Complementing Cancer Photodynamic Therapy with Ferroptosis through Iron Oxide Loaded Porphyrin-Grafted Lipid Nanoparticles

Abstract

Nanomaterials that combine multimodality imaging and therapeutic functions within a single nanoplatform have drawn extensive attention for molecular medicines and biological applications. Herein, we report a theranostic nanoplatform based on a relatively smaller (<20 nm) iron oxide loaded porphyrin-grafted lipid nanoparticles (Fe3O4@PGL NPs). The amphiphilic PGL easily self-assembled on the hydrophobic exterior surface of ultrasmall Fe3O4 NPs, resulting in a final ultrasmall Fe3O4@PGL NPs with diameter of ∼10 nm. The excellent self-assembling nature of the as-synthesized PGL NPs facilitated a higher loading of porphyrins, showed a negligible dark toxicity, and demonstrated an excellent photodynamic effect against HT-29 cancer cells in vitro. The in vivo experimental results further confirmed that Fe3O4@PGL NPs were ideally qualified for both the fluorescence and magnetic resonance (MR) imaging guided nanoplatforms to track the biodistribution and therapeutic responses of NPs as well as to simultaneously trigger the generation of highly cytotoxic reactive oxygen species (ROS) necessary for excellent photodynamic therapy (PDT). After recording convincing therapeutic responses, we further evaluated the ability of Fe3O4@PGL NPs/Fe3O4@Lipid NPs for ferroptosis therapy (FT) via tumor microenvironment (TME) modulation for improved anticancer activity. We hypothesized that tumor-associated macrophages (TAMs) could significantly improve the efficacy of FT by accelerating the Fenton reaction in vitro. In our results, the Fe ions released in vitro directly contributed to the Fenton reaction, whereas the presence of RAW 264.7 macrophages further accelerated the ROS generation as observed by the fluorescence imaging. The significant increase in the ROS during the coincubation of NPs, endocytosed by HT-29 cells and RAW264.7 cells, further induced increased cellular toxicity of cancer cells.

US/MR Bimodal Imaging-Guided Bio-Targeting Synergistic Agent for Tumor Therapy

“…which is conducive to accurate tumor diagnosis and can guide the selection of time windows and real-time monitoring during cancer therapy. 45,46 Therefore, MR imaging results were similar to fluorescence imaging results, both in vitro and in vivo, suggesting that B. bifidum-mediated PFH@CL/Fe 3 O 4 NPs can be retained in tumors and be used as a contrast agent for T2-weighted MRI. Bio-targeted nanoplatforms combined with B. bifidum and PFH@CL/Fe 3 O 4 NPs can provide guidance and monitoring during HIFU therapy.…”

Surfactant-Free Green Synthesis of Au@Chlorophyll Nanorods for NIR PDT-Elicited CDT in Bladder Cancer Therapy

“…After conjugation with carboxyphenylboronic acid (CPBA), the improved internalization of the Au@Chl-Fe nanorods enabled PDT and restricted cell growth upon exposure to 660 and 785 nm light irradiation at extremely low concentrations of 0.16–1.6 ppm [Au] compared to other Au-related therapeutics. − The previous development of NIR-PDT in BC required the integration of upconversion NPs as a NIR-to-visible light transducer. Importantly, NIR light can drive better tissue-penetrating treatment due to the low absorption cross section and scattering. ,, Although combining CDT and PDT will result in strong ROS induction and better therapeutic outcomes, ,,, it remains unclear how to properly combine the two strategies using one functional material with high biocompatibility and specificity to BC. − Our demonstration showed that the enhanced inhibition of BC cell growth by direct NIR light-induced PDT prior to a long CDT period caused the immediate consumption of GSH antioxidant molecules and induced membrane lipid peroxidation (Scheme b), thus exacerbating ferroptosis in BC cells and raising hope for a cure for BC. Such a low treatment dose is advantageous for reducing the risk of metal accumulation in the body.…”

“…Inspired by Chl construction in the chloroplast for enhanced synergic photosynthesis, Au nanoparticles assembled with a high density of Chl were developed to increase the photoproduction of 1 O 2 to combat malignant tumor lesions. Herein, iron chlorophyll (Chl-Fe), acting as a natural photosensitizer and chemodynamic ferroptosis − therapy (CDT) activator, was used for the surfactant-free green synthesis of Au@Chl-Fe nanomaterials. Compared to previously reported spherical Au nanoparticles synthesized by surfactant additive and plant extract biomaterial coating methods, − our current green synthesis involving J-aggregates of Chl-Fe for the shape-guided growth of Au nanocrystals led to the formation of Au@Chl-Fe nanorod composites (Scheme a) with controlled temperatures, concentrations, and Chl-metal species.…”

“…Importantly, NIR light can drive better tissuepenetrating treatment due to the low absorption cross section and scattering. 32,34,47 Although combining CDT and PDT will result in strong ROS induction and better therapeutic outcomes, 32,34,35,48 it remains unclear how to properly combine the two strategies using one functional material with high biocompatibility and specificity to BC. 29−32 Our demonstration showed that the enhanced inhibition of BC cell growth by direct NIR light-induced PDT prior to a long CDT period caused the immediate consumption of GSH antioxidant molecules and induced membrane lipid peroxidation (Scheme 1b), thus exacerbating ferroptosis in BC cells and raising hope for a cure for BC.…”

Multifunctional Nanosystems Powered Photodynamic Immunotherapy

“…Moreover, some nanoparticles are also ideal carriers for traditional photosensitizers ( Lucky et al, 2015 ; Xie et al, 2021 ). The nano-photosensitizers and nano-delivery systems are able to accumulate more efficiently in tumor tissue through the enhanced permeability and retention (EPR) effect owing to the particle size and the abnormal vascular structure of tumors ( Peer et al, 2007 ; Hao et al, 2020 ; Li et al, 2021b ; Liang et al, 2021b ). The nanomaterials can also be further modified or functionalized to improve the targeting efficacy, enhancing the dosage of in tumor and reducing toxicity to normal tissues ( Zhong et al, 2015 ; Seidi et al, 2018 ; Liang et al, 2021a ).…”