Image-guided combined chemo-thermal therapy assists in optimizing treatment time, enhancing therapeutic efficiency, and circumventing side effects. In the present study, we developed a chemo-photothermal theranostic platform based on polydopamine (PDA)-coated gold nanorods (GNRs). The PDA coating was thin; however, it significantly suppressed the cytotoxicity of the cetyltrimethylammonium bromide template and allowed high cisplatin loading efficiency, arginine-glycine-aspartic acid (RGD) peptide (c(RGDyC)) conjugation, and chelator-free iodine-125 labeling (RGD-IPt-PDA@GNRs). While loaded cisplatin was released in a pH-sensitive manner, labeled I was outstandingly stable under biological conditions. RGD-IPt-PDA@GNRs had a high specificity for αvβ integrin, and consequently, they could selectively accumulate in tumors, as revealed by single photon emission computed tomography/CT imaging, and in target tumor angiogenic vessels, as shown by high-resolution photoacoustic imaging. As RGD-IPt-PDA@GNRs targets tumor angiogenesis, it is a highly potent tumor therapy. Combined chemo-photothermal therapy with probes could thoroughly ablate tumors and inhibit tumor relapse via a synergistic antitumor effect. Our studies demonstrated that RGD-IPt-PDA@GNRs is a robust platform for image-guided, chemo-thermal tumor therapy with outstanding synergistic tumor killing and relapse inhibition effects.

In this work, we have developed multiple-armed DNA tetrahedral nanostructures (TDNs) for dual-modality in vivo imaging using near-infrared (NIR) fluorescence and single-photon emission computed tomography (SPECT). We found that the presence of arm strands in TDNs remarkably enhanced their in vitro stability, allowing them to stay intact for at least 12 h in serum. By using NIR fluorescence imaging, we evaluated in mice the pharmacokinetics of TDNs, which exhibited distinctly different in vivo biodistribution patterns compared with those of double-stranded (ds)DNA. We also noticed that TDNs had twofold longer circulation time in the blood system than that of dsDNA. With the use of multiple-armed TDNs, we could precisely anchor an exact number of functional groups including tumor-targeting folic acid (FA), NIR emitter Dylight 755, and radioactive isotope (99m)Tc on prescribed positions of TDNs, which showed the capability of targeted imaging ability in cancer cells. Furthermore, we realized noninvasive tumor-targeting imaging in tumor-bearing mice by using both NIR and SPECT modalities.

Despite all the advances in multimodal imaging, it remains a significant challenge to acquire both magnetic resonance and nuclear imaging in a single dose because of the enormous difference in sensitivity. Indeed, nuclear imaging is almost 10(6)-fold more sensitive than magnetic resonance imaging (MRI); thus, repeated injections are generally required to obtain sufficient MR signals after nuclear imaging. Here, we show that strategically engineered magnetoferritin nanoprobes can image tumors with high sensitivity and specificity using SPECT and MRI in living mice after a single intravenous injection. The magnetoferritin nanoprobes composed of (125)I radionuclide-conjugated human H-ferritin iron nanocages ((125)I-M-HFn) internalize robustly into cancer cells via a novel tumor-specific HFn-TfR1 pathway. In particular, the endocytic recycling characteristic of TfR1 transporters solves the nuclear signal blocking issue caused by the high dose nanoprobes injected for MRI, thus enabling simultaneous functional and morphological tumor imaging without reliance on multi-injections.

Brassinosteroids (BRs) play important roles in plant growth, development, and stress responses through the receptor, Brassinosteroid-insensitive 1 (BRI1), which perceives BRs and initiates BR signaling. There is considerable potential agricultural value in regulating BR signaling in crops. In this study, we investigated the effects of overexpressing the tomato (Solanum lycopersicum) BRI1 gene, SlBRI1, on major agronomic traits, such as seed germination, vegetative growth, fruit ethylene production, carotenoid accumulation, yield, and quality attributes. SlBRI1 overexpression enhanced the endogenous BR signaling intensity thereby increasing the seed germination rate, lateral root number, hypocotyl length, CO2 assimilation, plant height, and flower size. The transgenic plants also showed an increase in fruit yield and fruit number per plant, although the mean weight of individual fruit was reduced, compared with wild type. SlBRI1 overexpression also promoted fruit ripening and ethylene production, and caused an increase in levels of carotenoids, ascorbic acid, soluble solids, and soluble sugars during fruit ripening. An increased BR signaling intensity mediated by SlBRI1 overexpression was therefore positively correlated with carotenoid accumulation and fruit nutritional quality. Our results indicate that enhancing BR signaling by overexpression of SlBRI1 in tomato has the potential to improve multiple major agronomic traits.

Gold nanoparticles (AuNPs) have recently garnered great interest as potential radiosensitizers in tumor therapy. However, major challenges facing their application in this regard are further enhancement of tumor accumulation of the particles in addition to enhanced permeability retention (EPR) effect and an understanding of the optimal particle size and time for applying radiotherapy after the particle administration. In this study, we fabricated novel cyclic c(RGDyC)-peptide-conjugated, Gd- and 99 mTc-labeled AuNPs (RGD@AuNPs-Gd99 mTc) probes with different sizes (29, 51, and 80 nm) and evaluated their potential as radiosensitization therapy both in vitro and in vivo. We found that these probes have a high specificity for αvβ3 integrin positive cells, which resulted in their high cellular uptake and thereby enhanced radiosensitization. Imaging in vivo with MRI and SPECT/CT directly showed that the RGD@AuNPs-Gd99 mTc probes specifically target tumors and exhibit greater accumulation within tumors than the RAD@AuNPs-Gd99 mTc probes. Interestingly, we found that the 80 nm RGD@AuNPs-Gd99 mTc probes exhibit the greatest effects in vitro; however, the 29 nm RGD@AuNPs-Gd99 mTc probes were clearly most efficient in vivo. As a result, radiotherapy of tumors with the 29 nm probe was the most potent. Our study demonstrates that RGD@AuNPs-Gd99 mTc probes are highly useful radiosensitizers capable of guiding and enhancing radiation therapy of tumors.

The structurally novel bifunctional ligands C-NETA and C-NE3TA, each possessing both acyclic and macrocyclic moieties, were prepared and evaluated as potential chelates for radioimmunotherapy (RIT) and targeted magnetic resonance imaging (MRI). Heptadentate C-NE3TA was fortuitously discovered during the preparation of C-NETA. An optimized synthetic method to C-NETA and C-NE3TA including purification of the polar and tailing reaction intermediates, tert-butyl C-NETA (2) and tert-butyl C-NE3TA (3) using semiprep HPLC was developed. The new Gd(III) complexes of C-NETA and C-NE3TA were prepared as contrast enhancement agents for use in targeted MRI. The T 1 relaxivity data indicate that Gd(C-NETA) and Gd(C-NE3TA) possess higher relaxivity than Gd(C-DOTA), a bifunctional version of a commercially available MRI contrast agent; Gd(DOTA). C-NETA and C-NE3TA were radiolabeled with (177)Lu, (90)Y, (203)Pb, (205/6)Bi, and (153)Gd; and in vitro stability of the radiolabeled corresponding complexes was assessed in human serum. The in vitro studies indicate that the evaluated radiolabeled complexes were stable in serum for 11 days with the exception being the (203)Pb complexes of C-NETA and C-NE3TA, which dissociated in serum. C-NETA and C-NE3TA radiolabeled (177)Lu, (90)Y, or (153)Gd complexes were further evaluated for in vivo stability in athymic mice and possess excellent or acceptable in vivo biodistribution profile. (205/6)Bi- C-NE3TA exhibited extremely rapid blood clearance and low radioactivity level at the normal organs, while (205/6)Bi- C-NETA displayed low radioactivity level in the blood and all of the organs except for the kidney where relatively high renal uptake of radioactivity is observed. C-NETA and C-NE3TA were further modified for conjugation to the monoclonal antibody Trastuzumab.

Forced oscillation of spherical and rod-shaped iron oxide magnetic nanoparticles (MNPs) via low-power and low-frequency alternating magnetic field (AMF) was firstly used to kill cancer cells in vitro. After being loaded by human cervical cancer cells line (HeLa) and then exposed to a 35-kHz AMF, MNPs mechanically damaged cell membranes and cytoplasm, decreasing the cell viability. It was found that the concentration and morphology of the MNPs significantly influenced the cell-killing efficiency of oscillating MNPs. In this preliminary study, when HeLa cells were pre-incubated with 100 μg/mL rod-shaped MNPs (rMNP, length of 200 ± 50 nm and diameter of 50 to 120 nm) for 20 h, MTT assay proved that the cell viability decreased by 30.9% after being exposed to AMF for 2 h, while the cell viability decreased by 11.7% if spherical MNPs (sMNP, diameter of 200 ± 50 nm) were used for investigation. Furthermore, the morphological effect of MNPs on cell viability was confirmed by trypan blue assay: 39.5% rMNP-loaded cells and 15.1% sMNP-loaded cells were stained after being exposed to AMF for 2 h. It was also interesting to find that killing tumor cells at either higher (500 μg/mL) or lower (20 μg/mL) concentration of MNPs was less efficient than that achieved at 100 μg/mL concentration. In conclusion, the relatively asymmetric morphological rod-shaped MNPs can kill cancer cells more effectively than spherical MNPs when being exposed to AMF by virtue of their mechanical oscillations.

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