The term molecular imaging can be broadly defined as the in vivo characterization and measurement of biologic processes at the cellular and molecular level. In contradistinction to "classical" diagnostic imaging, it sets forth to probe the molecular abnormalities that are the basis of disease rather than to image the end effects of these molecular alterations. While the underlying biology represents a new arena for many radiologists, concomitant efforts such as development of novel agents, signal amplification strategies, and imaging technologies clearly dovetail with prior research efforts of our specialty. Radiologists will play a leading role in directing developments of this embryonic but burgeoning field. This article presents some recent developments in molecular sciences and medicine and shows how imaging can be used, at least experimentally, to assess specific molecular targets. In the future, specific imaging of such targets will allow earlier detection and characterization of disease, earlier and direct molecular assessment of treatment effects, and a more fundamental understanding of the disease process.

Molecular Imaging

Fluorescent semiconductor nanocrystals (quantum dots) have the potential to revolutionize biological imaging, but their use has been limited by difficulties in obtaining nanocrystals that are biocompatible. To address this problem, we encapsulated individual nanocrystals in phospholipid block–copolymer micelles and demonstrated both in vitro and in vivo imaging. When conjugated to DNA, the nanocrystal-micelles acted as in vitro fluorescent probes to hybridize to specific complementary sequences. Moreover, when injected into Xenopus embryos, the nanocrystal-micelles were stable, nontoxic (<5 × 109 nanocrystals per cell), cell autonomous, and slow to photobleach. Nanocrystal fluorescence could be followed to the tadpole stage, allowing lineage-tracing experiments in embryogenesis.

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In vivo imaging with quantum dots encapsulated in phospholipid micelles

Vaccines are powerful tools that can activate the immune system for protection against various diseases. As carbohydrates can play important roles in immune recognition, they have been widely applied in vaccine development. Carbohydrate antigens have been investigated in vaccines against various pathogenic microbes and cancer. Polysaccharides such as dextran and β-glucan can serve as smart vaccine carriers for efficient antigen delivery to immune cells. Some glycolipids, such as galactosylceramide and monophosphoryl lipid A, are strong immune stimulators, which have been studied as vaccine adjuvants. In this review, we focus on the current advances in applying carbohydrates as vaccine delivery carriers and adjuvants. We will discuss the examples that involve chemical modifications of the carbohydrates for effective antigen delivery, as well as covalent antigen-carbohydrate conjugates for enhanced immune responses.

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Carbohydrate conjugates in vaccine developments

Early diagnosis of tumors is crucial in selecting appropriate treatment options to achieve the desired therapeutic effect, but it is difficult to accurately diagnose cancer by a single imaging modality due to technical constraints. Therefore, we synthesized a type of Fe3O4 nanoparticle with manganese dioxide grown on the surface and then prepared it by loading photosensitive drugs and traditional Chinese medicine monomers to create an integrated diagnosis/treatment multifunctional nanoplatform: Fe3O4@MnO2-celastrol (CSL)/Ce6. This nanoplatform can have full advantage of the tumor microenvironment (TME) characteristics of hypoxia (hypoxia), acidic pH (acidosis), and increased levels of reactive oxygen species (e.g., H2O2), even outside the TME. Specific imaging and drug release can also enhance tumor therapy by adjusting the hypoxic state of the TME to achieve the combined effect of chemotherapy (CT) and photodynamic therapy (PDT). Moreover, the obtained Fe3O4@MnO2-CSL/Ce6 has H2O2- and pH-sensitive biodegradation and can release the anticancer drug celastrol (CSL) and photosensitizer Ce6 in TME and simultaneously generate O2 and Mn2+. Therefore, the "dual response" synergistic strategy also confers specific drug release on nanomaterials, relieves tumor hypoxia and antioxidant capacity, and achieves significant optimization of CT and PDT. Furthermore, the resulting Mn2+ ions and Fe3O4 nanoparticles can be used for T1/T2 magnetic resonance imaging on tumor-bearing mice, and the released Ce6 can simultaneously provide fluorescence imaging functions. Therefore, Fe3O4@MnO2-CSL/Ce6 realized the synergistic treatment of PDT and CT under multimodal near-infrared fluorescence/photoacoustic (photoacoustic) imaging monitoring, showing its great potential in the accurate medical treatment of tumors.

Manganese/iron-based nanoprobes for photodynamic/chemotherapy combination therapy of tumor guided by multimodal imaging.

Simple Summary Aberrant glycosylation is a common feature of many cancers, and it plays crucial roles in tumor development and biology. Cancer progression can be regulated by several physiopathological processes controlled by glycosylation, such as cell–cell adhesion, cell–matrix interaction, epithelial-to-mesenchymal transition, tumor proliferation, invasion, and metastasis. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs), which are suitable for selective cancer targeting, as well as novel antitumor immunotherapy approaches. This review summarizes the strategies developed in cancer immunotherapy targeting TACAs, analyzing molecular and cellular mechanisms and state-of-the-art methods in clinical oncology. Abstract Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control.

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Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

Cancer is a complex multifactorial disease for which many promising therapeutic strategies such as immunotherapy are emerging. Malignant cells frequently express aberrant cell surface carbohydrates, which differentiate them from normal “healthy” cells. This characteristic presents a window for the development of synthetic carbohydrate antigen-based cancer vaccines which can be recognized by the immune system and can bring about T cell-dependent immune responses. Antibodies generated against the carbohydrate antigens partake in the inactivation of carbohydrate-decorated cancer cells, by slowing down tumor cell growth and inducing cancer cell apoptosis. Novel synthetic strategies for carbohydrate antigens have led to several synthetic cancer vaccine candidates. In the present review, we describe the latest progress in carbohydrate-based cancer vaccines and their clinical evaluation in various cancers.

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Recent advances in carbohydrate-based cancer vaccines.

Incorporating nanotechnology into fluorescent imaging and magnetic resonance imaging (MRI) has shown promising potential for accurate diagnosis of cancer at an earlier stage than the conventional imaging modalities. Molecular imaging (MI) aims to quantitatively characterize, visualize, and measure the biological processes or living cells at molecular and genetic levels. MI modalities have been exploited in different applications including noninvasive determination and visualization of diseased tissues, cell trafficking visualization, early detection, treatment response monitoring, and in vivo visualization of living cells. High-affinity molecular probe and imaging modality to detect the probe are the two main requirements of MI. Recent advances in nanotechnology and allied modalities have facilitated the use of nanoparticles (NPs) as MI probes. Within the extensive group of NPs, fluorescent NPs play a prominent role in optical molecular imaging. The fluorescent NPs used in molecular and cellular imaging can be categorized into three main groups including quantum dots (QDs), upconversion, and dyedoped NPs. Fluorescent NPs have great potential in targeted theranostics including cancer imaging, immunoassay- based cells, proteins and bacteria detections, imaging-guided surgery, and therapy. Fluorescent NPs have shown promising potentials for drug and gene delivery, detection of the chromosomal abnormalities, labeling of DNA, and visualizing DNA replication dynamics. Multifunctional NPs have been successfully used in a single theranostic modality integrating diagnosis and therapy. The unique characteristics of multifunctional NPs make them potential theranostic agents that can be utilized concurrently for diagnosis and therapy. This review provides the state of the art of the applications of nanotechnologies in early cancer diagnosis focusing on fluorescent NPs, their synthesis methods, and perspectives in clinical theranostics.

Nanomedicine and Early Cancer Diagnosis: Molecular Imaging using Fluorescence Nanoparticles

Abstract Hyperhomocysteinaemia (HHcy) is associated with all-cause mortality in some disease states. However, the correlation between HHcy and the risk of mortality in the general population has rarely been researched. We aimed to evaluate the association between HHcy and all-cause and cause-specific mortality among adults in the USA. This study analysed data from the National Health and Nutrition Examination Survey database (1999–2002 survey cycle). A multivariable Cox regression model was built to evaluate the correlation between HHcy and all-cause and cause-specific mortality. Smooth curve fitting was used to analyse their dose-dependent relationship. A total of 8442 adults aged 18–70 years were included in this study. After a median follow-up period of 14·7 years, 1007 (11·9 %) deaths occurred including 197 CVD-related deaths, 255 cancer-related deaths and fifty-eight respiratory disease deaths. The participants with HHcy had a 93 % increased risk of all-cause mortality (hazard ratio (HR) 1·93; 95 % CI (1·48, 2·51)), 160 % increased risk of CVD mortality (HR 2·60; 95 % CI (1·52, 4·45)) and 82 % increased risk of cancer mortality (HR 1·82; 95 % CI (1·03, 3·21)) compared with those without HHcy. For unmeasured confounding, E-value analysis proved to be robust. In conclusion, HHcy was associated with high risk of all-cause and cause-specific (CVD, cancer) mortality among adults aged below 70 years.

Association between hyperhomocysteinaemia and the risk of all-cause and cause-specific mortality among adults in the USA

Background and Objective: The combined effect of insulin resistance (IR) and total plasma homocysteine (tHcy) levels on the risk of mortality in nondiabetic populations has rarely been studied. We aimed to examine the association of tHcy levels and IR with the risk of mortality in nondiabetic populations. Methods: This observational cohort study was based on data from the Third National Health and Nutrition Examination Survey (NHANES III) database (1999-2002). A generalized additive model based on the Cox proportional hazards models was applied to estimate the relationship of tHcy levels with all-cause and cardiovascular disease (CVD) mortality. Smooth curve fitting was used to analyze their dose-dependent relationship. Results: During 5.7 years of follow-up, a total of 146 (5.8%) deaths occurred, including 65 deaths from CVD among 2053 individuals aged 40-80 years. In the multivariable adjusted model, every 1-μM increment of the tHcy level was associated with a 15% increase in risk of all-cause mortality and 20% increase in risk of CVD mortality among participants with IR (adjusted HR [95% CI]: 1.15 [1.06-1.24] and 1.20 [1.04-1.38]). However, among participants without IR, an increase of 1 μM in the tHcy level was associated with a 6% increase in risk of all-cause mortality and 3% increase in risk of CVD mortality (adjusted HR [95% CI]: 1.06 [1.00-1.13] and 1.03 [0.92-1.16]). Conclusions: Homocysteine levels were associated with higher risk of all-cause and CVD mortality among individuals with IR than among those without IR in a nondiabetic population aged 40-80 years.

Association of Homocysteine and Insulin Resistance with Increased Risk of Mortality in a Nondiabetic Population: Third National Health and Nutrition Examination Survey.

Autophagy plays a key role in protecting cells against injury caused by foreign substances and maintaining the stability of cells. Nanomaterials easily cause cell autophagy, as foreign substances. In this experiment, we explored whether overexpressing miR-24 protects autophagy response
 of pancreatic cancer mediated by silica nanoparticles. Silica nanoparticles were first characterized and then used to treat pancreatic cancer cells in a co-culture system. Pancreatic cancer cells were divided into blank group (no transfection), miR-24 group (miR-24 mimics transfection), and
 control group (miR-24 inhibitors transfection). Immunohistochemistry (IHC) and immunoblots were used to monitor the expression of autophagy gene Beclin-1 and LC3-II. Transmission electron microscopy (TEM) was used to observe the formation of autophagosomes. The diameters of silica nanoparticles
 were about 100 nm before and after modification, with uniform size, high dispersion, and a negative potential state. The silica nanoparticles caused fluorescence aggregation in many pancreatic cancer cells, significantly increasing the LC3-I and LC3-II, and promoted the cytoprotective autophagy
 ability of pancreatic cancer cells. Transfection of miR-24 significantly inhibited Beclin-1 and LC3-II. Western blots also confirmed that the miR-24 significantly suppressed Beclin-1 and LC3-II. TEM results suggested that the miR-24 transfection significantly inhibited the release of autophagosomes.
 Silica nanomaterials can cause the protective autophagy response of pancreatic cancer cells and increase LC3-I and LC3-II. miR-24 can significantly inhibit the protective autophagy of pancreatic cancer cells caused by silica nanoparticles and suppressed Beclin-1 and LC3-II. miR-24 can also
 inhibited the release of autophagosomes in pancreatic cancer cells to inhibit the protective autophagy.

Yan Lin

Papers

Recent advances in carbohydrate-based cancer vaccines.

Nanomedicine and Early Cancer Diagnosis: Molecular Imaging using Fluorescence Nanoparticles

Association between hyperhomocysteinaemia and the risk of all-cause and cause-specific mortality among adults in the USA

Association of Homocysteine and Insulin Resistance with Increased Risk of Mortality in a Nondiabetic Population: Third National Health and Nutrition Examination Survey.

miR-24 Exerts Its Anticancer Effect by Inhibiting Protective Autophagy of Pancreatic Cancer Mediated by Silica Nanoparticles