A. C. Santos

Halogen atom effect on photophysical and photodynamic characteristics of derivatives of 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin.

Brominated and iodinated derivatives of 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin were synthesised directly from the corresponding aldehydes. Photophysical and photochemical properties, singlet oxygen formation quantum yields, photobleaching and log P were measured. Cellular uptake measurements and cytotoxicity assays on WiDr and A375 tumour cell lines were performed. 5,10,15,20-Tetrakis(2-bromo-5-hydroxyphenyl)porphyrin showed the best cytotoxicity with values of IC(50) of 113 nM over WiDr cells and 52nM over A375 cells.

Structural and in vivo studies of metal chelates of Ga(III) relevant to biomedical imaging.

The solution chemistry and structure of the complex of the triazamacrocyclic ligand NOTP (1,4,7-triazacyclononane-1,4,7-tris(methylenephosphonate)) with Ga3+ in D2O have been investigated by 1H, 71Ga and 31P NMR spectroscopy. These NMR results show the presence of a 1:1 Ga(NOTP)3- complex, with a highly symmetrical, pseudo-octahedral geometry, possibly with a C3 axis. The 1H spectrum shows that the triazamacrocyclic chelate ring is very rigid, with all the ring protons non-equivalent. The complex is stable in aqueous solution in a wide pH range. Its high thermodynamic stability agrees well with previous results from biodistribution and gamma imaging studies in Wistar rats with 67Ga3+ chelates of triaza macrocyclic ligands, which showed that the neutral chelates 67Ga(NOTA) (where NOTA is 1,4,7-triazacyclononane-1,4,7-triacetate) and 67Ga(NOTPME) (where NOTPME is 1,4,7-triazacyclononane-1,4,7-tris(methylenephosphonate monoethylester)) have similar in vivo behaviour, with high stability and rapid renal excretion, but the high negatively charged 67Ga(NOTP)3- has a considerably slower kidney uptake and elimination.

Silencing of phosphonate-gadolinium magnetic resonance imaging contrast by hydroxyapatite binding

Rationale and Objectives:GdDOTP5− is a highly charged, bone-seeking paramagnetic complex that could potentially detect bone lesions by magnetic resonance imaging (MRI). To date, its pharmacokinetics, effects on organ relaxivity, and interaction with hydroxyapatite (HA) has not been described. Methods:Liver, kidney, and bone MRI images were obtained on male white rabbits after the administration of GdDOTP5− or a gold standard MRI contrast agent, GdDTPA2−. Parallel in vitro experiments quantified the effect of HA binding on GdDOTP5− -induced changes in relaxivity. Results:The 2 compounds showed similar MRI enhancements in visceral tissues, but no enhancement of bone was evident with GdDOTP5− despite confirmation of bone and HA binding of the radioactive 153SmDOTP5− and 111InDOTP5− derivatives. In vitro experiments demonstrated that GdDOTP5−-induced changes in relaxivity were silenced upon HA binding but could be recovered by acid elution of the complex. Conclusions:HA binding assays revealed that GdDOTP5− is essentially MR silent when bound to bone, likely because of the exclusion of all outer sphere water molecules from the surface of the complex. These data suggest a novel strategy for creating highly sensitive, switchable MRI contrast agents.

Cardiac lymphatic dynamics after ischemia and reperfusion—experimental model

ABSTRACT. The aim of the present study was to investigate the lymphatic cardiac circulation in an experimental model of ischemia plus reperfusion in mongrel dogs (Canis familiaris L). As radiotracer we used 0.2-0.25 ml (111 MBq) of 99mTc-Re2S7 colloid (+/-10 microm), injected subcapsullary below the second diagonal of the descending anterior ligated coronary artery with a special needle. A gamma-camera/Starport + DecStation were used for data acquisition. Four experimental groups with five animals each were established: G I = controls; G II = immediately after acute myocardial infarction (AMI); G III = late infarction (5 days after AMI); G IV = ischemia (90 min) + reperfusion. Four regions of interest (ROIs) were chosen: injection area (ZA), above (ZB), near right (ZD), and far right (ZC) from ZA. Mean disappearance times in ZA and dynamic parameters in the other ROIs were determined from activity/time curves drawn in each area, using homemade software. The results obtained seem to indicate that the methodology is appropriate to a detailed study of lymphatic drainage in pathological situations in animal models.

153Sm3+ and 111In3+ DTPA derivatives with high hepatic specificity: in vivo and in vitro studies

Abstract Two DTPA derivatives, a mono-amide derivative containing an iodinated synthon, DTPA-IOPsp (L 1 ) and the ligand DTPA(BOM) 3 (BOM=benzyloxymethyl) (L 2 ), radiolabelled with 153 Sm 3+ and 111 In 3+ , were studied as potential hepatospecific gamma scintigraphic agents. In vivo studies with Wistar rats show that the main excretory pathway for all the chelates studied is the hepatobiliary system. The complexes of L 2 show even greater hepatobiliary specificity than L 1 , perhaps as a consequence of longer blood circulation times due to their strong affinity towards HSA. The 153 Sm 3+ chelates are also more hepatospecific than the corresponding 111 In 3+ chelates. The La 3+ and In 3+ chelates of L 1 and L 2 show some structural and dynamic differences in aqueous solution, as studied by 1 H NMR spectroscopy. While only two nona-coordinated isomers were observed for the La 3+ complexes with both ligands, its number is much larger in the In 3+ complexes, with both octa- and hepta-coordinated species (with unbound side arms), as well as structural isomers for each coordination number.

Characterization of 111In3+ complexes of DTPA amide derivatives: biodistribution and clearance studied by gamma imaging

A large series of structurally related diethylenetriaminepentaacetic acid amide derivatives with different structures and lipophilic properties were synthesized and radiolabeled with (111)In(3+). Two of the more hydrophobic compounds studied ([(111)In]L(9) and [(111)In]L(10)) showed high affinity for human serum albumin (HSA). The biodistribution and clearance properties shown by all complexes upon injection in Wistar rats were followed by gamma imaging. The blood retention time of the chelates correlates better with their binding to HSA than with their hydrophilic/lipophilic ratio. Hydrophilic and negatively charged complexes undergo renal retention, while the majority of the lipophilic complexes are retained in the blood for a longer period of time and are cleared through the liver.

Biodistribution of lipid nanoparticles: a comparative study of pulmonary versus intravenous administration in rats.

The advent of nanomedicine and increase knowledge on cellular and molecular biology has opened new opportunities on the clinical field. Selective drug targeting and protection of healthy tissues rules the rising interest that is being devoted to drug delivery system strategies, considering that the accurate choice of the carrier molecule will determine the pharmacokinetics and pharmacodynamics of drugs, yielding higher therapeutic efficacy. Despite the improvements in surgery and immunological approaches, tumor staging and cancer therapy remains a challenge, typically because they are ineffective in advanced stages of the disease, but also due to the conventional administration route (intravenous), and consequently the non-specificity of the potentially toxic drugs. The issue currently under the spotlight in drug targeting is the concept of drug delivery systems (DDS) and the impact that is inherent to their selectivity. Moreover, these particulate systems bring forth the possibility of using alternative routes to the conventional intravenous administration. This article reviews the applications of gamma-scintigraphic image technique to evaluate the advances and research on DDS engineering to the pulmonary administration, and the dependency of lung particle removal mechanism on both the administration route and the particulate system characteristic, based on literature data, as well as through the experimental studies performed in our group.

Visualização da Rede Linfática Pulmonar Profunda usando Radioliposomas

Deep lymphatic drainage plays an important role in the lung, as it removes foreign materials laying on the airways surface, such as pathogenic microorganisms. This drainage is also associated with lung tumour dissemination route. Liposomes with a specially tailored membrane were used as foreign particles to be removed by the lung lymphatics. We aim to obtain images of deep lung lymphatics in baboons using liposomes encapsulating (99m)Tc-HMPAO, as aerosols. Axillary lymph nodes were visualized 30 min post-inhalation, becoming more evident 1 hour after, when abdominal aortic and inguinal lymph nodes were also observed. Late images added no additional information. ROIs and their time-activity curves were drawn to obtain biokinetic information. In conclusion, we can say that the proposed technique enables visualization of the deep lymphatic lung network and lymph nodes. This methodology may be an important tool for targeted lung delivery of cytotoxic drugs.

Visualization of deep lung lymphatic network using radioliposomes

Abstract Deep lymphatic drainage plays an important role in the lung, as it removes foreign materials laying on the airways surface, such as pathogenic microorganisms. This drainage is also associated with lung tumour dissemination route. Liposomes with a specially tailored membrane were used as foreign particles to be removed by the lung lymphatics. We aim to obtain images of deep lung lymphatics in baboons using liposomes encapsulating 99mTc-HMPAO, as aerosols. Axillary lymph nodes were visualized 30 min post-inhalation, becoming more evident 1 hour after, when abdominal aortic and inguinal lymph nodes were also observed. Late images added no additional information. ROIs and their time-activity curves were drawn to obtain biokinetic information. In conclusion, we can say that the proposed technique enables visualization of the deep lymphatic lung network and lymph nodes. This methodology may be an important tool for targeted lung delivery of cytotoxic drugs.

In Vitro and In Vivo Behaviour of I111n Complexes of TTHA,TTHA-Bis(Butylamide) and TTHA-Bis(Glucamide): Stability,Biodistribution and Excretion Studied by Gamma Imaging

Aiming at radiopharmaceutical application, 111In3+ complexes of the polyaminocarboxylates TTHA, TTHA-bis(butylamide) and TTHA-bis(glucamide) were investigated. The in vitro stability of 111In(TTHA)3− and 111In(TTHA-bis(butylamide)- was evaluated by measuring the exchange of 111In3+ from the complexes to transferrin and the results were compared with those for 111In(DTPA)2−. We also performed biodistribution studies of the three 111In3+ complexes by gamma-imaging in Wistar rats and by measuring the radioactivity in their organs. TTHA and its derivatives seem to have similar in vivo biodistribution with prevailing renal excretion.