Tumor-Selective Immune-Active Mild Hyperthermia Associated with Chemotherapy in Colon Peritoneal Metastasis by Photoactivation of Fluorouracil–Gold Nanoparticle Complexes

Abstract

Peritoneal metastasis (PM) is considered as the terminal stage of metastatic colon cancer, with still poor median survival rate even with the best recent chemotherapy treatment. The current PM treatment combines cytoreductive surgery, which consists of resecting all macroscopic tumors, with hyperthermic intraperitoneal chemotherapy (HIPEC), which uses mild hyperthermia to boost the diffusion and cytotoxic effect of chemotherapeutic drugs. As HIPEC is performed via a closed circulation of a hot liquid containing chemotherapy, it induces uncontrolled heating and drug distribution in the whole peritoneal cavity with important off-site toxicity and a high level of morbidity. Here, we propose a safer precision strategy using near-infrared (NIR) photoactivated gold nanoparticles (AuNPs) coupled to the chemotherapeutic drug 5-fluorouracil (5-FU) to enable a spatial and temporal control of mild chemo-hyperthermia targeted to the tumor nodules within the peritoneal cavity. Both the 16 nm AuNPs and the corresponding complex with 5-FU (AuNP–5-FU) were shown as efficient NIR photothermal agents in the microenvironment of subcutaneous colon tumors as well as PM in syngeneic mice. Noteworthy, NIR photothermia provided additional antitumor effects to 5-FU treatment. A single intraperitoneal administration of AuNP–5-FU resulted in their preferential accumulation in tumor nodules and peritoneal macrophages, allowing light-induced selective hyperthermia, extended tumor necrosis, and activation of a pro-inflammatory immune response while leaving healthy tissues without any damage. From a translational standpoint, the combined and tumor-targeted photothermal and chemotherapy mediated by the AuNP–drug complex has the potential to overcome the current off-target toxicity of HIPEC in clinical practice.

Numerical Simulation of Enhancement of Superficial Tumor Laser Hyperthermia with Silicon Nanoparticles

“…However, they require a sophisticated fabrication technique, while the pulsed laser ablation of silicon nanostructures in liquids seems to be a promising, scalable technology. As for inert material studies, gold nanoparticles irradiated with NIR light permit selective tumor hyperthermia at 42−43 • C without side effects to surrounding healthy tissues due to the spatial and temporal control of heat generation (selective accumulation and irradiation of heat nanosources) [104]. Nevertheless, silicon demonstrates more prominent biodegradation compared to gold, since silicon presents in living organisms as a natural trace compound.…”

Cancer nanotechnology: current status and perspectives

“…Multi-modal treatments pose the possibility of eliminating cancer via physical activation such as photothermal, photodynamic, radiation, and magnetic. Specifically, gold and carbon nanomaterials have been extensively used to induce hyperthermal effects upon near-infrared light (NIR) irradiation [ 248 , 359 ]. They can further be utilized for triggered drug release with therapeutics tethered to the surface or encapsulated within, and payload can release upon change in temperature or irradiation [ 360 , 361 ].…”

A Review on Drug Delivery System for Tumor Therapy

“…Chinnaiyan et al (2019) prepared 5-FU-loaded Guar Gum-capped AuNPs (5FU-G-AuNPs) which exhibited potential cytotoxic and apoptotic effects on MiaPaCa-2 cell lines. Based on the combined and tumor-targeted PTT and chemotherapy, AuNPs coupled to 5-FU were photoactivated by near-infrared (NIR) to enable a spatial and temporal control of mild chemohyperthermia targeted to the tumor nodules within the peritoneal cavity which overcame the current off-target toxicity of hyperthermic intraperitoneal chemotherapy in clinical practice (Mulens-Arias et al, 2021). In order to enhance the efficacy and minimize the side effects of 5-FU, AgNPs were often conjugated with targeted agents such as FA or anti-EGFR antibodies, which exerted an effective targeted therapy for some cancers such as breast cancer, liver cancer, cholangiocarcinoma, and colorectal cancer, in vivo and in vitro (Ganeshkumar et al, 2014;Ngernyuang et al, 2016;Mani et al, 2018;Gajendiran et al, 2019;Liszbinski et al, 2020).…”