Imaging Nanomedicine-Based Drug Delivery: a Review of Clinical Studies.

Imaging plays a key role in the preclinical evaluation of nanomedicine-based drug delivery systems and it has provided important insights into their mechanism of action and therapeutic effect. Its role in supporting the clinical development of nanomedicine products, however, has been less explored. In this review, we summarize clinical studies in which imaging has provided valuable information on the pharmacokinetics, biodistribution, and target site accumulation of nanomedicine-based drug delivery systems.

Histidine-rich glycoprotein-induced vascular normalization improves EPR-mediated drug targeting to and into tumors.

Tumors are characterized by leaky blood vessels, and by an abnormal and heterogeneous vascular network. These pathophysiological characteristics contribute to the enhanced permeability and retention (EPR) effect, which is one of the key rationales for developing tumor-targeted drug delivery systems. Vessel abnormality and heterogeneity, however, which typically result from excessive pro-angiogenic signaling, can also hinder efficient drug delivery to and into tumors.

Semi-Automated Segmentation of the Tumor Vasculature in Contrast-Enhanced Ultrasound Data.

The vascular architecture in tumors contains relevant information for tumor classification and evaluation of therapy responses. To develop a reliable and user-independent analysis tool, a foreground detection algorithm was combined with a maximum-intensity projection to obtain a high signal-to-noise image from contrast-enhanced B-mode data sets, enabling vessel segmentation by thresholding. Parameters describing the density of the vascular network, the number of vessels and the number of branches were extracted.

Evaluation of subconjunctival liposomal steroids for the treatment of experimental uveitis.

Non-infectious anterior uveitis (AU) is a potentially sight threatening inflammatory condition. The current gold standard for treatment is topical steroids, but low ocular bioavailability and compliance issues with the intensive dosing regimen limit the efficacy of this treatment. Liposomes as a drug delivery system may help to overcome these problems.

A water-soluble PEGylated RGD-functionalized bisbithiophenyl diketopyrrolopyrrole as a photoacoustic sonophore.

Photoacoustic imaging presents an innocuous imaging modality with good penetration depth and resolution. To use this modality for detection and imaging of pathological sites, new imaging probes need to be developed to enhance the contrast over endogenous sonophores. These contrast agents should specifically bind to the site of interest, be non-toxic and be cleared renally if applied intravenously.

Influence of cholesterol inclusion on the doxorubicin release characteristics of lysolipid-based thermosensitive liposomes.

Fast hyperthermia (i.e. 39-42 °C) triggered doxorubicin release from lysolipid-containing thermosensitive liposomes (LTSL) in the tumor vasculature has been demonstrated to result in considerable enhancement of bioavailable drug levels in heated tumor tissue in preclinical tumor models.

Automated Generation of Reliable Blood Velocity Parameter Maps from Contrast-Enhanced Ultrasound Data.

Objectives: The purpose of this study was the automated generation and validation of parametric blood flow velocity maps, based on contrast-enhanced ultrasound (CEUS) scans.

Materials And Methods: Ethical approval for animal experiments was obtained. CEUS destruction-replenishment sequences were recorded in phantoms and three different tumor xenograft mouse models.

Bio-degradable highly fluorescent conjugated polymer nanoparticles for bio-medical imaging applications.

Conjugated polymer nanoparticles exhibit strong fluorescence and have been applied for biological fluorescence imaging in cell culture and in small animals. However, conjugated polymer particles are hydrophobic and often chemically inert materials with diameters ranging from below 50 nm to several microns. As such, conjugated polymer nanoparticles cannot be excreted through the renal system.

Recent advances in ultrasound-based diagnosis and therapy with micro- and nanometer-sized formulations.

Ultrasound (US) is one of the most frequently used imaging methods in the clinic. The broad spectrum of its applications can be increased by the use of gas-filled microbubbles (MB) as ultrasound contrast agents (UCA). In recent years, also nanoscale UCA like nanobubbles (NB), echogenic liposomes (ELIP) and nanodroplets have been developed, which in contrast to MB, are able to extravasate from the vessels into the tissue.

Physicochemical Characterization of the Shell Composition of PBCA-Based Polymeric Microbubbles.

Microbubbles (MB) are routinely used as contrast agents for ultrasound (US) imaging. In recent years, MB have also attracted interest as drug delivery systems. Soft-shelled lipidic MB tend to be more advantageous for US imaging, while hard-shelled polymeric MB appear to be more suitable for drug delivery purposes because of their thicker shell and the resulting higher drug loading capacity.

Targeting iron metabolism in drug discovery and delivery.

Iron fulfils a central role in many essential biochemical processes in human physiology; thus, proper processing of iron is crucial. Although iron metabolism is subject to relatively strict physiological control, numerous disorders, such as cancer and neurodegenerative diseases, have recently been linked to deregulated iron homeostasis. Consequently, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments for these diseases.

Targeting distinct myeloid cell populations in vivo using polymers, liposomes and microbubbles.

Identifying intended or accidental cellular targets for drug delivery systems is highly relevant for evaluating therapeutic and toxic effects. However, limited knowledge exists on the distribution of nano- and micrometer-sized carrier systems at the cellular level in different organs. We hypothesized that clinically relevant carrier materials, differing in composition and size, are able to target distinct myeloid cell subsets that control inflammatory processes, such as macrophages, neutrophils, monocytes and dendritic cells.

Bone regeneration induced by a 3D architectured hydrogel in a rat critical-size calvarial defect.

Bone regeneration can be stimulated by implantation of biomaterials, which is especially important for larger bone defects. Here, healing potency of the porous ArcGel was evaluated in a critical-size calvarial bone defect in rats in comparison with clinical standard autologous bone and Bio-Oss Collagen (BioOss), a bone graft material frequently used in clinics. Bone healing and metabolic processes involved were monitored longitudinally by [F]-fluoride and [F]-FDG μ-PET/CT 1d, 3d, 3w, 6w, and 12w post implantation.

Docosahexaenoic acid liposomes for targeting chronic inflammatory diseases and cancer: an in vitro assessment.

Inflammation, oxidative stress, and uncontrolled cell proliferation are common key features of chronic inflammatory diseases, such as atherosclerosis and cancer. ω3 polyunsaturated fatty acids (PUFAs; also known as omega3 fatty acids or fish oil) have beneficial effects against inflammation upon dietary consumption. However, these effects cannot be fully exploited unless diets are enriched with high concentrations of fish oil supplements over long periods of time.

Contrast-enhanced CT imaging in patients with chronic kidney disease.

Renal microvascular rarefaction characterizes chronic kidney disease (CKD). In murine models of CKD, micro-CT imaging reflected capillary rarefaction using quantification of renal relative blood volume (rBV). In addition, micro-CT imaging revealed morphological alterations of the intrarenal vasculature including reduced vascular branching and lumen diameter.

In Vivo Imaging of Antileukemic Drug Asparaginase Reveals a Rapid Macrophage-Mediated Clearance from the Bone Marrow.

Unlabelled: The antileukemic drug asparaginase, a key component in the treatment of acute lymphoblastic leukemia, acts by depleting asparagine from the blood. However, little is known about its pharmacokinetics, and mechanisms of therapy resistance are poorly understood. Here, we explored the in vivo biodistribution of radiolabeled asparaginase, using a combination of imaging and biochemical techniques, and provide evidence for tissue-specific clearance mechanisms, which could reduce the effectiveness of the drug at these specific sites.

Liposomal Treatment of Experimental Arthritis Can Be Monitored Noninvasively with a Radiolabeled Anti-Fibroblast Activation Protein Antibody.

Unlabelled: Rheumatoid arthritis is a chronic autoimmune disorder resulting in synovial inflammation. Fibroblast activation protein (FAP) is overexpressed by fibroblastlike synoviocytes in arthritic joints. Radioimmunoimaging with an anti-FAP antibody might be used to monitor the response to therapy, thus enabling tailored therapy strategies and therapeutic outcomes.

Targeting cellular and microenvironmental multidrug resistance.

Multidrug resistance (MDR) is one of the major factors restricting the efficacy of chemotherapy. Several pathophysiological mechanisms contribute to MDR, including the overexpression of drug efflux pumps. Strategies to overcome MDR have mostly focused on the modulation of cellular resistance, such as the use of drugs and drug delivery systems to inhibit or bypass drug efflux pumps.

Tailoring the physicochemical properties of core-crosslinked polymeric micelles for pharmaceutical applications.

To optimally exploit the potential of (tumor-) targeted nanomedicines, platform technologies are needed in which physicochemical and pharmaceutical properties can be tailored according to specific medical needs and applications. We here systematically customized the properties of core-crosslinked polymeric micelles (CCPM). The micelles were based on mPEG-b-pHPMAmLac (i.

Radionuclide imaging of liposomal drug delivery.

Introduction: Ever since their discovery, liposomes have been radiolabeled to monitor their fate in vivo. Despite extensive preclinical studies, only a limited number of radiolabeled liposomal formulations have been examined in patients. Since they can play a crucial role in patient management, it is of importance to enable translation of radiolabeled liposomes into the clinic.

The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance.

Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a form of programmed cell death that promotes inflammation in various pathological conditions, suggesting that it might be a privileged pharmacological target. However, its function in glucose homeostasis and obesity has been unknown. Here we show that RIPK3 is over expressed in the white adipose tissue (WAT) of obese mice fed with a choline-deficient high-fat diet.

Multiple pathway assessment to predict anti-atherogenic efficacy of drugs targeting macrophages in atherosclerotic plaques.

Background: Macrophages play a central role in atherosclerosis development and progression, hence, targeting macrophage activity is considered an attractive therapeutic. Recently, we documented nanomedicinal delivery of the anti-inflammatory compound prednisolone to atherosclerotic plaque macrophages in patients, which did however not translate into therapeutic efficacy. This unanticipated finding calls for in-depth screening of drugs intended for targeting plaque macrophages.

Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis.

The activation and transdifferentiation of hepatic stellate cells (HSCs) into contractile, matrix-producing myofibroblasts (MFBs) are central events in hepatic fibrogenesis. These processes are driven by autocrine- and paracrine-acting soluble factors (i.e.