Current Drug Targets - Volume 16, Issue 6, 2015

Rapid technical advances in the field of non-linear microscopy have made intravital microscopy a vital pre-clinical tool for research and development of imaging-guided drug delivery systems. The ability to dynamically monitor the fate of macromolecules in live animals provides invaluable information regarding properties of drug carriers (size, charge, and surface coating), physiological, and pathological processes that exist between point-of-injection and the projected of site of delivery, all of which influence delivery and effectiveness of drug delivery systems. In this Review, we highlight how integrating intravital microscopy imaging with experimental designs (in vitro analyses and mathematical modeling) can provide unique information critical in the design of novel disease-relevant drug delivery platforms with improved diagnostic and therapeutic indexes. The Review will provide the reader an overview of the various applications for which intravital microscopy has been used to monitor the delivery of diagnostic and therapeutic agents and discuss some of their potential clinical applications.

Optical molecular imaging has been frequently used in many preclinical researches including cancer detection, tumor mechanism study, drug efficacy evaluation and targeted drug delivery. Among optical molecular imaging modalities, bioluminescence imaging and fluorescence imaging have acquired certain degree of development and attracted more and more attention in recent years for their high sensitivity and low cost. With the development of optical technology and probe technology, two-photon microscopy imaging and Raman imaging have been widely used in drug evaluation and tumor studies through cell and tissue imaging. This paper focuses on the occurrence and development of optical molecular imaging especially for its imaging method imaging system and its application in target drug delivery. Finally, the existing challenges and brand new applications of optical imaging techniques in drug delivery research are discussed.

Nanoparticles are emerging as versatile nanoplatforms for the construction of multifunctional nanoprobes, which not only can deliver drugs into desired tumor regions but also are able to monitor the delivery, release and biodistribution of drugs in real time. In order to assist drug delivery, fluorescent imaging that can make the transportation viewable is often used. Then, various fluorescent nanoprobes that are composed of fluorescent or non-fluorescent nanocarrier, small-molecular fluorophore, drug, targeting ligand are developed and applied in biomedical applications. In this review paper, we will summarize chemical strategies for the construction of multifunctional nanoprobes and for controlled release of drugs. Then, recent examples on fluorescent nanoprobes, which are based on quantum dots, carbon nanodots, upconversion nanoparticles and other nanomaterials, and their applications in optical-guided drug delivery will be reviewed.

Nanoparticles have recently had a major impact on basic biosciences, the pharmaceutical industry, and preclinical and translational medicine by enabling targeted delivery of therapeutic cargo to cells and tissues. The capacity to specifically tailor the pharmacokinetics, biodistribution, and longterm fate of therapeutic molecules for specific diseases and to avoid off-target side effects is a tremendously promising capability of these materials. However targeting of nanoparticle therapies from systemic circulation is very inefficient, and our understanding of the fundamental processes dictating in vivo fate remains limited, making it challenging to determine how to optimally and rationally design these materials for maximum efficacy. Recently multi-modal, multi-scale imaging technologies have emerged that have helped to improve our insight into these processes. Theranostic imaging agents have provided real-time and quantitative readouts of drug distribution and therapeutic response, multimodal imaging platforms have allowed a multi-scale analysis of distribution from the levels of cells to tissues, and exciting applications in live-animal tissue microscopy have provided key insights at the cellular level. In this review, we describe how multiscale imaging has shaped our ability to optimize nanoparticle drugs and discuss future directions that are expected to further catalyze clinical translation.

Photoacoustic imaging (PAI) is rapidly becoming established as a viable imaging modality for small animal research, with promise of near-future human clinical translation. In this review, we discuss emerging prospects for photoacoustic-guided drug delivery. PAI presents opportunities for applications related to drug delivery, mainly with respect to either monitoring drug effects or monitoring drugs themselves. PAI is well-suited for imaging disease pathology and treatment response. Alternatively, PAI can be used to directly monitor the accumulation of various light-absorbing contrast agents or carriers with theranostic properties.

Lead-compound optimization is an iterative process in the cancer drug development pipeline, in which small molecule inhibitors or biological compounds that are selected for their ability to bind specific targets are synthesised, tested and optimised. This process can be accelerated significantly using molecular imaging with nuclear medicine techniques, which aim to monitor the biodistribution and pharmacokinetics of radiolabelled versions of compounds. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can be used to quantify fourdimensional (temporal and spatial) clinically relevant information, to demonstrate tumor uptake of, and monitor the response to treatment with lead-compounds. This review discusses the pre-clinical and clinical value of the information provided by nuclear medicine imaging compared to the histological analysis of biopsied tissue samples. Also, the role of nuclear medicine imaging is discussed with regard to the assessment of the treatment response, radiotracer biodistribution, tumor accumulation, toxicity, and pharmacokinetic parameters, with mention of microdosing studies, pre-targeting strategies, and pharmacokinetic modelling.

Tremendous resources are being invested all over the world for prevention, diagnosis, and treatment of various types of cancer. Successful cancer management depends on accurate diagnosis of the disease along with precise therapeutic protocol. The conventional systemic drug delivery approaches generally cannot completely remove the competent cancer cells without surpassing the toxicity limits to normal tissues. Therefore, development of efficient drug delivery systems holds prime importance in medicine and healthcare. Also, molecular imaging can play an increasingly important and revolutionizing role in disease management. Synergistic use of molecular imaging and targeted drug delivery approaches provides unique opportunities in a relatively new area called ‘image-guided drug delivery’ (IGDD). Single-photon emission computed tomography (SPECT) is the most widely used nuclear imaging modality in clinical context and is increasingly being used to guide targeted therapeutics. The innovations in material science have fueled the development of efficient drug carriers based on, polymers, liposomes, micelles, dendrimers, microparticles, nanoparticles, etc. Efficient utilization of these drug carriers along with SPECT imaging technology have the potential to transform patient care by personalizing therapy to the individual patient, lessening the invasiveness of conventional treatment procedures and rapidly monitoring the therapeutic efficacy. SPECT-IGDD is not only effective for the treatment of cancer but might also find utility in the management of several other diseases. Herein, we provide a concise overview of the latest advances in SPECT-IGDD procedures and discuss the challenges and opportunities for advancement of the field.

Positron emission tomography (PET) is a functional imaging modality that measures pathophysiology status of disease noninvasively, and has become a key component for innovative drug delivery system (DDS) studies recently. The development of multifunctional chelating agents is critical for developing PET radiopharmaceuticals and therefore has become a hot and demanding research topic recently. The optimal chelators should be readily attached to biomolecules covalently, able to form stable complexes with radiometals, and demonstrate good bio-distribution pattern in vivo. Indeed, the selection of suitable chelators can facilitate the development of an effective PET imaging probe by improving targeting properties and providing favorable in vivo pharmacokinetics of radiolabeled probes. This review focuses on the recent developments of multifunctional chelators that are suitable for both imaging and radiation therapy.

Due to their high target affinity and specificity, antib odies are very suitable tumor-targeting vehicles for imaging and therapeutic application. This enables a theranostic approach of imaging targeted drug delivery in oncology and opens the way for personalized medicine, predicting drug delivery, response, and treatment outcome in the individual patient. Of the currently available molecular imaging techniques, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are the best suited imaging techniques to visualize and determine drug delivery to the target tissue quantitatively. Using the same antibody for imaging and targeted therapy may eliminate some limitations of antibody-based molecular imaging and therapy, like heterogeneous antigen expression and poor accessibility. However, challenges of this approach remain, for example in the pharmacokinetic behavior of radiolabeled antibodies and antibody-drug-conjugates. Despite these challenges, also exciting opportunities are at the horizon, by using antibodies as multimodal vehicles carrying both a diagnostic agent and a therapeutic agent. In this review, both the challenges and the opportunities of using radiolabeled antibodies for image-guided drug delivery are discussed.

Cancer-targeted radionuclide therapy is a promising approach for the treatment of a wide variety of malignancies, especially those resistant to conventional therapies. However, to improve the use of targeted radionuclide therapy for the management of cancer patients, the in vivo behaviors, dosimetry, and efficacy of radiotherapeutic agents need to be well characterized and monitored. Molecular imaging, which is a powerful tool for the noninvasive characterization and quantification of biological processes in living subjects at the cellular and molecular levels, plays an important role in the guidance of cancer radionuclide therapy. In this review, we introduce the radiotherapeutics for cancertargeted therapy and summarize the most recent evidence supporting the use of molecular imaging to guide cancer radionuclide therapy.

Success of medical treatments for any pathological disorders majorly depends on the efficacy of the therapeutic molecules and their delivery to the target sites. Non-invasive molecular imaging technologies have emerged as prime methods for validating both these aspects ranging from preclinical level to clinical application. Reporter genes and the respective reporter probes are essential components of molecular functional imaging that gained wide popularity throughout the world due to easy adaptation, user friendly software and cost-effective experiments. However, to monitor the therapeutic effects, reporter gene-reporter probes (RG-RP) are often combined with separate introductions of therapeutics whose delivery at target sites are not appropriately measured. A small group of reporter genes is associated with probes that behave like a signature as well as a therapeutic molecule thereby having theranostic properties. This Reporter Gene-Therapeutic Reporter Probe (RG-TRP) system bears additional advantages over RG-RP system and holds the promise of direct translational applications in humans. This short review focuses on describing the currently available and validated RG-TRP systems, delivery vehicles, associated imaging modalities, applications in various pathological conditions along with the merits and demerits. Identification of new RG-TRP system will open new direction in theranostic imaging with potential human applications.

Stem cell therapeutics is the future of regenerative medicine in the modern world. Many studies have been instigated with the hope of translating the outcome for the treatment of several disease conditions ranging from heart and neuronal disease to malignancies as grave as cancers. Stem cell therapeutics undoubtedly holds great promise on the front of regenerative medicine, however, the correct distribution and homing of these stem cells to the host site remained blinded until the recent advances in the discipline of molecular imaging. Herein, we discuss the various imaging guidance applied for determination of the proper delivery of various types of stem cell used as therapeutics for various maladies. Additionally, we scrutinize the use of several indirect labeling mechanisms for efficient tagging of the reporter entity for image guidance. Further, the promise of improving patient healthcare has led to the initiation of several clinical trials worldwide. However, in number of the cases, the benefits arrive with a price heavy enough to pose a serious health risk, one such being formation of teratomas. Thus numerous challenges and methodological obstacles must be overcome before their eloquent clinical impact can be realized. Therefore, we also discuss several clinical trials that have taken into consideration the various imaging guided protocols to monitor correct delivery and understand the distribution of therapeutic stem cells in real time.

Implantable drug delivery systems (DDS) provide a platform for sustained release of therapeutic agents over a period of weeks to months and sometimes years. Such strategies are typically used clinically to increase patient compliance by replacing frequent administration of drugs such as contraceptives and hormones to maintain plasma concentration within the therapeutic window. Implantable or injectable systems have also been investigated as a means of local drug administration which favors high drug concentration at a site of interest, such as a tumor, while reducing systemic drug exposure to minimize unwanted side effects. Significant advances in the field of local DDS have led to increasingly sophisticated technology with new challenges including quantification of local and systemic pharmacokinetics and implant- body interactions. Because many of these sought-after parameters are highly dependent on the tissue properties at the implantation site, and rarely represented adequately with in vitro models, new nondestructive techniques that can be used to study implants in situ are highly desirable. Versatile imaging tools can meet this need and provide quantitative data on morphological and functional aspects of implantable systems. The focus of this review article is an overview of current biomedical imaging techniques, including magnetic resonance imaging (MRI), ultrasound imaging, optical imaging, X-ray and computed tomography (CT), and their application in evaluation of implantable DDS.