Chongwei Chi

Intraoperative Imaging-Guided Cancer Surgery: From Current Fluorescence Molecular Imaging Methods to Future Multi-Modality Imaging Technology

Cancer is a major threat to human health. Diagnosis and treatment using precision medicine is expected to be an effective method for preventing the initiation and progression of cancer. Although anatomical and functional imaging techniques such as radiography, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) have played an important role for accurate preoperative diagnostics, for the most part these techniques cannot be applied intraoperatively. Optical molecular imaging is a promising technique that provides a high degree of sensitivity and specificity in tumor margin detection. Furthermore, existing clinical applications have proven that optical molecular imaging is a powerful intraoperative tool for guiding surgeons performing precision procedures, thus enabling radical resection and improved survival rates. However, detection depth limitation exists in optical molecular imaging methods and further breakthroughs from optical to multi-modality intraoperative imaging methods are needed to develop more extensive and comprehensive intraoperative applications. Here, we review the current intraoperative optical molecular imaging technologies, focusing on contrast agents and surgical navigation systems, and then discuss the future prospects of multi-modality imaging technology for intraoperative imaging-guided cancer surgery.

DNA-Nanostructure-Gold-Nanorod Hybrids for Enhanced In Vivo Optoacoustic Imaging and Photothermal Therapy.

A functional cancer theranostic nanoplatform is developed, specifically tailored toward the optoacoustic modality by combining gold nanorods with DNA nanostructures (D-AuNR). DNA origami is used as an efficient delivery vehicle owing to its prominent tumor-targeting property. The D-AuNR hybrids display an enhanced tumor diagnostic sensitivity by improved optoacoustic imaging and excellent photothermal therapeutic properties in vivo.

Use of Indocyanine Green for Detecting the Sentinel Lymph Node in Breast Cancer Patients: From Preclinical Evaluation to Clinical Validation

Assessment of the sentinel lymph node (SLN) in patients with early stage breast cancer is vital in selecting the appropriate surgical approach. However, the existing methods, including methylene blue and nuclides, possess low efficiency and effectiveness in mapping SLNs, and to a certain extent exert side effects during application. Indocyanine green (ICG), as a fluorescent dye, has been proved reliable usage in SLN detection by several other groups. In this paper, we introduce a novel surgical navigation system to detect SLN with ICG. This system contains two charge-coupled devices (CCD) to simultaneously capture real-time color and fluorescent video images through two different bands. During surgery, surgeons only need to follow the fluorescence display. In addition, the system saves data automatically during surgery enabling surgeons to find the registration point easily according to image recognition algorithms. To test our system, 5 mice and 10 rabbits were used for the preclinical setting and 22 breast cancer patients were utilized for the clinical evaluation in our experiments. The detection rate was 100% and an average of 2.7 SLNs was found in 22 patients. Our results show that the usage of our surgical navigation system with ICG to detect SLNs in breast cancer patients is technically feasible.

Core–Shell Gold Nanorod@Metal–Organic Framework Nanoprobes for Multimodality Diagnosis of Glioma

One of the most significant challenges in the diagnosis of brain cancer is efficient in vivo imaging using nontoxic nanoprobes. Core-shell gold nanorod@MIL-88(Fe) nanostars are successfully constructed as triple-modality imaging (computed tomography/magnetic-resonance imaging/photoacoustic imaging) nanoprobes that show low cytotoxicity, high contrast, high penetration depth, and high spatial resolution for accurate and noninvasive imaging and diagnosis of gliomas.

Fast and robust reconstruction for fluorescence molecular tomography via a sparsity adaptive subspace pursuit method

Fluorescence molecular tomography (FMT), as a promising imaging modality, can three-dimensionally locate the specific tumor position in small animals. However, it remains challenging for effective and robust reconstruction of fluorescent probe distribution in animals. In this paper, we present a novel method based on sparsity adaptive subspace pursuit (SASP) for FMT reconstruction. Some innovative strategies including subspace projection, the bottom-up sparsity adaptive approach, and backtracking technique are associated with the SASP method, which guarantees the accuracy, efficiency, and robustness for FMT reconstruction. Three numerical experiments based on a mouse-mimicking heterogeneous phantom have been performed to validate the feasibility of the SASP method. The results show that the proposed SASP method can achieve satisfactory source localization with a bias less than 1mm; the efficiency of the method is much faster than mainstream reconstruction methods; and this approach is robust even under quite ill-posed condition. Furthermore, we have applied this method to an in vivo mouse model, and the results demonstrate the feasibility of the practical FMT application with the SASP method.

The enhanced chemotherapeutic effects of doxorubicin loaded PEG coated TiO2 nanocarriers in an orthotopic breast tumor bearing mouse model

Many chemotherapeutics used for cancer treatments encounter issues during delivery to tumors in vivo and have high levels of systemic toxicity. One of the most prominent progresses in improving drug delivery efficiency is through exploring various types of nanoparticles (NPs) as drug carriers. Recent studies have demonstrated that titanium dioxide (TiO2) nanocarriers have potential for drug delivery and therapy even in multidrug resistant cancers in vitro. Moreover, it was proved that the anticancer activity of doxorubicin (DOX) was enhanced by loading onto TiO2 nanoparticles in breast cancer cells in vitro. However, there is no evidence from the animal model in vivo, which is a critical step for their further clinical applications. The aim of this study was to explore novel TiO2-PEG-DOX nanoparticles, the DOX loaded polyethylene glycol (PEG) coated TiO2 nanocarriers, and investigate their potential application in enabling controlled drug release and enhancing the chemotherapeutic efficacy of DOX in the orthotopic breast tumor bearing mice. The tumor growth and drug treatment efficacy were dynamically monitored by bioluminescence imaging (BLI), and the safety of NPs for in vivo usage was also evaluated. It was found that TiO2-PEG-DOX nanoparticles possessed improved antitumor efficacy without observable side effects compared to the free DOX treatment. Our study suggested that the PEG coated TiO2 nanocarrier is a safe and potential platform for the efficient drug delivery and minimizing the systemic toxicity of chemotherapeutic agents. It has been proved for the first time that TiO2-based nanocarriers enhance the chemotherapeutic effects of doxorubicin in vivo.

Intraoperative Identification of Liver Cancer Microfoci Using a Targeted Near-Infrared Fluorescent Probe for Imaging-Guided Surgery

Difficulties in the highly sensitive detection of tumour microfoci represent a critical obstacle toward improved surgical intervention in liver cancer. Conventional preoperative imaging methods and surgeons’ subjective experience are limited by their inability to effectively detect tumour lesions measuring less than 2 mm; however, intraoperative fluorescence molecular imaging may overcome this limitation. Here, we synthesised an arginine-glycine-aspartic acid (RGD)-conjugated mesoporous silica nanoparticle (MSN) highly loaded with indocyanine green (ICG) dye that could accurately delineate liver cancer margins and provide excellent tumour-to-normal tissue contrast intraoperatively. The increased ICG loading capacity and tumour specificity enabled the identification of residual microtumours and satellite lesions measuring less than 1 mm in living mice. Histological analysis validated the sensitivity and accuracy of this approach. We believe this technique utilising a new fluorescent nanoprobe with intraoperative optical imaging may offer a more sensitive and accurate method for liver cancer resection guidance, resulting in better surgical outcomes.

Optical Molecular Imaging Frontiers in Oncology: The Pursuit of Accuracy and Sensitivity

Cutting-edge technologies in optical molecular imaging have ushered in new frontiers in cancer research, clinical translation, and medical practice, as evidenced by recent advances in optical multimodality imaging, Cerenkov luminescence imaging (CLI), and optical image-guided surgeries. New abilities allow in vivo cancer imaging with sensitivity and accuracy that are unprecedented in conventional imaging approaches. The visualization of cellular and molecular behaviors and events within tumors in living subjects is improving our deeper understanding of tumors at a systems level. These advances are being rapidly used to acquire tumor-to-tumor molecular heterogeneity, both dynamically and quantitatively, as well as to achieve more effective therapeutic interventions with the assistance of real-time imaging. In the era of molecular imaging, optical technologies hold great promise to facilitate the development of highly sensitive cancer diagnoses as well as personalized patient treatment—one of the ultimate goals of precision medicine.

A Novel Region Reconstruction Method for Fluorescence Molecular Tomography

Fluorescence molecular tomography (FMT) could exploit the distribution of fluorescent biomarkers that target tumors accurately and effectively, which enables noninvasive real-time 3-D visualization as well as quantitative analysis of small tumors in small animal studies in vivo. Due to the difficulties of reconstruction, continuous efforts are being made to find more practical and efficient approaches to accurately obtain the characteristics of fluorescent regions inside biological tissues. In this paper, we propose a region reconstruction method for FMT, which is defined as an L1-norm regularization piecewise constant level set approach. The proposed approach adopts a priori information including the sparsity of the fluorescent sources and the fluorescent contrast between the target and background. When the contrast of different fluorescent sources is low to a certain degree, our approach can simultaneously solve the detection and characterization problems for the reconstruction of FMT. To evaluate the performance of the region reconstruction method, numerical phantom experiments and in vivo bead-implanted mouse experiments were performed. The results suggested that the proposed region reconstruction method was able to reconstruct the features of the fluorescent regions accurately and effectively, and the proposed method was able to be feasibly adopted in in vivo application.

Reconstruction of fluorescence molecular tomography via a nonmonotone spectral projected gradient pursuit method

Abstract. Fluorescence molecular tomography (FMT) is a promising imaging technique in preclinical research, enabling three-dimensional location of the specific tumor position for small animal imaging. However, FMT presents a challenging inverse problem that is quite ill-posed and ill-conditioned. Thus, the reconstruction of FMT faces various challenges in its robustness and efficiency. We present an FMT reconstruction method based on nonmonotone spectral projected gradient pursuit (NSPGP) with l1-norm optimization. At each iteration, a spectral gradient-projection method approximately minimizes a least-squares problem with an explicit one-norm constraint. A nonmonotone line search strategy is utilized to get the appropriate updating direction, which guarantees global convergence. Additionally, the Barzilai–Borwein step length is applied to build the optimal step length, further improving the convergence speed of the proposed method. Several numerical simulation studies, including multisource cases as well as comparative analyses, have been performed to evaluate the performance of the proposed method. The results indicate that the proposed NSPGP method is able to ensure the accuracy, robustness, and efficiency of FMT reconstruction. Furthermore, an in vivo experiment based on a heterogeneous mouse model was conducted, and the results demonstrated that the proposed method held the potential for practical applications of FMT.