Current Topics in Medicinal Chemistry - Volume 10, Issue 12, 2010

This issue (volume 10, number 12) and the previous issue (volume 10, number 11) of Current Topics in Medicinal Chemistry, dedicated to “The Medicinal Chemistry of Targeted Tumor Imaging,” are aimed at describing and highlighting the state-of-the-art of current research and development in the field of molecular imaging probe development. Last issue contained a total of 5 review articles covering the chemistry of positron emission tomography (PET), single-photon emission computed tomography (SPECT), and activatable optical fluorescence imaging. The remaining 7 review articles on quantum dot based fluorescence imaging, T1 and T2 weighted MR contrast agents, gas microbubbles for contrast-enhanced ultrasound, theranostic nanoparticles, general design of cancer imaging probe and strategies to label cells for cancer are discussed in this issue. This issue starts by a review article from Jinhao Gao et al. summarizing recent advances of quantum dot (QD) nanoparticlebased near-infrared fluorescence (NIR) optical imaging probes. Compared with the organic dyes and fluorescent proteins, QDs show many unique optical properties, such as symmetrical, narrow, and tunable emission spectra, superior photostability, high quantum yields, and the capacity of simultaneous excitation of multiple fluorescence colors. Based on the availability of various Cd and non-Cd based quantum dots, how the physicochemical properties, surface chemistry and bioconjugation chemistry of QDs profoundly affect the absorption, distribution, metabolism, excretion, toxicity, and tumor targeting efficiency were elaborated in this article. The next review article by Nazila Kamaly et al. talked about the development and implementation of tumor targeted T1 MRI contrast agents, with an emphasis on the chemistry used to modify pre-existing clinical MRI contrast agents for targeted tumor imaging. MRI is capable of producing three dimensional images of tissues containing water with a high degree of spatial resolution. MRI contrast agents provide reliable means to enhance images and play a key role in clinical investigations. MRI contrast agents consist of molecules which incorporate a paramagnetic metal ion, most commonly Gd or iron (Fe). Image improvement arises from the modulation of longitudinal (T1) or transverse (T2) relaxation times of the surrounding bulk water protons by the coordinated metal ions. Both small molecules that carry single and nanoparticles (NPs) carrying multiple paramagnetic metal ions were discussed. The third review article by Lise-Marie Lacroix et al. described the synthesis of iron based magnetic nanoparticle (MNP) contrast agents for T2-weighted MRI or as heaters for magnetic fluid hyperthermia (MFH). It first introduced the nanomagnetism and elucidated the critical parameters to optimize the superparamagnetic NPs for MRI and ferromagnetic NPs for MFH. It then further outlined the new chemistry developed for making monodisperse MNPs with controlled magnetic properties. The review finally highlighted the NP functionalization with biocompatible molecules and biological targeting agents for tumor diagnosis and therapy. The fourth review article by Francesca Cavalieri et al. described the use of gas-filled microbubbles for ultrasound imaging guided cancer therapy. Combining diagnostic and therapeutic ultrasound for tumor imaging and treatment is especially attractive for reasons of simplicity and cost-effectiveness. The development of microbubbles acting as targeted and smart drug carriers is however a very challenging goal as these systems present difficult and inherent problems of stability. The methods of preparation, mechanism of action, in vitro and in vivo stability, structural/functional characterization of microbubbles were described in details. New mechanisms for ultrasound-enhanced local drug and gene delivery were also reviewed. Different strategies used to target microbubbles to regions of disease and some of the recent experiences in ultrasound image-guided therapy were illustrated. The fifth review article by Debatosh Majumdar et al. summarized the current status and future prospects of using nanotechnology for targeted cancer imaging. Theragnostics (or sometimes called theranostics) is an approach based on the fusion of diagnostics and therapeutics. In theragnostics, the results of diagnostic tests are used to design and decide the appropriate targeted therapy, in which an anti-cancer drug is delivered specifically to the targeted cancer site with the help of appropriate targeting ligands. Theragnostics is also aimed to monitor the treatment response, increase the drug efficacy and safety. This review provided a number of nanoparticle platforms for multimodality imaging and simultaneous imaging and therapy applications....

Molecular imaging plays a key role in personalized medicine, which is the goal and future of patient management. Among the various molecular imaging modalities, optical imaging may be the fastest growing area for bioanalysis, and the major reason is the research on fluorescence semiconductor quantum dots (QDs) and dyes have evolved over the past two decades. The great efforts on the synthesis of QDs with fluorescence emission from UV to nearinfrared (NIR) regions speed up the studies of QDs as optical probes for in vitro and in vivo molecular imaging. For in vivo applications, the fluorescent emission wavelength ideally should be in a region of the spectrum where blood and tissue absorb minimally and tissue penetration reach maximally, which is NIR region (typically 700-1000 nm). The goal of this review is to provide readers the basics of NIR-emitting QDs, the bioconjugate chemistry of QDs, and their applications for diagnostic tumor imaging. We will also discuss the benefits, challenges, limitations, perspective, and the future scope of NIR-emitting QDs for tumor imaging applications.

For effective tumour imaging by magnetic resonance imaging (MRI) there is a clear need to develop organ, tissue and cell specific contrast agents that can selectively bind to tumour biomarkers. The versatility of a range of bioconjugation techniques and facile coupling chemistries has facilitated the synthesis of MRI contrast agents bearing tumour targeting moieties that comprise small molecule affinity ligands, peptides, antibodies and even proteins. The aim of this review is to describe the development and implementation of tumour targeted T1 MRI contrast agents, with an emphasis on the chemistry used to modify pre-existing clinical MRI contrast agents for targeted tumour imaging.

Magnetic nanoparticles (MNPs) have been explored extensively as contrast agents for magnetic resonance imaging (MRI) or as heating agents for magnetic fluid hyperthermia (MFH) [1]. To achieve optimum operation conditions in MRI and MFH, these NPs should have well-controlled magnetic properties and biological functionalities. Although numerous efforts have been dedicated to the investigations on MNPs for biomedical applications [2-5], the NP optimizations for early diagnostics and efficient therapeutics are still far from reached. Recent efforts in NP syntheses have led to some promising MNP systems for sensitive MRI and efficient MFH applications. This review summarizes these advances in the synthesis of monodisperse MNPs as both contrast probes in MRI and as therapeutic agents via MFH. It will first introduce the nanomagnetism and elucidate the critical parameters to optimize the superparamagnetic NPs for MRI and ferromagnetic NPs for MFH. It will further outline the new chemistry developed for making monodisperse MNPs with controlled magnetic properties. The review will finally highlight the NP functionalization with biocompatible molecules and biological targeting agents for tumor diagnosis and therapy.

Gas-filled microbubbles are widely used in diagnostic imaging. Recent developments have greatly enhanced the potential use of microbubbles for both diagnostic and therapeutic applications. For the potential use of microbubbles in therapeutic applications, the chemical nature of the shell and its mechanical properties are crucial, and require a tailored synthetic approach. This review describes methods of preparation, mechanism of action, in vitro and in vivo stability and structural/functional characterization of microbubbles. New mechanisms for ultrasound-enhanced local drug and gene delivery are reviewed. Different strategies used to target microbubbles to regions of disease and some of the recent experiences in ultrasound image-guided therapy are also discussed.

Targeted imaging of cancer is crucial to modern-day cancer management. This review summarizes the current status and future prospects of targeted cancer imaging with MRI, PET, SPECT, CT, and optical imaging techniques. It describes various approaches of cancer imaging and therapy, based on targeting of integrins, somatostatin receptor, epidermal growth factor receptor (EGFR), Her-2/neu receptor, glucose transporter (GLUT), folate receptor, steroid receptor, and others. It also discusses the applications of nanotechnology in imaging and therapy of cancer. Techniques for imaging of cancer in multiple modalities, using a single agent in a single session, have been developed, and this technique is known as 'multimodality imaging'. In order to develop target-specific imaging probes, various targeting ligands, such as small molecules, antibodies, peptides and aptamers have been used. These new imaging agents will help to develop cancer imaging probes that are highly target specific, biocompatible, have high sensitivity, give high signal to noise ratio, and have optimum pharmacokinetic and pharmacodynamic profiles. In another approach, novel agents have been synthesized, suitable for use in imaging as well as in therapy, and they are known as 'theragnostic (or theranostic) agents'. Multidisciplinary approaches and collaborative research efforts from chemists, biologists, biomedical engineers, pharmaceutical scientists, and medical doctors will lead to the discovery of clinically useful imaging and therapeutic agents that can diagnose, prevent, and cure cancer.

Molecular imaging, the visualization, characterization and measurement of biological processes at the cellular, subcellular level, or even molecular level in living subjects, has rapidly gained importance in the dawning era of personalized medicine. Molecular imaging takes advantage of the traditional diagnostic imaging techniques and introduces molecular imaging probes to determine the expression of indicative molecular markers at different stages of diseases and disorders. As a key component of molecular imaging, molecular imaging probe must be able to specifically reach the target of interest in vivo while retaining long enough to be detected. A desirable molecular imaging probe with clinical translation potential is expected to have unique characteristics. Therefore, design and development of molecular imaging probe is frequently a challenging endeavor for medicinal chemists. This review summarizes the general principles of molecular imaging probe design and some fundamental strategies of molecular imaging probe development with a number of illustrative examples.

Cell-based therapy holds great promise for cancer treatment. The ability to non-invasively track the delivery of various therapeutic cells (e.g. T cells and stem cells) to the tumor site, and/or subsequent differentiation/proliferation of these cells, would allow better understanding of the mechanisms of cancer development and intervention. This brief review will summarize the various methods for non-invasive cell tracking in cancer and cancer therapy. In general, there are two approaches for cell tracking: direct (cells are labeled with certain tags that can be detected directly with suitable imaging equipment) and indirect cell labeling (which typically uses reporter genes approach). The techniques for tracking various cell types (e.g. immune cells, stem cells, and cancer cells) in cancer are described, which include fluorescence, bioluminescence, positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI). Non-invasive tracking of immune and stem cells were primarily intended for (potential) cancer therapy applications while tracking of cancer cells could further our understanding of cancer development and tumor metastasis. Safety is a major concern for future clinical applications and the ideal imaging modality for tracking therapeutic cells in cancer patients requires the imaging tags to be non-toxic, biocompatible, and highly specific. Each imaging modality has its advantages and disadvantages and they are more complementary than competitive. MRI, radionuclide-based imaging techniques, and reporter gene-based approaches will each have their own niches towards the same ultimate goal: personalized medicine for cancer patients.