A C Santos

University of Lisbon, Lisbon, Lisbon, Portugal

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Publications (25)51.26 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Liposomes, usually assembled from organic/synthetic lipidic compounds, are biocompatible, biodegradable, non-toxic, and do not induce immune response. Due to their structural versatility in terms of size, composition, surface charge, bilayer fluidity and ability to encapsulate drugs regardless of their solubility, liposomes enable the production of a vast number and type of formulations with potential clinical use. They can be administered through several routes of administration (e.g. i.v., i.m., oral, nasal, etc.). The use of liposomes enables the variation and control retention of drugs in biologic fluids, enhancing blood circulation and specific compartments residence. They can be tailored to target specific tissues and cells. They can play a very important role for imaging diagnosis and/or therapy. After an extensive literature review of the subject, we selected a particular area of potential clinical application: pulmonary ɶdema. This clinical entity has a variety of possible etiologies, conducing to two main types of edema: cardiogenic and non-cardiogenic. At the moment a dedicated technique for the early diagnosis/therapy of this pathology is lacking. We propose a new methodology using a specially designed GUV formulation, encapsulating chosen radiotracers labeled with 99mTc. The aim of the work has been successfully achieved in an experimental animal model of cardiogenic pulmonary oedema. Experiments using an animal model of non-cardiogenic pulmonary oedema are in course (simultaneous study with two different drugs), using the same GUV methodology. Preliminary results are very promising.
    Current radiopharmaceuticals. 01/2012; 5(2):166-74.
  • M A Videira, A C Santos, M F Botelho
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    ABSTRACT: 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.
    Current radiopharmaceuticals. 01/2012; 5(2):158-65.
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    ABSTRACT: The design and development of radiolabelled estradiol derivatives has been an important area of research due to their recognized value in breast cancer management. The estrogen receptor (ER) is a relevant biomarker in the diagnosis, prognosis and prediction of the therapeutic response in estrogen receptor positive breast tumours. Hence, many radioligands based on estradiol derivatives have been proposed for targeted functional ER imaging. The main focus of this review is to survey the current knowledge on estradiol-based radioiodinated receptor ligands synthesis for breast tumour functional imaging. The main preclinical and clinical achievements in the field will also be briefly presented to make the manuscript more comprehensive.
    Current Radiopharmaceuticals 01/2012; 5:124-141.
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    ABSTRACT: Depending on the final application envisaged for a given biomaterial, many surfaces must be modified before use. The material performance in a biological environment is mainly mediated by its surface properties that can be improved using suitable modification methods. The aim of this work was to coat poly(dimethyl siloxane) (PDMS) surfaces with biosurfactants (BSs) and to evaluate how these compounds affect the PDMS surface properties. BSs isolated from four probiotic strains (Lactococcus lactis, Lactobacillus paracasei, Streptococcus thermophilus A, and Streptococcus thermophilus B) were used. Bare PDMS and PDMS coated with BSs were characterized by contact angle measurements, infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM). The influence of the surface modifications on the materials blood compatibility was studied through thrombosis and hemolysis assays. The cytotoxicity of these materials was tested against rat peritoneal macrophages. AFM results demonstrated the successful coating of the surfaces. Also, by contact angle measurements, an increase of the coated surfaces hydrophilicity was seen. Furthermore, XPS analysis indicated a decrease of the silicon content at the surface, and ATR-FTIR results showed the presence of BS characteristic groups as a consequence of the modification. All the studied materials revealed no toxicity and were found to be nonhemolytic. The proposed approach for the modification of PDMS surfaces was found to be effective and opens new possibilities for the application of these surfaces in the biomedical field.
    Journal of Biomedical Materials Research Part A 06/2011; 98(4):535-43. · 2.83 Impact Factor
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    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 30min post-inhalation, becoming more evident 1 hour after, when abdominal aortic and inguinal lymph nodes were also observed. Late images added no additional information. ROI's 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.
    Revista Portuguesa De Pneumologia - REV PORT PNEUMOL. 01/2011; 17(3):124-130.
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    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 (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. ROI's 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.
    Revista portuguesa de pneumologia 01/2011; 17(3):124-30. · 0.56 Impact Factor
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    ABSTRACT: Poly(dimethyl siloxane) elastomer, (PDMS) is widely used as a biomaterial. However, PDMS is very hydrophobic and easily colonized by several bacteria and yeasts. Consequently, surface modification has been used to improve its wettability and reduce bacterial adhesion. The aim of this work was to modify the PDMS surface in order to improve its hydrophilicity and bacterial cell repulsion to be used as a biomaterial. Plasma was used to activate the PDMS surface and sequentially promote the attachment of a synthetic surfactant, Pluronic F-68, or a polymer, Poly(ethylene glycol) methyl methacrylate, PEGMA. Bare PDMS, PDMS argon plasma activated, PDMS coated with Pluronic F-68 and PEGMA-grafted PDMS were characterized by contact angle measurements, X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). The influence of the surface modifications on blood compatibility of the materials was evaluated by thrombosis and haemolysis assays. The cytotoxicity of these materials was tested for mouse macrophages. After modification, AFM results suggest the presence of a distinct layer at the surface and by the contact angle measures it was observed an increase of hydrophilicity. XPS analysis indicates an increase of the oxygen content at the surface as a result of the modification. All the studied materials revealed no toxicity and were found to be non-haemolytic or in some cases slightly haemolytic. Therefore, plasma was found to be an effective technique for the PDMS surface modification.
    Colloids and surfaces B: Biointerfaces 11/2010; 81(1):20-6. · 3.55 Impact Factor
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    ABSTRACT: The characterization of biodistribution is a central requirement in the development of biomedical applications based on the use of nanoparticles, in particular for controlled drug delivery. The blood circulation time, organ biodistribution and rate of excretion must be well characterized in the process of product development. In this work, the biodistribution of recently developed self-assembled dextrin nanoparticles is addressed. Functionalization of the dextrin nanoparticles with a DOTA-monoamide-type metal chelator, via click chemistry, is described. The metal chelator functionalized nanoparticles were labelled with a gamma-emitting (153)Sm(3+) radioisotope and the blood clearance rate and organ biodistribution of the nanoparticles were obtained. The effect of PEG surface coating on the blood clearance rate and organ biodistribution of the nanoparticles was also studied.
    Nanotechnology 07/2010; 21(29):295103. · 3.84 Impact Factor
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    ABSTRACT: 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.
    Journal of Photochemistry and Photobiology B Biology 08/2008; 92(1):59-65. · 3.11 Impact Factor
  • Ejc Supplements - EJC SUPPL. 01/2008; 6(9):138-138.
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    ABSTRACT: The characterization of a new class of hydrophilic liver-targeted agents for gamma-scintigraphy and MRI, consisting, respectively, of [(153)Sm](3+) or Gd(3+) complexes of DOTA monoamide or bisamide linked glycoconjugates (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), is reported. In vitro studies show high uptake of radiolabeled [(153)Sm]-DOTAGal(2) by the human hepatocyte carcinoma cell line Hep G2 containing the asialoglycoprotein receptor (ASGP-R), which is decreased to less than 50% by the presence of its high-affinity ligand asialofetuin (ASF). In vivo biodistribution, gamma-imaging and pharmacokinetic studies on Wistar rats using the [(153)Sm](3+)-labeled glycoconjugates show a high uptake in the receptor-rich organ liver of the radiolabeled compounds containing terminal galactosyl groups, but very little uptake for those compounds with terminal glycosyl groups. Blocking the receptor in vivo reduced liver uptake by 90%, strongly suggesting that the liver uptake of these compounds is mediated by their binding to the asyaloglycoprotein receptor (ASGP-R). This study also demonstrated that the valency increase improves the targeting capability of the glycoconjugates, which is also affected by their topology. However despite the specific liver uptake of the radiolabeled galactose-bearing multivalent compounds, the animal MRI assessment of the corresponding Gd(3+) chelates shows liver-to-kidney contrast effects which are not significantly better than those shown by GdDTPA. This probably results from the quick wash-out from the liver of these highly hydrophilic complexes, before they can be sufficiently concentrated within the hepatocytes via receptor-mediated endocytosis.
    Contrast Media & Molecular Imaging 12/2006; 1(6):246-58. · 2.87 Impact Factor
  • European journal of nuclear medicine and molecular imaging 09/2006; 33(2):S340. · 5.11 Impact Factor
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    ABSTRACT: Two novel radioiodinated areno-annelated estra-1,3,5(10),16-tetraenes, [125I]2-iodo-1′-methoxybenzo[4′,3′:16,17]estra-1,3,5(10),16-tetraene-3-ol (2-[125I]-MEBE) and [125I]4-iodo-1′-methoxybenzo[4′,3′:16,17]estra-1,3,5(10),16-tetraene-3-ol, (4-[125I]-MEBE) were synthesized for evaluation as potential ligands for the estrogen receptor. Radioiodination of 1′-methoxybenzo[4′,3′:16,17]estra-1,3,5(10),16-tetraene-3-ol at the A ring was accomplished by electrophilic aromatic substitution using [125I] sodium iodide and chloramine-T as oxidant. After purification by reverse phase HPLC, the two radioisomers (2-[125I]-MEBE and 4-[125I]-MEBE) were obtained in a radiochemical yield of 42 and 48%, respectively, in a radiochemical purity of greater than 95% and a high specific activity. The effect of the site of radioiodination (C2 vs C4) on the biological behaviour of the molecules was evaluated through biodistribution studies in immature female Sprague-Dawley rats. Both 2-[125I]-MEBE and 4-[125I]-MEBE are stable in vivo and are mainly excreted through the hepatobiliary pathway. Both localize in the uterus and ovaries via a receptor-mediated process, where the 2-[125I]-MEBE isomer has the higher specific ER binding and uterus selectivity. The favourable in vitro/in vivo stability and biodistribution profiles suggest that these radioligands are good candidates for further exploration of their potential clinical application. Copyright © 2006 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 05/2006; 49(6):559 - 569.
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    ABSTRACT: {Fe[Gd2bpy(DTTA)2(H2O)4]3}4- is a self-assembled, metallostar-structured potential MRI contrast agent, with six efficiently relaxing Gd3+ centers confined into a small mol. space. Its proton relaxivity is particularly remarkable at very high magnetic fields (r1 = 15.8 mM-1 s-1 at 200 MHz, 37°C, in H2O). Here we report the first in vivo MRI feasibility study, complemented with dynamic g scintigraphic imaging and biodistribution expts. using the 153Sm-enriched compd. Comparative MRI studies have been performed at 4.7 T in mice with the metallostar and the small mol. wt. contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate ([Gd(DOTA)(H2O)]- = GdDOTA). The metallostar was well tolerated by the animals at the concns. of 0.0500 (high dose) and 0.0125 (low dose) mmol Gd kg-1 body wt.; (BW). The signal enhancement in the inversion recovery fast low angle shot (IR FLASH) images after the high-dose metallostar injection was considerably higher than after GdDOTA injection (0.1 mmol Gd kg-1 BW), despite the higher dose of the latter. The high-dose metallostar injection resulted in a greater drop in the spin-lattice relaxation time (T1), as calcd. from the inversion recovery true fast imaging with steady-state precession (IR TrueFISP) data for various tissues, than the GdDOTA or the low dose metallostar injection. In summary, these studies have confirmed that the approx. four times higher relaxivity measured in vitro for the metallostar is retained under in vivo conditions. The pharmacokinetics of the metallostar was found to be similar to that of GdDOTA, involving fast renal clearance, a leakage to the extracellular space in the muscle tissue and no leakage to the brain. As expected on the basis of its moderate mol. wt., the metallostar does not function as a blood pool agent. The dynamic g scintigraphic studies performed in Wistar rats with the metallostar compd. having 153Sm enrichment also proved the renal elimination pathway. The biodistribution expts. are in full accordance with the MR and scintigraphic imaging. At 15 min post-injection the activity is primarily localized in the urine, while at 24 h post-injection almost all radioactivity is cleared from tissues and organs.
    Contrast Media & Molecular Imaging 02/2006; · 2.87 Impact Factor
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    ABSTRACT: Two novel radioiodinated areno-annelated estra-1,3,5(10),16-tetraenes, [125I]2-iodo- 10-methoxybenzo[40,30:16,17]estra-1,3,5(10),16-tetraene-3-ol ð2-½125I�-MEBEÞ and [125I]4-iodo-10-methoxybenzo[40,30:16,17]estra-1,3,5(10),16-tetraene-3-ol, ð4-½125I�- MEBEÞ were synthesized for evaluation as potential ligands for the estrogen receptor. Radioiodination of 10-methoxybenzo[40,30:16,17]estra-1,3,5(10),16-tetraene-3-ol at the A ring was accomplished by electrophilic aromatic substitution using [125I] sodium iodide and chloramine-T as oxidant. After purification by reverse phase HPLC, the two radioisomers (2-½125I�-MEBE and 4-½125I�-MEBE) were obtained in a radiochemical yield of 42 and 48%, respectively, in a radiochemical purity of greater than 95% and a high specific activity. The effect of the site of radioiodination (C2 vs C4) on the biological behaviour of the molecules was evaluated through biodistribution studies in immature female Sprague-Dawley rats. Both 2-½125I�-MEBE and 4-½125I�- MEBE are stable in vivo and are mainly excreted through the hepatobiliary pathway. Both localize in the uterus and ovaries via a receptor-mediated process, where the 2-½125I�-MEBE isomer has the higher specific ER binding and uterus selectivity.
    J Label Compd Radiopharm. 01/2006;
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    ABSTRACT: 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. 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. 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. 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.
    Investigative Radiology 01/2004; 38(12):750-60. · 5.46 Impact Factor
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    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.
    Journal of Inorganic Biochemistry 08/2002; 91(1):312-9. · 3.20 Impact Factor
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    ABSTRACT: Two DTPA derivatives, a mono-amide derivative containing an iodinated synthon, DTPA-IOPsp (L1) and the ligand DTPA(BOM)3 (BOM=benzyloxymethyl) (L2), radiolabelled with 153Sm3+ and 111In3+, 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 L2 show even greater hepatobiliary specificity than L1, perhaps as a consequence of longer blood circulation times due to their strong affinity towards HSA. The 153Sm3+ chelates are also more hepatospecific than the corresponding 111In3+ chelates. The La3+ and In3+ chelates of L1 and L2 show some structural and dynamic differences in aqueous solution, as studied by 1H NMR spectroscopy. While only two nona-coordinated isomers were observed for the La3+ complexes with both ligands, its number is much larger in the In3+ complexes, with both octa- and hepta-coordinated species (with unbound side arms), as well as structural isomers for each coordination number.
    Journal of Inorganic Biochemistry. 07/2002; 91(1):312–319.
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    ABSTRACT: A monoreactive NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) derived prochelator (1-(1-carboxy-3-carbo-tert-butoxypropyl)-4,7-(carbo-tert-butoxymethyl)-1,4,7-triazacyclononane (NODAGA(tBu)(3))) was synthesized in five steps with an overall yield of 21%. It is useful for the coupling to the N-terminus of peptides on solid phase and in solution; it was coupled to [Tyr3]-octreotide (TOC) on solid phase, and the resulting peptide, NODAGA-Tyr3-octreotide (NODAGATOC), was labeled with the radiometals 111In and 67Ga in high yields and good specific activities. [67Ga]- and [111In]-NODAGA-Tyr3-octreotide appear to be useful to visualize primary tumors and metastases which express somatostatin receptors subtype 2 (sstr2), such as neuroendocrine tumors, because of their high affinity to this receptor subtype with IC(50) = 3.5 +/- 1.6 nM and 1.7 +/- 0.2 nM, respectively. NODAGATOC could be used as a SPECT and PET tracer, when labeled with 111In, 67Ga, or 68Ga, and even for therapeutic applications. Surprisingly, [111In]-NODAGATOC shows 2 times higher binding affinity to sstr2, but also a factor of 4 higher affinity to sstr5 compared to [67Ga]-NODAGATOC. [67Ga]-NODAGATOC is very stable in serum and rat liver homogenate. There is no difference in the rate of internalization into AR4-2J rat pancreatic tumor cells; both radioligands are highly internalized, at 4 h a 3 times higher uptake compared to [111In]-DOTA-Tyr3-octreotide ([111In]-DOTATOC) was found. The biodistribution of [67Ga]-NODAGATOC in AR4-2J tumor bearing nude mice is very favorable at short times after injection; there is fast excretion from all nontarget organs except the kidneys and high uptake in sst receptor rich organs and in the AR4-2J tumor. Again it is superior to [111In]-DOTATOC in this respect. The results indicate an improved biological behavior which is likely due to the fact that an additional spacer group separates the chelate from the pharmacophoric part of the somatostatin analogue.
    Bioconjugate Chemistry 01/2002; 13(3):530-41. · 4.58 Impact Factor
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    ABSTRACT: 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.
    Nuclear Medicine and Biology 09/2000; 27(6):605-10. · 2.52 Impact Factor

Publication Stats

156 Citations
106 Downloads
1k Views
51.26 Total Impact Points

Institutions

  • 2012
    • University of Lisbon
      • Faculdade de Farmácia
      Lisbon, Lisbon, Portugal
  • 1998–2012
    • University of Coimbra
      • • Instituto de Biofísica / Biomatemática
      • • Departamento de Química
      • • Faculdade de Medicina
      Coimbra, Distrito de Coimbra, Portugal
  • 2010
    • Association for Innovation and Biomedical Research on Light and Image
      Coímbra, Coimbra, Portugal