A Multi‐Gradient Targeting Drug Delivery System Based on RGD‐l‐TRAIL‐Labeled Magnetic Microbubbles for Cancer Theranostics

Abstract

The accurately and efficiently targeted delivery of therapeutic/diagnostic agents into tumor areas in a controllable fashion remains a big challenge. Here, a novel cancer targeting magnetic microbubble is elaborately fabricated. First, the γ-Fe 2 O 3 magnetic iron oxide nanoparticles are optimized to chemically conjugate on the surface of polymer microbubbles. Then, arginineglycine-aspartic acid-l-tumor necrosis factor-related apoptosis-inducing ligand (RGD-l-TRAIL), antitumor targeting fusion protein, is precisely conjugated with magnetic nanoparticles of microbubbles to construct RGD molecularly targeted magnetic microbubble, which is defined as RGD-l-TRAIL@MMBs. Such RGD-l-TRAIL@MMBs is endowed with the multigradient cascade targeting ability following by magnetic targeting, RGD, as well as enhanced permeability and retention effect regulated targeting to result in high cancerous tissue targeting efficiency. Due to the highly specific accumulation of RGD-l-TRAIL@MMBs in the tumor, the accurate diagnostic information of tumor can be obtained by dual ultrasound and magnetic resonance imaging. After imaging, the TRAIL molecules as anticancer agent also get right into the cancer cells by nanoparticle-and RGD-mediated endocytosis to effectively induce the tumor cell apoptosis. Therefore, RGD-l-TRAIL conjugated magnetic microbubbles could be developed as a molecularly targeted multimodality imaging delivery system with the addition of chemotherapeutic cargoes to improve cancer diagnosis and therapy.

Click‐Chemistry‐Mediated Rapid Microbubble Capture for Acute Thrombus Ultrasound Molecular Imaging

“…Although many imaging strategies—including magnetic resonance imaging (MRI), ultrasound, computed tomography (CT), etc.—for visualization of the thrombus formation process have been developed, the specific detection and rapid evaluation of thrombotic events, especially at the molecular level, still presents a major clinical challenge. Ultrasound is a clinical diagnostic imaging modality that is widely available, portable, and non‐invasive for visualizing anatomy and physiology . Contrast‐enhanced ultrasound with the aid of gas‐filled micro‐sized bubbles (MBs, 1∼10 μm) has further enhanced the utility of ultrasound, and MBs have proved to be an effective imaging contrast agent to image blood flow more specifically, to discern the locations of certain molecular targets .…”

“…Ultrasound is ac linicald iagnostic imaging modality that is widely available, portable, and non-invasive for visualizing anatomy and physiology. [19] Contrast-enhanced ultrasound with the aid of gas-filled micro-sized bubbles (MBs, 1~10 mm) has further enhanced the utility of ultrasound, and MBs have provedt ob e an effective imagingc ontrast agentt oi mage bloodf low more specifically,t od iscern the locations of certain molecular targets. [20,21] As at hrombus formation imaging tool, contrast-enhanced ultrasound has been shown to be very effective if the targeting microbubblec oncentration attached to the clot is enough in the short term.…”

Progress in Bioinspired Dry and Wet Gradient Materials from Design Principles to Engineering Applications

“…Earlier researches have demonstrated that some inorganic gradient devices and organic functional materials have a medical application in blood and tissue engineering ( Le Duigou and Castro, 2016 ; Di Luca et al., 2015 ; Karabanova et al., 2012 ; Major et al., 2007 ; Shi et al., 2019 ). Because of its outstanding stimuli-response and fast response capabilities, the functional gradient materials' applications in biomedical applications have been reviewed and include scaffolding ( Liu et al., 2009 ; Singh et al., 2010 ; Wang et al., 2019 ), hydrogel ( Wei et al., 2017 ; Jo et al., 2019 ; Khorshidi and Karkhaneh, 2018 ), bioimaging ( Ng et al., 2017 ; Zhao et al., 2019a ; Moreno and Smedby, 2015 ), biocompatibility ( Li et al., 2017 ; O'Connor et al., 2000 ; Donnelly et al., 2012 ), and therapeutic agent delivery system ( Li et al., 2014 ; Duan et al., 2016 ). Finally, the challenges for fabrication of these materials and future perspective are also summarized.…”

Tumor‐Microenvironment‐Induced Degradation of Ultrathin Gadolinium Oxide Nanoscrolls for Magnetic‐Resonance‐Imaging‐Monitored, Activatable Cancer Chemotherapy

“…Currently, cancer poses an increasing threat to human health . Accordingly, various pre‐clinical studies have demonstrated the usefulness of inorganic nanoparticles .…”