A Telomerase-Activated Magnetic Resonance Imaging Probe for Consecutively Monitoring Tumor Growth Kinetics and In Situ Screening Inhibitors

Abstract

Telomerase has long been considered as a biomarker for cancer diagnosis and a therapeutic target for drug discovery. Detecting telomerase activity in vivo could provide more direct information of tumor progression and response to drug treatment, which, however, is hampered by the lack of an effective probe that can generate an output signal without a tissue penetration depth limit. In this study, using the principle of distance-dependent magnetic resonance tuning, we constructed a telomerase-activated magnetic resonance imaging probe (TAMP) by connecting superparamagnetic ferroferric oxide nanoparticles (SPFONs) and paramagnetic Gd-DOTA (Gd(III) 1,4,7,10tetraazacyclododecane-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) complexes via telomerase-responsive DNA motifs. Upon telomerase-catalyzed extension of the primer in TAMP, Gd-DOTA-conjugated oligonucleotides can be liberated from the surface of SPFONs through a DNA strand displacement reaction, restoring the T 1 signal of the Gd-DOTA for a direct readout of the telomerase activity. Here we show that, by tracking telomerase activity, this probe provides consistent monitoring of tumor growth kinetics during progression and in response to drug treatment and enables in situ screening of telomerase inhibitors in whole-animal models. This study provides an alternative toolkit for cancer diagnosis, treatment response assessment, and anticancer drug screening.

Nucleic acid sensors in vivo: challenges and opportunities

“…22,23 Therefore, there has been a lot of work in recent years to involve the specific binding of telomerase to specific sequences as a recognition modality in the design of biosensors for telomerase activity detection. Yang's group 39 has constructed a telomerase-activated MRI probe, achieving the monitoring of telomerase activity in vivo. The probe displaces down the paramagnetic complexlabeled NA strand through recognition and extension of the primer by telomerase, thus enabling a distancedependent shift of the MRI signal from off to on.…”

“…By modifying DNA strands with NIR fluorophores/quencher pair, they have achieved an effective combination of the activatable properties of NA probes with high resolution at a deep penetration depth of PA imaging. In addition to PET and PA imaging, Wang's group 39 developed a telomerase‐activated magnetic resonance (MR) imaging probe for telomerase detection in vivo. Paramagnetic Gd‐DOTA ((Gd(III) 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tet‐raacetic acid) complexes was conjugated to the oligonucleotides, which hybridized with anchor DNA.…”

Interaction of G‐quadruplex Forming DNA Aptamers with PAMAM Dendrimers Studied by Dynamic Light Scattering and UV‐VIS Spectrophotometry**

“…It was also shown that TBA and its TBA535 analogue exhibit antimotility properties [5] . To improve the therapeutic and diagnostic potential of aptamers, their complexation with various types of nanoparticles is advantageous [6–9] …”

“…[5] To improve the therapeutic and diagnostic potential of aptamers, their complexation with various types of nanoparticles is advantageous. [6][7][8][9] Dendrimers represent a synthetic group of polymer nanoparticles with an unique well defined radially branched structure being highly investigated as non-viral vectors and drug delivery carriers. [10] For these purposes, various types of dendrimers have been synthetized, such as carbosilane dendrimers, [11,12] polylysine dendrimers, [13] phosphorus-containing dendrimers [14] as well as commercially available polyamidoamine (PAMAM) dendrimers.…”

Flower-like porous BCN assembled by nanosheets for paclitaxel delivery

“…1 Despite advances in diagnostic and therapeutic technologies, as well as clinical treatments, the incidence of cancer continues to rise and the mortality rates still remain at high levels. [2][3][4][5] Currently, chemotherapy is widely used in clinical treatment; however, many chemotherapeutic drugs fail to specifically target cancer cells and tissues or exhibit low cellular uptake, resulting in high toxicity to normal tissues. 6,7 As a result, the dosage of drugs that can be used in clinical treatment is limited.…”