Cell-Permeable, MMP-2 Activatable, Nickel Ferrite and His-Tagged Fusion Protein Self-Assembled Fluorescent Nanoprobe for Tumor Magnetic-Targeting and Imaging

Abstract

Matrix metalloproteinases (MMPs) activatable imaging probe has been explored for tumor detection. However, activation of the probe is mainly done in the extracellular space without intracellular uptake of the probe for more sensitivity. Although cell-penetrating peptides (CPPs) have been demonstrated to enable intracellular delivery of the imaging probe, they nevertheless encounter off-target delivery of the cargos to normal tissues. Herein, we have developed a dual MMP-2-activatable and tumor cell-permeable magnetic nanoprobe to simultaneously achieve selective and intracellular tumor imaging. This novel imaging probe was constructed by self-assembling a hexahistidine-tagged (His-tagged) fluorescent fusion protein chimera and nickel ferrite nanoparticles via a chelation mechanism. The His-tagged fluorescent protein chimera consisted of a red fluorescent protein mCherry that acted as the fluorophore, the low-molecular-weight protamine peptide as the CPP, and the MMP-2 cleavage sequence fused with the hexahistidine tag, whereas the nickel ferrite nanoparticles functioned as the His-tagged protein binder and also the fluorescent quencher. Both in vitro and in vivo results revealed that this imaging probe would not only remain nonpermeable to normal tissues, thereby offsetting the nonselective cellular uptake, but was also suppressed of fluorescent signals during magnetic tumor-targeting in the circulation, primarily because of the masking of the CPP activity and quenching of the fluorophore by the associated NiFeO nanoparticles. However, these properties were recovered or "turned on" by the action of tumor-associated MMP-2 stimuli, leading to cell penetration of the nanoprobes as well as fluorescence restoration and visualization within the tumor cells. In this regard, the presented tumor-activatable and cell-permeable system deems to be an appealing platform to achieve selective tumor imaging and intracellular protein delivery. Its impact is therefore significant, far-reaching, and wide-spread.

Tumor microenvironment-responsive nanoparticles for cancer theragnostic applications

“…The upregulated levels of MMP enzymes in TME makes them the most common target for enzyme-based TME nanoparticles. Sun et al [ 47 ] reported the development of MMP-2 activatable nanoprobes, which can be used for selective and specific intracellular imaging of the tumor (Fig. 3 ).…”

Synthesis and Characterization of Magnetic Zeolite Y–Palladium–Nickel Ferrite by Ultrasonic Irradiation and Investigating Its Catalytic Activity in Suzuki–Miyaura Cross-Coupling Reactions

“…The nickel ferrite (NF) compound, NiFe 2 O 4 , is a well-known inverse spinel including Ni 2+ and Fe 3+ ions distributed between the octahedral and tetrahedral sites, respectively . There are many reports about the use of nickel ferrite such as biomedical, electric, and electronic devices, ferro-fluids, magnetic refrigeration, color imaging, and microwave devices. − Also, there are many techniques like citric acid combustion, organic gel-thermal decomposition, sol–gel autocombustion, hydrothermal process, thermolysis, co-precipitation, gel-assistant hydrothermal process, self-propagation, and use of microemulsion for the preparation of nanocrystallite NF. − Amongst the reported techniques for the preparation of NF nanostructures, the microwave technique has gathered the most attention because of some benefits such as feasibility, inexpensiveness, environmental friendliness, and short reaction time …”

Overcoming the cellular barriers and beyond: Recent progress on cell penetrating peptide modified nanomedicine in combating physiological and pathological barriers

“…MMP-activatable CPPs also enhance the specificity in tumor imaging. Taking advantage of the over-expressed MMP-2 enzyme, Sun et al designed an MMP-2 activatable, cell permeable magnetic nanoprobe in which the fluorescence doner (mCherry fusion protein) and fluorescence quencher (a nickel ferrite NP) were conjugated with MMP-2 substrate peptide [58] . MMP-sensitive PEG cleavable strategy has endowed CPP-NPs with both stealth circulation and in time targeted cellular internalization, especially in tumor treatment.…”