Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Metastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may improve the therapeutic effect of targeted alpha therapy by combining two radionuclides from the same decay chain in the same solution. We hypothesize that the dual targeting solution containing bone-seeking 224Ra and cell-directed complexes of progeny 212Pb is a promising approach to treat metastatic cancers with bone and soft tissue lesions as well as skeletal metastases of mixed lytic/osteoblastic nature. A novel liquid 224Ra/212Pb-generator for rapid preparation of a dual targeting solution is described. Cancer cell targeting monoclonal antibodies, their fragments, synthetic proteins or peptides can all be radiolabeled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, 224Ra targets stromal elements in sclerotic bone metastases and 212Pb-chelated-conjugate targets tumor cells of metastatic prostate cancer or osteosarcoma. The dual targeting solution may also be explored to treat metastatic breast cancer or multiple myeloma after manipulation of bone metastases to a more osteoblastic phenotype by the use of bisphosphonates, denosumab, bortezomib or hormone therapy prior to treatment. This may improve targeting of bone-seeking 224Ra and render an augmented radiation dose deposited within metastases. Our preliminary preclinical studies provide conceptual evidence that the dual 224Ra-solution with bone or tumor-targeted delivery of 212Pb has potential to inhibit cancer metastases without significant toxicity. In some settings, the use of a booster dose of purified 212Pb-conjugate alone could be required to elevate the effect of this tumor cell directed component, if needed, e.g., in a fractionated treatment regimen, where the dual targeting solution will act as maintenance treatment

Solar radiation and human health

The Sun has played a major role in the development of life on Earth. In Western culture, people are warned against Sun exposure because of its adverse effects: erythema, photoimmunosuppression, photoageing, photocarcinogenesis, cataracts and photokeratitis. However, Sun exposure is also beneficial, since moderate doses give beneficial physiological effects: vitamin D synthesis, reduction of blood pressure and mental health. Shortage of Sun exposure may be even more dangerous to human health than excessive exposure. Avoiding Sun exposure leads to vitamin D deficiency which is associated not only with rickets and osteomalacia, but also with increased risk of cardiovascular disease, multiple sclerosis, rheumatoid arthritis, diabetes, influenza, many types of cancer and adverse pregnancy outcomes. Solar radiation induces nitric oxide release in tissue and immediate pigment darkening which certainly play important roles, although these are still unknown. Action spectra relevant for health are described. We will also review what is known about spectral and intensity variations of terrestrial solar radiation as well as its penetration through the atmosphere and into human skin and tissue

Photostability of commercial sunscreens upon sun exposure and irradiation by ultraviolet lamps

BACKGROUND: Sunscreens are being widely used to reduce exposure to harmful ultraviolet (UV) radiation. The fact that some sunscreens are photounstable has been known for many years. Since the UV-absorbing ingredients of sunscreens may be photounstable, especially in the long wavelength region, it is of great interest to determine their degradation during exposure to UV radiation. Our aim was to investigate the photostability of seven commercial sunscreen products after natural UV exposure (UVnat) and artificial UV exposure (UVart). METHODS: Seven commercial sunscreens were studied with absorption spectroscopy. Sunscreen product, 0.5 mg/cm(2), was placed between plates of silica. The area under the curve (AUC) in the spectrum was calculated for UVA (320–400 nm), UVA1 (340–400 nm), UVA2 (320–340 nm) and UVB (290–320 nm) before (AUC(before)) and after (AUC(after)) UVart (980 kJ/m(2 )UVA and 12 kJ/m(2 )of UVB) and before and after UVnat. If theAUC Index (AUCI), defined as AUCI = AUC(after)/AUC(before), was > 0.80, the sunscreen was considered photostable. RESULTS: Three sunscreens were unstable after 90 min of UVnat; in the UVA range the AUCI was between 0.41 and 0.76. In the UVB range one of these sunscreens was unstable with an AUCI of 0.75 after 90 min. Three sunscreens were photostable after 120 min of UVnat; in the UVA range the AUCI was between 0.85 and 0.99 and in the UVB range between 0.92 and 1.0. One sunscreen showed in the UVA range an AUCI of 0.87 after UVnat but an AUCI of 0.72 after UVart. Five of the sunscreens were stable in the UVB region. CONCLUSION: The present study shows that several sunscreens are photounstable in the UVA range after UVnat and UVart. There is a need for a standardized method to measure photostability, and the photostability should be marked on the sunscreen product

Influence of Light Exposure on the Kinetics of Protoporphyrin IX Formation in Normal Skin of Hairless Mice After Application of 5-Aminolevulinic Acid Methyl Ester

The rates of protoporphyrin IX (PpIX) photodegradation and reappearance after light exposure at 420 and 632 nm were measured in mouse skin at different times after 1 h topical application of 5-aminolevulinic acid methyl ester (ALA-Me). After ALA-Me application (1 h) and removal, the fluorescence of PpIX increased for about 1 h, and then reached a maximum and started to decrease. Reappearance of PpIX fluorescence after exposures (degrading 60%–80% of the PpIX) was faster for exposures 0.5 h after ALA-Me application than for exposures 3 h. The bleaching rate was largest in the former case. This indicates that PpIX is located deeper in the skin after 3 h than after 0.5 h, whereas the pool of ALA-Me in the skin is largest at 0.5 h. In all cases, the reappearance was faster at a skin temperature of 35°C than at 23°C. Reappearance of PpIX fluorescence was faster after exposure to light at 420 nm than at 632 nm. The rate of elimination of PpIX from the volume of detection was faster after 420 nm light irradiation than that after 632 nm. These findings are discussed in view of penetration depths of light and ALA-Me, and diffusion of PpIX

On the selectivity of 5-aminolevulinic acid-induced protoporphyrin IX formation

Due to its capability to induce accumulation of protoporphyrin IX (PpIX) selectively in a multitude of different pathologies, 5-aminolevulinic acid (ALA) and its derivatives have attracted enormous attention in the field of photodynamic therapy (PDT) in the past two decades. The photochemical and photophysical properties of PpIX have been used for the fluorescence photodetection and photodynamic treatment of neoplasms in several medical indications in which conversion of ALA into PpIX seems to take place preferentially. Recently, this has led to the approval of this therapy for the treatment of actinic keratosis and basal cell carcinoma. When applied topically or systemically, ALA bypasses the negative feedback control that haem exerts on the enzyme ALA synthase (ALAS), which catalyses the natural production of this delta-amino acid, thereby temporarily boosting the generation of PpIX, the direct precursor of haem. Despite considerable interest in this treatment methodology, only little is known concerning the reasons for the selective accumulation of PpIX in neoplastic tissue upon ALA administration. Following an introduction into the biochemical as well as the chemical principles of haem synthesis, the present review tries to summarise experimental evidences of the mechanisms underlying preferential production of PpIX in neoplastic tissues. Thereby, morphological, environmental, enzymatic, as well as cell-specific factors will be discussed

In situ Generated 212Pb-PSMA Ligand in a 224Ra-Solution for Dual Targeting of Prostate Cancer Sclerotic Stroma and PSMA-positive Cells

Background: New treatments combating bone and extraskeletal metastases are needed for patients with metastatic castration-resistant prostate cancer. The majority of metastases overexpress prostate-specific membrane antigen (PSMA), making it an ideal candidate for targeted radionuclide therapy. Objective: The aim of this study was to test a novel liquid 224Ra/212Pb-generator for the rapid preparation of a dual-alpha targeting solution. Here, PSMA-targeting ligands are labelled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, natural bone-seeking 224Ra targeting sclerotic bone metastases and 212Pb-chelated PSMA ligands targeting PSMA-expressing tumour cells are obtained. Methods: Two PSMA-targeting ligands, the p-SCN-Bn-TCMC-PSMA ligand (NG001), specifically developed for chelating 212Pb, and the most clinically used DOTA-based PSMA-617 were labelled with 212Pb. Radiolabelling and targeting potential were investigated in situ, in vitro (PSMA-positive C4-2 human prostate cancer cells) and in vivo (athymic mice bearing C4-2 xenografts). Results: NG001 was rapidly labelled with 212Pb (radiochemical purity >94% at concentrations of ≥15 μg/ml) using the liquid 224Ra/212Pb-generator. The high radiochemical purity and stability of [212Pb]Pb-NG001 were demonstrated over 48 hours in the presence of ascorbic acid and albumin. Similar binding abilities of the 212Pb-labelled ligands were observed in C4-2 cells. The PSMA ligands displayed comparable tumour uptake after 2 hours, but NG001 showed a 3.5-fold lower kidney uptake than PSMA-617. Radium-224 was not chelated and, hence, showed high uptake in bones. Conclusion: A fast method for the labelling of PSMA ligands with 212Pb in the 224Ra/212Pb-solution was developed. Thus, further in vivo studies with dual tumour targeting by alpha-particles are warranted

Preclinical and clinical status of psma-targeted alpha therapy for metastatic castration-resistant prostate cancer

Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a molecular target for imaging diagnostics and targeted radionuclide therapy (theragnostics). PSMA-targeted α therapies (PSMA-TAT) may deliver potent and local radiation more selectively to cancer cells than PSMA-targeted β− therapies. In this review, we summarize both the recent preclinical and clinical advances made in the development of PSMA-TAT, as well as the availability of therapeutic α-emitting radionuclides, the development of small molecules and antibodies targeting PSMA. Lastly, we discuss the potentials, limitations, and future perspectives of PSMA-TAT