Gossypol‐Crosslinked Nanoclusters of Ultrasmall Iron Oxide Nanoparticles for Ultrasound‐Enhanced Precision Tumor Theranostics

Abstract

Development of tumor microenvironment (TME)‐responsive nanomedicines with simple components for precision tumor theranostics still maintains a great challenge. Here, the design of an intelligent nanocluster (NC) system assembled from gossypol‐mediated crosslinking of phenylboronic acid‐modified ultrasmall iron oxide nanoparticles (USIO NPs) is presented. The gossypol functions as both a chemotherapy (CT) drug and a crosslinker through phenylborate ester bonds that are sensitive to both reactive oxygen species (ROS) and pH. The developed gossypol‐USIO NCs (for short, G‐USIO NCs), having a size of 34.2 nm, possess stability under physiological conditions, enable intracellular ROS generation and glutathione depletion to modulate TME, promote apoptosis of cancer cells in vitro, and inhibit tumor/lung metastasis in vivo through gossypol‐mediated CT and USIO‐mediated chemodynamic therapy owing to the ROS‐ and pH‐triggered dissociation of the NCs to release gossypol and Fe at the tumor site. Likewise, the dissociated USIO NPs from the NCs afford TME‐facilitated T1‐weighted magnetic resonance (MR) imaging. Furthermore, the effects of the tumor T1 MR imaging and the combination therapy can be elevated by ultrasound‐targeted microbubble destruction‐induced cavitation and sonoporation. The designed G‐USIO NCs with simple ingredients are likely developed to be a promising theranostic nanomedicine formulation for ultrasound‐facilitated precision theranostics of various tumor types.

Macrophage membrane-camouflaged nanoclusters of ultrasmall iron oxide nanoparticles for precision glioma theranostics

“…C6 cells treated with USIO NPs show a total apoptosis and necrosis rate of 24.5%, validating the CDT performance of USIO NPs. 39,42,43 In addition, the total apoptosis and necrosis rate of C6 cells treated with free gossypol is 25.8%, showing the tendency of gossypol to induce cancer cell apoptosis, in agreement with the literature. 44 The sum of apoptotic and necrosis rate of G-USIO@MM NCs group is greater than that of G-USIO NCs group ( p < 0.001), which should be ascribed to the MMassisted specific targeting of NCs to C6 cells.…”

“…The citric acid-stabilized USIO NPs were prepared according to our earlier work. 39 To obtain the G-USIO NCs, USIO NPs were dispersed in water, activated by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, and reacted with EDA to generate aminated USIO NPs, which were further functionalized with 4-(bromomethyl) PBA. The created USIO-PBA NPs were subsequently crosslinked by gossypol through PBE bonding to get G-USIO NCs.…”

Ultrasmall iron oxide nanoparticles with MRgFUS for enhanced magnetic resonance imaging of orthotopic glioblastoma

“…It has been reported that ultrasmall iron oxide nanoparticles (USIO NPs) with a maximum size of 5.0 nm possess excellent T 1 -weighted imaging performance, which can effectively shorten the T 1 relaxation time of water protons. Moreover, USIO NPs can achieve flexible conversion between T 2 -and T 1 -weighted MRI via switchable size and structure upon certain stimulations with pH and glutathione (GSH), [23][24][25] which greatly broaden the application of USIO NPs in various bio-imaging applications. 26,27 In addition, due to the large specific surface area and high loading capacity, USIO NPs have been designed with targeting ligands for active targeting to satisfy the accurate diagnosis of various diseases and track certain living cells or biomarkers.…”