₄ nanoparticles. (A) Infrared thermographic images of tumor-bearing mice (CAL27 xenografts) receiving an 808 nm laser for 10 min at 1 W cm⁻². (B) Corresponding temperature profiles. (L: laser; M: magnet).

Fig. 8. Tumor suppression efficacy of CDDP@PPy@Fe₃O₄ nanoparticles in CAL27 tumor-bearing mice. (A) Treatment process. Changes in (B) tumor volume and (C) nude mice body weight in diverse experimental conditions. (D) Images and (E) excised tumor weights on day 28. (F) Hematoxylin and eosin and (G) Ki-67 antigen staining showing excised tumors from different experimental groups. Scale bar: 100 μm. (L: laser; M: magnet).