Zirconium-89 labeled antibodies: a new tool for molecular imaging in cancer patients.

Antibody based positron emission tomography (immuno-PET) imaging is of increasing importance to visualize and characterize tumor lesions. Additionally, it can be used to identify patients who may benefit from a particular therapy and monitor the therapy outcome. In recent years the field is focused on (89)Zr, a radiometal with near ideal physical and chemical properties for immuno-PET. In this review we will discuss the production of (89)Zr, the bioconjugation strategies, and applications in (pre-)clinical studies of (89)Zr-based immuno-PET in oncology. To date, (89)Zr-based PET imaging has been investigated in a wide variety of cancer-related targets. Moreover, clinical studies have shown the feasibility for (89)Zr-based immuno-PET to predict and monitor treatment, which could be used to tailor treatment for the individual patient. Further research should be directed towards the development of standardized and robust conjugation methods and improved chelators to minimize the amount of released Zr(4+) from the antibodies. Additionally, further validation of the imaging method is required. The ongoing development of new (89)Zr-labeled antibodies directed against novel tumor targets is expected to expand applications of (89)Zr-labeled immuno-PET to a valuable method in the medical imaging.

Pretargeted imaging and radioimmunotherapy of cancer using antibodies and bioorthogonal chemistry.

Selective delivery of radionuclides to tumors may be accomplished using a two-step approach, in which in the first step the tumor is pretargeted with an unlabeled antibody construct and in the second step the tumor is targeted with a radiolabeled small molecule. This results in a more rapid clearance of the radioactivity from normal tissues due to the fast pharmacokinetics of the small molecule as compared to antibodies. In the last decade, several pretargeting approaches have been tested, which have shown improved tumor-to-background ratios and thus improved imaging and therapy as compared to directly labeled antibodies. In this review, we will discuss the strategies and applications in (pre-)clinical studies of pretargeting concepts based on the use of bispecific antibodies, which are capable of binding to both a target antigen and a radiolabeled peptide. So far, three generations of the bispecific antibody-based pretargeting approach have been studied. The first clinical studies have shown the feasibility and potential for these pretargeting systems to detect and treat tumor lesions. However, to fully integrate the pretargeting approach in clinic, further research should focus on the best regime and pretargeting protocol. Additionally, recent developments in the use of bioorthogonal chemistry for pretargeting of tumors suggest that this chemical pretargeting approach is an attractive alternative strategy for the detection and treatment of tumor lesions.

The biological performance of injectable calcium phosphate/PLGA cement in osteoporotic rats.

Calcium phosphate cements (CPCs) including poly(D,L-lactic-co-glycolic) acid (PLGA) microparticles are promising candidates for bone regenerative applications. Previous studies with CPC/PLGA demonstrated that the material is non-toxic, biocompatible and osteoconductive. However, the outcome of these studies was based on healthy individuals and consequently does not provide information on bone substitute material performance in a compromised situation, such as osteoporosis. Therefore, this study comparatively evaluated the performance of injectable CPC/PLGA in healthy (SHAM) and osteoporotic rats (OVX) using a rat femoral condyle defect with implantation periods of 4 and 12 weeks. It was hypothesized that in OVX rats the degradation of CPC/PLGA would increase due to a higher osteoclastic activity present in osteoporotic animals and that the obtained space would be rapidly filled with newly formed bone. The results revealed an accelerated degradation of the used CPC/PLGA in osteoporotic animals, but bone formation was less compared to that in healthy animals at 4 and 12 weeks after implantation. In addition, after 4 weeks, the amount of newly formed bone under osteoporotic conditions was less in the femoral condyle defect compared to that present in a non-defect, osteoporotic control femoral condyle, but equal after 12 weeks. On the other hand, in healthy animals, the amount of newly formed bone in the femoral condyle defect was equal to that present in a non-defect control femoral condyle at 4 weeks, while higher after 12 weeks. This indicates that bone regeneration at a defect site under osteoporotic conditions is slower, but can reach native amounts after longer time periods. Consequently, bone regenerative treatments under osteoporotic conditions seem to require additional empowerment of bone substitute materials.

Differential loading methods for BMP-2 within injectable calcium phosphate cement.

Clinical application of calcium phosphate cement (CPC; with incorporated polymeric porogens) in an injectable form implicates that loading methods for growth factors are limited. In view of this, the current study evaluated the in vitro and in vivo release kinetics of bone morphogenetic protein-2 (BMP-2) loaded on poly(d,l-lactic-co-glycolic acid) (PLGA) microparticles (CPC/PLGA), BMP-2 incorporation into the liquid phase of CPC (CPC/liquid), and BMP-2 absorbed to the surface of preset, porous CPC (CPC/surface) as a control via an in vitro release experiment and in vivo using microSPECT imaging with (125)I-labeled BMP-2. In addition, the osteoinductive capacity of scaffolds generated via the different BMP-2 loading methods was assessed in a subcutaneous rat model. Additional controls consisted of porous CPC scaffolds (CPC/porous) and CPC/PLGA (CPC/control) without BMP-2 loading. The results revealed that it is feasible to load BMP-2 into CPC via adsorption to PLGA-microparticles or the liquid phase of CPC, which resulted in a similar release profile over the course of 28 days, despite distinct protein distribution patterns. Compared to CPC-scaffolds with surface-loaded BMP-2, these loading methods showed a similar release profile, except for a significantly decreased burst release. As such, the observed osteoinductive capacity for only CPC-scaffolds with surface-loaded BMP-2 is likely to be related to this difference in burst release. It remains unclear to what extent the differential BMP-2 loading methods for injectable CPC can affect the biological response in a bone environment.

Calcium phosphate/poly(D,L-lactic-co-glycolic acid) composite bone substitute materials: evaluation of temporal degradation and bone ingrowth in a rat critical-sized cranial defect.

OBJECTIVES: The present study aimed to provide temporal information on material degradation and bone formation using composite (C) bone defect filler materials consisting of calcium phosphate cement (CaP) and poly(D,L-lactic-co-glycolic acid) (PLGA) microparticles (20 or 30 wt%) in rat critical-sized cranial defects. MATERIALS AND METHODS: Critical-sized bicortical cranial defects were created in 48 rats and CaP/PLGA cement composites were implanted for 4, 8 and 12 weeks (n=8). RESULTS: Histological analysis of the retrieved specimens revealed that implant degradation was significantly faster for C30% (remaining implant up to 89.4 ± 4.4% at 12 weeks) compared with C20% (remaining implant upto 94.8 ± 2.1% at 12 weeks), albeit that overall degradation was limited. Although bone formation was limited in both experimental groups (upto 685765.9 µm(2) for C20% vs. 917603.3 µm(2) for C30%), C30% showed a significant temporal increase of total bone formation. The percentage of defect bridging was comparable for C20% and C30% at all implantation periods (range 40 ± 25.5% at week 4 to 65 ± 20% at week 12 for C20%; range 51.8 ± 7.8% at week 4 to 70.5 ± 16.2% at week 12 for C30%). CONCLUSION: The amount of PLGA-microparticles in the CaP/PLGA cement composites demonstrated acceleration of material degradation, while bone formation was found not to be influenced. Further optimization of the composite material is necessary to increase control over degradation and tissue ingrowth.