Exploring the role of the membrane bilayer in the recognition of candesartan by its GPCR AT1 receptor

Cardiovascular diseases and hypertension in particular are major health risks worldwide and the improvement on their treatment will be beneficial for the human health. AT1R antagonists belong to the sartans family that targets the renin-angiotensin aldosterone system (RAAS) through blocking the hormone angiotensin II to exert its detrimental effects in pathological states. As a consequence, they are beneficial to treat hypertension, diabetes related kidney failure and hyperaemic episodes. Long unbiased Molecular Dynamics (MD) simulations are performed in order to explore candesartan's possible 2D and 3D diffusion mechanisms towards AT1R receptor. 3D diffusion mechanism is referred to the direct binding of the AT1 antagonist candesartan to the AT1R 3D structure (PDB ID: 4YAY). 2D diffusion mechanism involves first, the incorporation of candesartan in the bilayer core and then its localization on the AT1R binding cavity, through a diffusion mechanism. The obtained results indicate that membranes interact significantly with the neutral form of candesartan, which is indeed approaching the receptors' active site through diffusion via the lipids. On the other hand, the deprotonated form of the drug is interacting with AT1R's extracellular loop and fails to enter the membrane, pointing out the importance of the pH microenvironment around the receptor. To validate the calculated diffusion coefficients of the drug in the lipid bilayers 2D DOSY NMR experiments were recorded and they were in good agreement. Information on the impact that has the interaction of candesartan with the membrane is very important for the rationally design and development of potent ARBs. Thus, its conformational features as well as its localization in the membrane core have to be thoroughly explore

The impact of scattering and peak spectrum of i-123 in scintigraphy by I-123 MIBG

Metaiodobenzylguanidine (MIBG) scintigraphy is used to image tumors of neuroendocrine origin and study disorders of sympathetic innervation of the myocardium. Scintigraphic imaging methods offer the possibility of qualitative and quantitative assessment of tracer concentration. Accurate correction for the physical degrading factors (attenuation, scatter, partial volume effects) is demanded. An analytical study of the I-123 energy spectrum, scattering and attenuation contribution to the resulting image of an I-123 MIBG scintigraphy, has been undergone, so as to improve the data that could be collected by I-123-MIBG use. In this work, quantitative data were gathered at various source depths, volumes and crystal to phantom distances to determine the effect of these variables on source activity data. The final image is being extracted from the combination of three different images, each and every one being acquired by a different energy window. The middle one has been obtained from the main I-123 photopeak and the others, from the left and right peaks respectively. The problem of Compton scattering as the dominant photon interaction phenomenon and its impact on both the quality of clinical images and the accuracy of quantitative analysis is taken into consideration for a scatter modeling in non-uniform media. © 2010 World Scientific Publishing Co. Pte. Ltd

The impact of scattering and peak spectrum of i-123 in scintigraphy by I-123 MIBG

Metaiodobenzylguanidine (MIBG) scintigraphy is used to image tumors of neuroendocrine origin and study disorders of sympathetic innervation of the myocardium. Scintigraphic imaging methods offer the possibility of qualitative and quantitative assessment of tracer concentration. Accurate correction for the physical degrading factors (attenuation, scatter, partial volume effects) is demanded. An analytical study of the I-123 energy spectrum, scattering and attenuation contribution to the resulting image of an I-123 MIBG scintigraphy, has been undergone, so as to improve the data that could be collected by I-123-MIBG use. In this work, quantitative data were gathered at various source depths, volumes and crystal to phantom distances to determine the effect of these variables on source activity data. The final image is being extracted from the combination of three different images, each and every one being acquired by a different energy window. The middle one has been obtained from the main I-123 photopeak and the others, from the left and right peaks respectively. The problem of Compton scattering as the dominant photon interaction phenomenon and its impact on both the quality of clinical images and the accuracy of quantitative analysis is taken into consideration for a scatter modeling in non-uniform media. © 2010 World Scientific Publishing Co. Pte. Ltd

Dose perturbation in the radiotherapy of breast cancer patients implanted with the Magna-Site: A Monte Carlo study

External beam radiation therapy (RT) is often offered to breast cancer patients after surgical mastectomy followed by breast reconstruction with silicone implants. In some cases, the RT is administered while the patient is still implanted with a temporary tissue expander including a high-density metallic port, which is expected to affect the planned dose distribution. This work uses Monte Carlo (MC) simulation in order to evaluate the aforementioned effect when the McGhan Style 133 Tissue Expander with the Magna-Site injection port is used. Simulations have been performed on a patient model built using the actual CT images of the patient for two irradiation schemes, involving two tangential photon beams of 6 MV and 18 MV respectively. MC results show that the presence of the Magna-Site within the two irradiation fields leads to an overall reduction of absorbed dose for points lying in the shadow of the metallic port (relative to each of the opposing beams). The relative reduction compared to dose results without the expander in place ranges from 7% to 13% for the 6 MV beam and is around 6% for the 18 MV photon beam. However, in the close vicinity of the metallic port, increased absorbed doses are observed, due to the increase of secondary electrons emerging from the metallic part of the insert

Encapsulation of temozolomide in a calixarene nanocapsule improves its stability and enhances its therapeutic efficacy against glioblastoma

The alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic for glioblastoma (GBM), a common and aggressive primary brain tumour in adults. However, its poor stability and unfavourable pharmacokinetic profile limit its clinical efficacy. There is an unmet need to tailor the therapeutic window of TMZ, either through complex derivatization or by utilizing pharmaceutical excipients. To enhance stability and aqueous solubility, we encapsulated TMZ in a p-sulphonatocalix[4]arene (Calix) nanocapsule and employed 1H-NMR, LC-MS and UV-Vis spectroscopy to chart the stability of this novel TMZ@Calix complex according to FDA and EMA guidelines. LC-MS/MS plasma stability assays were conducted in mice to further explore the stability profile of TMZ@Calix in vivo. The therapeutic efficacy of TMZ@Calix was compared to that of unbound TMZ in GBM cell lines and patient derived primary cells with known O6-methylguanine-DNA methyltransferase (MGMT) expression status and in vivo in an intracranial U87 xenograft mouse model. Encapsulation significantly enhanced the stability of TMZ in all conditions tested. TMZ@Calix was more potent than native TMZ at inhibiting the growth of established GBM cell lines and patient derived primary lines expressing MGMT and highly resistant to TMZ. In vivo, native TMZ was rapidly degraded in mouse plasma, whereas the stability of TMZ@Calix was enhanced 3-fold with increased therapeutic efficacy in an orthotopic model. In the absence of new effective therapies, this novel formulation is of clinical importance serving as an inexpensive and highly efficient treatment that could be made readily available to GBM patients and warrants further pre-clinical and clinical evaluation