Kalevi Kairemo

Targeted liposomal drug delivery in cancer.

Liposomes, which are biodegradable and essentially non-toxic vehicles, can encapsulate both hydrophilic and hydrophobic materials, and are utilized as drug carriers in drug delivery systems. In addition, liposomes can be used to carry radioactive compounds as radiotracers can be linked to multiple locations in liposomes. One option is the hydrated compartment inside the liposome, another the lipid core into which especially hydrophobic conjugates can be attached, and the third option is the outer lipid leaflet where molecules can be bound by covalent linkage. Delivery of agents to the reticuloendothelial system (RES) is easily achieved, since most conventional liposomes are trapped by the RES. For the purpose of delivery of agents to target organs other than RES, long-circulating liposomes have been developed by modifying the liposomal surface. Understanding of the in vivo dynamics of liposome-carried agents is required for the evaluation of the bioavailability of drugs encapsulated in liposomes. In this review, we focus on the in vivo trafficking of liposomes visualized by positron emission tomography (PET) and discuss the characteristics of liposomes that affect the targeting of drugs in vivo.

Elimination of Stabilised Hyaluronan from the Knee Joint in Healthy Men

ObjectiveTo investigate the elimination of stabilised hyaluronan following intra-articular injection into the knee joint.DesignThis was a single-centre, single-dose study in healthy human volunteers.ParticipantsSix healthy men, aged 28 to 47 (mean 38) years, were enrolled in the study.MethodsSubjects received a single intra-articular injection (3ml; 20 mg/ml) of 131I-labelled non-animal stabilised hyaluronic acid (NASHA). Radioactivity in the knee, blood, urine and over the liver was measured with gamma counters for 3 weeks post-injection; magnetic resonance and gamma camera imaging of the knee were also performed at 24 hours post-injection. Radioactivity uptake data were tested for conformity of fit to different mathematical models.ResultsElimination of 131I-labelled NASHA from the knee was characterised by a fast initial phase and a slow late phase, and conformed to a three-exponential-function model with elimination half-lives of 1.5 hours, 1.5 days and 4 weeks. Radioactivity distribution within the knee joint was homogenous, and no local leakage was observed. Hepatic radioactivity uptake was low, but significantly above background levels, for the first 2 days post-injection, before declining to background levels. Visual imaging indicated an increase in intra-articular fluid volume at 24 hours post-injection.ConclusionsThe elimination kinetics of 131I-labelled NASHA from the human knee joint were described by three distinct phases, with half-times of 1.5 hours, 1.5 days and 4 weeks. Most likely, the last value reflects the true half-life of NASHA following intra-articular injection since the labelling method used causes minimal modification of hyaluronan.

[18F]Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography/Computed Tomography Imaging in Oncology: Initial Staging and Evaluation of Cancer Therapy

Positron emission tomography (PET) with [18F]fluoro-2-deoxy-D-glucose (FDG) has proven to be a valuable diagnostic modality in various diseases. Its accuracy has been improved with the hybrid PET/computed tomography (CT) technique because of precise anatomic location of areas of abnormal FDG accumulation. This integrated PET/CT modality has been widely adopted, particularly in oncology. This paper reviews the role of FDG-PET/CT imaging in breast cancer, non-small-cell lung cancer, colorectal cancer, head and neck cancer as well as lymphoma on the basis of recent key articles. Special attention is paid to preoperative diagnostic workup, evaluation of treatment response and survival prognosis. Experience from specialized centers indicates that there is strong evidence for the clinical effectiveness of FDG-PET/CT in staging, restaging and the prediction of response to therapy in the above-mentioned malignancies. It is concluded that this imaging modality contributes considerably to improved patient management and paves the way to personalize cancer treatment in a cost-effective way.

Liposomal Tumor Targeting in Drug Delivery Utilizing MMP-2- and MMP-9-Binding Ligands

Nanotechnology offers an alternative to conventional treatment options by enabling different drug delivery and controlled-release delivery strategies. Liposomes being especially biodegradable and in most cases essentially nontoxic offer a versatile platform for several different delivery approaches that can potentially enhance the delivery and targeting of therapies to tumors. Liposomes penetrate tumors spontaneously as a result of fenestrated blood vessels within tumors, leading to known enhanced permeability and subsequent drug retention effects. In addition, liposomes can be used to carry radioactive moieties, such as radiotracers, which can be bound at multiple locations within liposomes, making them attractive carriers for molecular imaging applications. Phage display is a technique that can deliver various high-affinity and selectivity peptides to different targets. In this study, gelatinase-binding peptides, found by phage display, were attached to liposomes by covalent peptide-PEG-PE anchor creating a targeted drug delivery vehicle. Gelatinases as extracellular targets for tumor targeting offer a viable alternative for tumor targeting. Our findings show that targeted drug delivery is more efficient than non-targeted drug delivery.

Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer—Preliminary Results of the Response Evaluation Using F-18-Fluoride PET/CT

The purpose of this study was to evaluate the outcome after Radium-223-dichloride (223RaCl2) treatment of patients with skeletal metastases of castration resistant prostate cancer using whole-body 18F-Fluoride PET/CT. Sodium 18F-fluoride [18F]-NaF PET/CT was performed prior the treatment of 223RaCl2, after the first cycle and after the sixth cycle. The skeletal metastases were analyzed quantitatively using modified PET response evaluation PERCIST criteria. The patients were also analyzed for S-PSA. All ten patients responded in [18F]-NaF scans after 6 cycles, but interim analysis after the 1st cycle did not give additional information about the outcome. The S-PSA decrease correlated with [18F]-NaF response, only 1 patient demonstrated progressive disease, i.e., >25% increase in S-PSA values during 223RaCl2. Our results (although preliminary) suggest that 18F-Fluoride PET/CT is useful in the follow-up of castration resistant prostate cancer with skeletal metastases.

Fatty acid facts, Part IV: docosahexaenoic acid and Alzheimer's disease. A story of mice, men and fish

The primary pathological hallmark of Alzheimers disease (AD) is neurodegeneration by neuronal cell death caused by the development of aggregates of beta- amyloid peptide. Epidemiologically, low fish intake and low blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) have been related to an increased risk of AD. Test animals on dietary DHA depletion show learning and memory deficits, whereas their brains show inflammatory and oxidative damage to neurons and synaptic defects. The behavioral defects could be reversed by DHA supplementation exemplified by improved cognitive function. Mechanistically, these phenomena have been explained by the antiinflammatory action of DHA. This immunomodulation has been ascribed to incorporation of increased amounts of DHA in cell membrane phospholipids, leading to decreased production of proinflammatory omega-6 eicosanoids. The latter molecules may cause vascular damage which promotes the clinical signs of AD. This review will provide an overview on the available knowledge with regard to the role of DHA in AD with a focus on mechanistic and epidemiological investigations.

Microdosing, Imaging Biomarkers and SPECT: A Multi-Sided Tripod to Accelerate Drug Development

The advances of nuclear medicine imaging instrumentation and radiopharmaceutical sciences allow their involvement in the developmental processes of therapeutic drugs. New chemical entities, meant as potential drugs, need to comply with the proof-of-principle. Tomographic imaging methods as PET, SPECT and CT have been used for small animal and human studies at an early stage of drug development. Using a drug candidate in a radiolabeled form in obtaining quantitative imaging data provides opportunity for a complete morphological and functional overview of targeting properties and overall pharmacokinetics. This can be helpful in go/no-go decision making. Microdosing, using e.g.1% of the proposed dose of the radiolabeled potential drug plays an important part in this early development and notably reduces the risk of serious adverse effects in human volunteers or patients. This paper primarily focuses on the way in which microdosing and SPECT imaging may contribute to the development of drugs. Furthermore, this paper illustrates how these techniques may help to eliminate weak drug candidates at early stage, making time and funds available for potential lead compounds. Eventually this approach facilitates and accelerates new drug approval. The present paper highlights how these techniques make drug development easier in the field of oncology and neurology.

Evaluation of Alpha-Therapy with Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer—the Role of Gamma Scintigraphy in Dosimetry and Pharmacokinetics

Radium-223-dichloride (223RaCl2) is a new bone-seeking calcium analogue alpha-emitter, which has obtained marketing authorization for the treatment skeletal metastases of hormone-refractory prostate cancer. The current treatment regimen is based on six consecutive doses of 223RaCl2 at 4 week intervals and the administered activity dose, 50 kBq/kg per cycle is based on patient weight. We analyzed two patients using quantitative serial gamma imaging to estimate dosimetry in tumors and see possible pharmacokinetic differences in the treatment cycles. The lesions were rather well visualized in gamma scintigraphy in spite of low gamma activity (<1.1% gamma radiation) at 0, 7 and 28 days using 30–60 min acquisition times. Both our patients analyzed in serial gamma imagings, had two lesions in the gamma imaging field, the mean counts of the relative intensity varied from 27.8 to 36.5 (patient 1), and from 37.4 to 82.2 (patient 2). The half-lives varied from 1.8 days to 4.5 days during the six cycles (patient 1), and from 1.5 days to 3.6 days (patient 2), respectively. In the lesion half-lives calculated from the imaging the maximum difference between the treatment cycles in the same lesion was 2.0-fold (1.8 vs. 3.6). Of these patients, patient 1 demonstrated a serum PSA response, whereas there was no PSA response in patient 2. From our data, there were maximally up to 4.0-fold differences (62.1 vs. 246.6 ) between the relative absorbed radiation doses between patients as calculated from the quantitative standardized imaging to be delivered in only two lesions, and in the same lesion the maximum difference in the cycles was up to 2.3-fold (107.4 vs. 246.6). Our recommendation based on statistical simulation analysis, is serial measurement at days 0–8 at least 3 times, this improve the accuracy significantly to study the lesion activities, half-lives or calculated relative absorbed radiation doses as calculated from the imaging. Both our patients had originally two metastatic sites in the imaging field; the former patient demonstrated a serum PSA response and the latter demonstrated no PSA response. In these two patients there was no significant difference in the lesion activities, half-lives or calculated relative absorbed radiation doses as calculated from the quantitative imaging. Our results, although preliminary, suggest that dose monitoring can be included as a part of this treatment modality. On the other hand, from the absorbed radiation doses, the response cannot be predicted because with very similar doses, only the former patient responded.

Targeting of a Head and Neck Squamous Cell Carcinoma Xenograft Model Using the Chimeric Monoclonal Antibody U36 Radioiodinated with a closo-Dodecaborate-containing Linker

Objective —High rates of local recurrence and distant metastases following surgery of high-grade head and neck squamous cell carcinoma (HNSCC) necessitate the use of adjuvant systemic treatment. Radioimmunotargeting might be a possible treatment modality in this case. The nuclear properties of 131I make it a suitable isotope for treatment of minimal residual disease and small metastases, but the conventional radioiodine label has poor cellular retention and its radiocatabolites accumulate in the thyroid. We attempted to overcome these problems by using closo-dodecaborate derivatives for attachment of radioiodine. Material and Methods —We investigated the feasibility of targeting an SCC25 HNSCC xenograft in vivo using a benzylisothiocyanate derivative of closo-dodecaborate (DABI) as radioiodine linker and the chimeric anti-CD44v6 antibody U36. 125I was used in biodistribution studies. Results —The use of DABI enabled tumor targeting and decreased the radioactivity uptake of the thyroid. Conclusion —Tumor localization of DABI-labeled U36 was similar to its para-iodobenzoate-labeled counterpart, presumably due to the strong dependence of targeting efficiency on tumor size.

Performance of coincidence imaging with long-lived positron emitters as an alternative to dedicated PET and SPECT

An important application of quantitative imaging in nuclear medicine is the estimation of absorbed doses in radionuclide therapy. Depending on the radionuclide used for therapy, quantitative imaging of the kinetics of the therapeutic radiopharmaceutical could be done using planar imaging, SPECT or PET. Since many nuclear medicine departments have a gamma camera system that is also suitable for coincidence imaging, the performance of these systems with respect to quantitative imaging of PET isotopes that could be of use in radionuclide dosimetry is of interest. We investigated the performance of a gamma camera with coincidence imaging capabilities with 99mTc, 111In, 18F and 76Br and a dedicated PET system with 18F and 76Br, using a single standard set of phantom measurements. Here, 76Br was taken as a typical example of prompt gamma-emitting PET isotopes that are applicable in radionuclide therapy dosimetry such as 86Y and 124I. Image quality measurements show comparable image contrasts for 76Br coincidence imaging and 111In SPECT. Although the spatial resolution of coincidence imaging is better than single photon imaging, the contrast obtained with 76Br is not better than that with 99mTc or 111In because of the prompt gamma involved. Additional improvements are necessary to allow for quantitative coincidence imaging of long-lived, prompt gamma producing positron emitters.