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High-quality multimodal imaging requires exogenous contrast agents with high sensitivity, spatial-temporal resolution, and high penetration depth for the accurate diagnosis and surveillance of cancer. Herein, we design a highly efficient fluorescent and magnetic multimodal probe by doping fluorescent molecule 2-(4-bromophenyl)-3-(4-(4-(diphenylamino)styryl)phenyl)fumaronitrile (TB) with near-infrared (NIR) fluorescent emission (714 nm) and superparamagnetic iron oxide (SPIO) into a polystyrene-polyethylene glycol (PS-PEG) matrix to form TB/SPIO@PS-PEG nanoparticles (TSP NPs). The as-prepared TSP NPs exhibit red aggregation-induced emission (AIE) with a maximum wavelength at 655 nm and high fluorescence quantum yield (QY) of 14.6%, facilitating the improvement of sensitivity and signal-to-background ratio for fluorescence molecular imaging (FMI). Phase behavior investigation of the TB/SPIO@PS-PEG probe system by Flory-Huggins lattice theory elucidates the highly efficient fluorescence of the multimodal probe, originating from the poor miscibility between TB and SPIO. Meanwhile, the TSP NPs possess good superparamagnetism and relaxivity and can thus be used as appropriate magnetic contrast agents for magnetic resonance imaging (MRI) and magnetic particle imaging (MPI). In addition, the good biocompatibility and photostability of the TSP NPs make them suitable for long-term monitoring. In vivo fluorescence imaging results indicate that the TSP NPs can facilitate monitoring of subcutaneous tumor growth for more than 24 days in a real-time manner. Multimodal imaging consisting of FMI, MRI, and MPI reveals that TSP NPs can monitor a liver tumor in situ with almost unlimited depth in tissues and high temporal-spatial resolution. As a multimodal probe, the TSP NPs manifest obvious synergistic advantages of long-term monitoring and high penetration depth and hold great prospects in tumor imaging.

Stem cell therapies are increasingly recognized as the future direction of regenerative medicine, but the biological fate of the administrated stem cells remains a major concern for clinical translation, which calls for an approach to efficiently monitoring the stem cell behaviors in vivo. Magnetic particle imaging (MPI) is an emerging technology for cell tracking; however, its utility has been largely restricted due to the lack of optimal magnetic nanoparticle tracers. Herein, by controlled engineering of the size and shape of magnetic nanoparticles tailored to MPI physics theory, a specialized MPI tracer, based on cubic iron oxide nanoparticles with an edge length of 22 nm (CIONs-22), is developed. Due to the inherent lower proportion of disordered surface spins, CIONs-22 exhibit significantly larger saturation magnetization than that of spherical ones, while they possess similar saturation magnetization but smaller coercivity compared to larger-sized CIONs. These magnetic properties of CIONs-22 warrant high sensitivity and resolution of MPI. With their efficient cellular uptake, CIONs-22 exhibit superior MPI performance for stem cell labeling and tracking compared to the commercialized tracer Vivotrax. By virtue of these advantages, CIONs-22 enable real-time and prolonged monitoring of the spatiotemporal trajectory of stem cells transplanted to hindlimb ischemia mice, which demonstrates the great potential of CIONs-22 as MPI tracers to advance stem cell therapies.

SM5-1 is a humanized mouse monoclonal antibody, targeting an over-expressed membrane protein of approximately 230 kDa in hepatocellular carcinoma (HCC). SM5-1 can be used for target therapy in hepatocellular carinoma due to its ability of inhibiting cell growth and inducing apoptosis. However, the tumor inhibition efficacy of SM5-1 in HCC cancer treatment remains low. In this study, we synthesized SM5-1-conjugated gold nanoparticles (Au-SM5-1 NPs) and investigated their anticancer efficacy in HCC both in vitro and in vivo. The tumor inhibition rates of Au-SM5-1 NPs for subcutaneous tumor mice were 40.10% ± 4.34%, 31.37% ± 5.12%, and 30.63% ± 4.87% on day 12, 18, and 24 post-treatment as determined by bioluminescent intensity. In addition, we investigated the antitumor efficacy of Au-SM5-1 NPs in orthotopic HCC tumor models. The results showed that the inhibition rates of Au-SM5-1 NPs can reach up to 39.64% ± 4.87% on day 31 post-treatment determined by the bioluminescent intensity of the abdomen in tumor-bearing mice. Furthermore, three-dimensional reconstruction results of the orthotopic tumor revealed that Au-SM5-1 NPs significantly inhibited tumor growth compared with SM5-1 alone. Our results suggested that the developed Au-SM5-1 NPs has great potential as an antibody-based nano-drug for HCC therapy.

Tumor cell complete extinction is a crucial measure to evaluate antitumor efficacy. The difficulties in defining tumor margins and finding satellite metastases are the reason for tumor recurrence. A synergistic method based on multimodality molecular imaging needs to be developed so as to achieve the complete extinction of the tumor cells. In this study, graphene oxide conjugated with gold nanostars and chelated with Gd through 1,4,7,10-tetraazacyclododecane-N,N′,N,N′-tetraacetic acid (DOTA) (GO-AuNS-DOTA-Gd) were prepared to target HCC-LM3-fLuc cells and used for therapy. For subcutaneous tumor, multimodality molecular imaging including photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) and the related processing techniques were used to monitor the pharmacokinetics process of GO-AuNS-DOTA-Gd in order to determine the optimal time for treatment. For orthotopic tumor, MRI was used to delineate the tumor location and margin in vivo before treatment. Then handheld photoacoustic imaging system was used to determine the tumor location during the surgery and guided the photothermal therapy. The experiment result based on orthotopic tumor demonstrated that this synergistic method could effectively reduce tumor residual and satellite metastases by 85.71% compared with the routine photothermal method without handheld PAI guidance. These results indicate that this multimodality molecular imaging-guided photothermal therapy method is promising with a good prospect in clinical application.

SM5-1 is a humanized mouse antibody which has a high binding specificity for a membrane protein of about 230 kDa overexpressed in hepatocellular carcinoma (HCC), melanoma and breast cancer. In this study, SM5-1-conjugated poly d, l (lactide-coglycolide) (PLA) PLA containing Cy7 (PLA-Cy7-SM5-1) was prepared to study the targeting specificity of the bioconjugate to HCC-LM3-fLuc cell. Then, SM5-1-conjugated PLA containing 5-fluorouracil (5-FU) (PLA-5FU-SM5-1) and PLA containing 5-FU (PLA-5FU) were prepared for treatment of subcutaneous HCC-LM3-fLuc tumor mice. The results showed that PLA-5FU-SM5-1, PLA-5FU and 5-FU induced a 45.07%, 23.56% and 19.05% tumor growth inhibition rate, respectively, on day 31 post-treatment as determined by bioluminescent intensity. In addition, in order to evaluate the antitumor efficacy of PLA-5FU-SM5-1, HCC-LM3-fLuc cells were injected into the liver to establish the experimental orthotopic liver tumor models. The experiments showed that PLA-5FU-SM5-1, PLA-5FU and 5-FU induced a 53.24%, 31.00%, and 18.11% tumor growth inhibition rate, respectively, on day 31 post-treatment determined by the bioluminescent intensity of the abdomen in tumor-bearing mice. Furthermore, we have calculated the three-dimensional location of the liver cancer in mice using a multilevel adaptive finite element algorithm based on bioluminescent intensity decay calibration. The reconstruction results demonstrated that PLA-5FU-SM5-1 inhibited the tumor rapid progression, which were consistent with the results of subcutaneous tumor mice experiments and in vitro cell experiment results.

Bioluminescence tomography (BLT) is a molecular imaging modality which can three-dimensionally resolve the molecular processes in small animalsin vivo. The ill-posedness nature of BLT problem makes its reconstruction bears nonunique solution and is sensitive to noise. In this paper, we proposed a sparse BLT reconstruction algorithm based on semigreedy method. To reduce the ill-posedness and computational cost, the optimal permissible source region was automatically chosen by using an iterative search tree. The proposed method obtained fast and stable source reconstruction from the whole body and imposed constraint without using a regularization penalty term. Numerical simulations on a mouse atlas, andin vivomouse experiments were conducted to validate the effectiveness and potential of the method.

Theranostic tantalum oxide nanoparticles (TaOxNPs) of about 40 nm were successfully developed by conjugating functional molecules including polyethylene glycol (PEG), near-infrared (NIR) fluorescent dye, doxorubicin (DOX), and hyaluronic acid (HA) onto the surface of the nanoparticles (TaOx@Cy7-DOX-PEG-HA NPs) for actively targeting delivery, pH-responsive drug release, and NIR fluorescence/X-ray CT bimodal imaging. The obtained nanoagent exhibits good biocompatibility, high cumulative release rate in the acidic microenvironments, long blood circulation time, and superior tumor-targeting ability. Both in vitro and in vivo experiments show that it can serve as an excellent contrast agent to simultaneously enhance fluorescence imaging and CT imaging greatly. Most importantly, such a nanoagent could enhance the therapeutic efficacy of the tumor greatly and the tumor growth inhibition was evaluated to be 87.5%. In a word, multifunctional TaOx@Cy7-DOX-PEG-HA NPs can serve as a theranostic nanomedicine for fluorescence/X-ray CT bimodal imaging, remote-controlled therapeutics, enabling personalized detection, and treatment of cancer with high efficacy.

As a high-sensitivity imaging modality, bioluminescence tomography can reconstruct the three-dimensional (3-D) location of an internal luminescent source based on the 3-D surface light distribution. However, we can only get the multi-orientation two-dimensional (2-D) bioluminescence distribution in the experiments. Therefore, developing an accurate universal registration method is essential for following bioluminescent source reconstruction. We can then map the multi-orientation 2-D bioluminescence distribution to the 3-D surface derived from anatomical information with it. We propose a 2-D -to-3-D registration method based on iterated optimal projection and applied it in a registration and reconstruction study of three transgenic mice. Compared with traditional registration methods based on the fixed points, our method was independent of the markers and the registration accuracy of the three experiments was improved by 0.3, 0.5, and 0.4 pixels, respectively. In addition, based on the above two registration results using the two registration methods, we reconstructed the 3-D location of the inner bioluminescent source in the three transgenic mice. The reconstruction results showed that the average error distance between the center of the reconstructed element and the center of the real element were reduced by 0.32, 0.48, and 0.39 mm, respectively.

As a novel molecular imaging technology, bioluminescence tomography (BLT) has become an important tool for biomedical research in recent years, which can perform a quantitative reconstruction of an internal light source distribution with the scattered and transmitted bioluminescent signals measured on the external surface of a small animal. However, BLT is severely ill-posed because of complex photon propagation in the biological tissue and limited boundary measured data with noise. Therefore, sufficient a priori knowledge should be fused for the uniqueness and stability of BLT solution. Permissible source region strategy and spectrally resolved measurements are two kinds of a priori knowledge commonly used in BLT reconstruction. This paper compares their performance with simulation and in vivo heterogeneous mouse experiments. In order to improve the efficiency of large-scale source restoration, this paper introduces an efficient iterative shrinkage thresholding method that not only has faster convergence rate but also has better reconstruction accuracy than the modified Newton-type optimization approach. Finally, a discussion of these two kinds of a priori knowledge is given based on the comparison results.

Bioluminescence tomography (BLT) is an effective molecular imaging (MI) modality. Because of the ill-posedness, the inverse problem of BLT is still open. We present a trust region method (TRM) for BLT source reconstruction. The TRM is applied in the source reconstruction procedure of BLT for the first time. The results of both numerical simulations and the experiments of cube phantom and nude mouse draw us to the conclusion that based on the adaptive finite element (AFE) framework, the TRM works in the source reconstruction procedure of BLT. To make our conclusion more reliable, we also compare the performance of the TRM and that of the famous Tikhonov regularization method after only one step of mesh refinement of the AFE framework. The conclusion is that the TRM can get faster and better results after only one mesh refinement step of AFE framework than the Tikhonov regularization method when handling large scale data. In the TRM, all the parameters are fixed, while in the Tikhonov method the regularization parameter needs to be well selected.

The purpose of this study was to noninvasively monitor the therapeutic efficacy of cyclophosphamide (CTX) in a mouse model by dual-modality molecular imaging: positron emission tomography (PET) and bioluminescence imaging (BLI). Firefly luciferase (fLuc) transfected HCC-LM3-fLuc human hepatocellular carcinoma cells were injected subcutaneously into BALB/c nude mice to establish the experimental tumor model. Two groups of HCC-LM3-fLuc tumor-bearing mice (n = 7 per group) were treated with saline or CTX (100 mg/kg on days 0, 2, 5, and 7). BLI and (18)F-fluorodeoxyglucose ((18)F-FDG) PET scans were done to evaluate the treatment efficacy. CTX induced a 25.25 ± 13.13% and 35.91 ± 25.85% tumor growth inhibition rate on days 9 and 12 posttreatment, respectively, as determined by BLI. A good linear correlation was found between the tumor sizes measured by caliper and the BLI signals determined by optical imaging (R(2) = .9216). (18)F-FDG imaging revealed a significant uptake reduction in the tumors of the CTX-treated group compared to that in the saline control group (5.30 ± 1.97 vs 3.00 ± 2.11% ID/g) on day 16 after CTX treatment. Dual-modality molecular imaging using BLI and small-animal PET can play important roles in the process of chemotherapy and will provide noninvasive and reliable monitoring of the therapeutic response.

Bioluminescence tomography (BLT) can three-dimensionally and quantitatively resolve the molecular processes in small animals in vivo. In this paper, we propose a BLT reconstruction algorithm based on duality and variable splitting. By using duality and variable splitting to obtain a new equivalent constrained optimization problem and updating the primal variable as the Lagrangian multiplier in the dual augmented Lagrangian problem, the proposed method can obtain fast and stable source reconstruction even without the permissible source region and multispectral measurements. Numerical simulations on a mouse atlas and in vivo mouse experiments were conducted to validate the effectiveness and potential of the method.

As a new modality of molecular imaging, bioluminescence imaging has been widely used in tumor detection and drug evaluation. However, BLI cannot present the depth of information for internal diseases such as a liver tumor in situ or a lung tumor in situ. In this paper, we describe a bioluminescence tomography (BLT) method based on the bioluminescent intensity attenuation calibration and applied it to the early detection of liver cancer in situ. In comparison with BLT without calibration, this method could improve the reconstruction accuracy by more than 10%. In comparison with micro-computed tomography and other traditional imaging modalities, this method can detect a liver tumor at a very early stage and provide reliable location information.

In vivo bioluminescence imaging (BLI) has played a more and more important role in biomedical research of small animals. Bioluminescence tomography (BLT) further translates the BLI optical information into three-dimensional bioluminescent source distribution, which could greatly facilitate applications in related studies. Although the diffusion approximation (DA) is one of the most widely-used forward models, higher-order approximations are still needed for in vivo small animal imaging. In this work, as a relatively accurate and higher-order approximation theory, the performance of the simplified spherical harmonics approximation (SPN) in BLT is evaluated detailedly in heterogeneous small animals. In the numerical validations, the SPN based results demonstrate better imaging quality compared with diffusion approximation heterogeneously under various source locations over wide optical domain. Although the evaluation for the effects of the optical property mismatch indicates the sensitivity of SPN is similar with DA model in the source localization, it may offer improved performance with much less artifacts. In what follows, heterogeneous experimental BLT reconstructions using in vivo mouse further evaluate the capability of the higher-order method for practical biomedical applications.

Tomographic bioluminescence imaging suffers from poor imaging robustness, since it is severely affected by selection of regularization parameter (RP) and initialization for source distribution. In this paper, a global-inexact-Newton based reconstruction methodology, which is regularized by a dynamic sparse term, is demonstrated for in vivo tomographic imaging. The novel method can enhance higher imaging reliability and efficiency. Mouse experimental reconstructions were performed to validate the proposed method. These results demonstrate that the source distribution can be accurately located over a wide range of values of RP and iteration initializations. Moreover, the reconstruction efficiency was also studied.