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<a class="elsevierStyleCrossRefs" href="#bb0115"><span class="elsevierStyleSup">23&#8211;26</span></a> The columns were washed with 0&#46;9 &#37; saline&#44; pH &#61; 7&#46;4&#44; with a flow of &#177; 21<span class="elsevierStyleHsp" style=""></span>mL&#47;h&#46;<a class="elsevierStyleCrossRefs" href="#bb0075"><span class="elsevierStyleSup">15&#44;22&#44;27</span></a></p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Labelling procedures</span><p id="p0035" class="elsevierStylePara elsevierViewall">Liposome labelling was done according to Phillips et al&#46; <a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a> Ceretec&#174; kits&#44; containing 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg exametazime&#44; 7&#46;6<span class="elsevierStyleHsp" style=""></span>&#956;g SnCl<span class="elsevierStyleInf">2</span> and 4&#46;5<span class="elsevierStyleHsp" style=""></span>mg NaCl were reconstituted with 740<span class="elsevierStyleHsp" style=""></span>MBq &#40;20<span class="elsevierStyleHsp" style=""></span>mCi&#41; of <span class="elsevierStyleSup">99m</span>Tc pertechnetate in 1<span class="elsevierStyleHsp" style=""></span>mL of 0&#46;9 &#37; NaCl solution&#44; and incubated for 5<span class="elsevierStyleHsp" style=""></span>min&#46;</p><p id="p0040" class="elsevierStylePara elsevierViewall">Using a three step ITLC system&#44; according to the manufacturer&#44; the reconstituted kits were tested for contamination by free pertechnetate&#44; reduced hydrolysed <span class="elsevierStyleSup">99m</span>Tc and hydrophilic <span class="elsevierStyleSup">99m</span>Tc-exametazime complex&#44; as well as for lipophilic <span class="elsevierStyleSup">99m</span>Tc- exametazime&#46;<a class="elsevierStyleCrossRef" href="#bb0140"><span class="elsevierStyleSup">28</span></a> Only kits with lipophilic <span class="elsevierStyleSup">99m</span>Tc-exametazime &#62; 80 &#37; were used for liposome labelling&#46;</p><p id="p0045" class="elsevierStylePara elsevierViewall">Approximately 3<span class="elsevierStyleHsp" style=""></span>mL of liposomal solution were mixed with 0&#46;5<span class="elsevierStyleHsp" style=""></span>mL of <span class="elsevierStyleSup">99m</span>Tc-exametazine&#46; After 10<span class="elsevierStyleHsp" style=""></span>min of incubation&#44; liposomes were separated of any free <span class="elsevierStyleSup">99m</span>Tc using a sephadex G-25 column&#46; Labelling efficiency of <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes was checked by ITLC-SG in 0&#46;9 &#37; saline&#46; In this system&#44; liposomes remain at the origin&#44; while contaminants move with the solvent front&#46;<a class="elsevierStyleCrossRefs" href="#bb0140"><span class="elsevierStyleSup">28&#8211;30</span></a></p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">Liposome size and surface-charge measurements</span><p id="p0050" class="elsevierStylePara elsevierViewall">Liposome surface charge was determined by laser Doppler velocitometry&#44; using a Coulter Delsa 440 at 4 light incidence degrees&#58; 34&#46;7&#176;&#44; 26&#176;&#44; 17&#46;4&#176; and 8&#46;7&#176;&#46; These data were used to calculate the electrophoretic mobility and zeta potential of the samples&#46;</p><p id="p0055" class="elsevierStylePara elsevierViewall">Vesicle size distribution was determined by dynamic light scattering or photon correlation spectroscopy analysis with a Coulter N4 Plus&#46;<a class="elsevierStyleCrossRefs" href="#bb0155"><span class="elsevierStyleSup">31&#44;32</span></a> The obtained diffusion coefficient was used to calculate the average hydrodynamic radius and&#44; therefore&#44; the mean diameter of the vesicles&#46;<a class="elsevierStyleCrossRefs" href="#bb0160"><span class="elsevierStyleSup">32&#44;33</span></a></p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Stability studies</span><p id="p0060" class="elsevierStylePara elsevierViewall">Liposome membrane permeability was evaluated in vitro along time by ITLC-SG with 0&#46;9 &#37; saline&#46; A decrease of labelling efficiency&#44; i&#46;e&#46;&#44; loss of aqueous core content&#44; can be used as an index of membrane integrity&#46;</p><p id="p0065" class="elsevierStylePara elsevierViewall">Liposome stability was evaluated by two methods&#58; <span class="elsevierStyleItalic">a&#41;</span> incubation at 37<span class="elsevierStyleHsp" style=""></span>&#176;C with&#58; saline&#44; human serum&#44; human plasma and human serum albumin solution &#40;4<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#41;&#44; both fresh and after complement deactivation of blood fractions &#40;56<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; 30<span class="elsevierStyleHsp" style=""></span>min&#41;&#44; being saline and human serum albumin solution the controls&#59;<a class="elsevierStyleCrossRefs" href="#bb0030"><span class="elsevierStyleSup">6&#44;34</span></a>&#44; and <span class="elsevierStyleItalic">b&#41;</span> ITLC-SG with saline&#44; each 30<span class="elsevierStyleHsp" style=""></span>min&#44; during 5&#46;5 hours after a second sephadex G-25 gel molecular exclusion chromatography&#46;</p><p id="p0070" class="elsevierStylePara elsevierViewall">Effect of ultrasound &#40;2&#46;7<span class="elsevierStyleHsp" style=""></span>MHz frequency&#41; on the integrity of the liposome membrane was also studied&#46; Liposomes were evaluated before and after 3<span class="elsevierStyleHsp" style=""></span>min nebulization by microchromatography&#44; using the previously described system&#46;<a class="elsevierStyleCrossRefs" href="#bb0175"><span class="elsevierStyleSup">35&#8211;37</span></a></p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Aerosol production and administration</span><p id="p0075" class="elsevierStylePara elsevierViewall">Aerosols were produced using an ultrasonic nebulizer &#40;Heyer Ultraschall Verebler 69&#44; Germany&#41;&#44; generating US &#40;ultrasound&#41; of 2&#46;7<span class="elsevierStyleHsp" style=""></span>MHz frequency<a class="elsevierStyleCrossRef" href="#fn0010"><span class="elsevierStyleSup">2</span></a>&#46;</p><p id="p0080" class="elsevierStylePara elsevierViewall">The obtained heterodispersed aerosol was administered directly into a intratracheal tube inserted in the baboons&#39; trachea &#40;4 adult males&#44; 25&#8211;27<span class="elsevierStyleHsp" style=""></span>kg&#41;&#44; until about 2000 Kcounts&#47;min in the total field of view of the gamma camera were recorded &#40;&#177; 3<span class="elsevierStyleHsp" style=""></span>min&#41;&#46; Animals were anaesthetised throughout the study&#46; To induce anaesthesia Ketalar&#174; &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;Kg&#44; i&#46;m&#46;&#41; was used&#44; immediately followed by a controlled infusion of Sagatal&#174; &#40;25&#8211;30<span class="elsevierStyleHsp" style=""></span>mg&#47;kg at 30<span class="elsevierStyleHsp" style=""></span>mL&#47;h&#44; i&#46;v&#46;&#41;&#46;</p><p id="p0085" class="elsevierStylePara elsevierViewall">The urinary bladder of all animals was catheterized throughout the study&#44; to drain the urine and enabling better pelvic image acquisition&#46;</p><p id="p0090" class="elsevierStylePara elsevierViewall">The effectively inhaled radioactivity dose &#40;74 to 148<span class="elsevierStyleHsp" style=""></span>MBq&#41; was determined using a calibrator &#40;Capintec&#41; and measuring the remaining labelled solution in the nebulizer after aerosolisation&#46;</p><p id="p0095" class="elsevierStylePara elsevierViewall">The protocol for the <span class="elsevierStyleItalic">in vivo</span> studies was approved by the Ethics Committee of the University of Pretoria&#44; according to the guidelines of the national Code for Animal Use in Research&#44; Education&#44; Diagnosis and Testing of Drugs and Related Substances in South Africa&#46;<a class="elsevierStyleCrossRef" href="#fn0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Biodistribution studies</span><p id="p0100" class="elsevierStylePara elsevierViewall">Biodistribution studies were performed in four baboons <span class="elsevierStyleItalic">&#40;Papio ursinus&#41;</span> placed in dorsal <span class="elsevierStyleItalic">decubitus</span>&#44; over the gamma camera &#40;Siemens Orbiter&#44; Siemens&#44; Erlangen&#44; Germany&#41;&#44; following preliminary results obtained in <span class="elsevierStyleItalic">Sus scrofa</span>&#46;<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a> For dynamic acquisition &#40;64 &#215; 64 matrix&#44; 1 frame&#47;min for 30<span class="elsevierStyleHsp" style=""></span>min&#41; the collimator was placed under the thorax&#46; The acquisition was synchronized with <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposome inhalation&#46; A series of static images &#40;128 &#215; 128 matrix&#44; 2<span class="elsevierStyleHsp" style=""></span>min&#47;frame&#41; of thorax and pelvis was acquired at 30&#44; 60&#44; 90 and 120<span class="elsevierStyleHsp" style=""></span>min post-inhalation&#46;</p><p id="p0105" class="elsevierStylePara elsevierViewall">Indirect lymphoscintigraphy was done in one baboon&#44; to confirm the inguinal lymph nodes localization&#46; 18&#46;5<span class="elsevierStyleHsp" style=""></span>MBq of <span class="elsevierStyleSup">99m</span>Tc- Re<span class="elsevierStyleInf">2</span>S<span class="elsevierStyleInf">7</span> were injected into the first interdigital space of both feet to perform a 30<span class="elsevierStyleHsp" style=""></span>min dynamic acquisition &#40;64 &#215; 64 matrix&#44; 1 frame&#47;min&#41; of the pelvis&#46; Immediately after a pelvic static image &#40;128 &#215; 128 matrix&#41; was acquired&#44; doing passive movements of both feet&#46;</p><p id="p0110" class="elsevierStylePara elsevierViewall">As a control&#44; one baboon inhaled a <span class="elsevierStyleSup">99m</span>Tc-exametazime aerosol&#46; Dynamic acquisition followed the previously referred protocol&#44; as well as the static images&#46; These images were used as background for subtraction in the <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposome images&#46;</p><p id="p0115" class="elsevierStylePara elsevierViewall">ROIs were drawn over lung&#44; heart&#44; axillary lymph nodes&#44; liver&#44; kidney&#44; and bladder dynamic images&#46; In order to obtain biokinetic information&#44; time-activity curves were plotted&#46;</p></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Statistical methods</span><p id="p0120" class="elsevierStylePara elsevierViewall">Data are reported as mean &#177; standard deviation&#46; A t-Student analysis was applied to the means&#44; being the accepted probability for a significant statistical difference <span class="elsevierStyleItalic">p</span> &#60; &#46;05&#46;</p></span></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Results</span><p id="p0125" class="elsevierStylePara elsevierViewall">The used methodology enabled production of unilamellar vesicles &#40;mean diameter 50&#8211;100<span class="elsevierStyleHsp" style=""></span>nm&#41; with a small polydispersity index &#40;0&#46;17&#44; n &#61; 3&#41;&#44; and a surface charge of &#8211;45&#46;8<span class="elsevierStyleHsp" style=""></span>mV &#40;n &#61; 3&#41;&#44; confirmed by zeta potential and by photon correlation spectroscopy determination&#46;</p><p id="p0130" class="elsevierStylePara elsevierViewall">The labelling efficiency of the liposome formulation was tested by ascendant instant thin layer microchromatography &#40;ITLC-SG&#41; with saline&#46; The average labelling efficiency obtained for <span class="elsevierStyleSup">99m</span>Tc-exametazime was 74&#46;1 &#177; 13&#46;9 &#37; &#40;n &#61; 12&#41;&#46; The previously referred <span class="elsevierStyleItalic">in vitro</span> stability studies are shown in <a class="elsevierStyleCrossRef" href="#f0005">Figure 1A</a>f&#46; Labelling efficiency of <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes was good&#44; but the most important feature was that <span class="elsevierStyleItalic">in vitro</span> stability in the presence of human serum&#44; human plasma and albumin solution was higher than in the presence of blood fraction&#46;</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0135" class="elsevierStylePara elsevierViewall">The liposomal formulation was administered as an aerosol&#44; and its labelling efficiency &#40;after 3<span class="elsevierStyleHsp" style=""></span>min of US action&#41; was not significantly different from the values determined pre- and post-US exposure&#46; Study of liposomal aqueous core content loss&#44; during 5&#46;5 hours after the second ITLC&#44; showed a good stability before and after ultrasonication &#40;<a class="elsevierStyleCrossRef" href="#f0005">Fig&#46; 1B</a>&#41;&#46;</p><p id="p0140" class="elsevierStylePara elsevierViewall">Dynamic scintigraphic studies&#44; both of <span class="elsevierStyleSup">99m</span>Tc-exametazime and <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes aerosol inhalation&#44; showed a good deposition in the lung&#44; confirming that the produced liposomes reached the small airways and&#44; hence&#44; the alveolar surface&#46;</p><p id="p0145" class="elsevierStylePara elsevierViewall">Axillary lymph nodes were visualized 30<span class="elsevierStyleHsp" style=""></span>min post-inhalation&#46; 1 hour post-inhalation they became more evident&#44; and abdominal aortic and inguinal lymph nodes were also observed&#46; Later images did not give additional information&#44; although activity is observed in abdominal organs &#40;<a class="elsevierStyleCrossRef" href="#f0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0150" class="elsevierStylePara elsevierViewall">The mean activity&#47;pixel in each ROI&#44; after background and decay correction&#44; was used to plot regional time-activity curves&#44; showing the radiotracer biokinetics variations in certain target areas during the study &#40;<a class="elsevierStyleCrossRef" href="#f0015">Fig&#46; 3</a>&#41;&#46; Total activity was measured in the lungs post-inhalation&#44; as well as clearance rate &#40;t1&#47;2 &#61; 77<span class="elsevierStyleHsp" style=""></span>min&#41; &#40;<a class="elsevierStyleCrossRef" href="#f0015">Fig&#46; 3A</a>&#41;&#46; An increase of activity was simultaneously observed in axillary lymph nodes&#44; reaching maximum activity values for axillary and inguinal nodes &#177; 60<span class="elsevierStyleHsp" style=""></span>min &#40;<a class="elsevierStyleCrossRef" href="#f0015">Fig&#46; 3B-D</a>&#41;&#46;</p><elsevierMultimedia ident="f0015"></elsevierMultimedia><p id="p0155" class="elsevierStylePara elsevierViewall">Promoting passive movement of the feet&#44; after <span class="elsevierStyleSup">99m</span>Tc-Re<span class="elsevierStyleInf">2</span>S<span class="elsevierStyleInf">7</span> injection&#44; the left inguinal node was visualized at 45<span class="elsevierStyleHsp" style=""></span>min&#44; corresponding to the area visualized with <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes &#40;<a class="elsevierStyleCrossRef" href="#f0020">Fig&#46; 4A</a>&#41;&#46; In a control animal&#44; <span class="elsevierStyleSup">99m</span>Tc-exametazime biodistribution showed a lung fast clearance through alveolar-capillary permeability&#44; which enabled a quick visualization of several organs &#40;liver&#44; gallbladder&#44; spleen&#44; kidneys and the ascending and transverse colon &#40;Product datasheet&#44; Ceretec&#174;&#44; 2001&#41;&#46; Nevertheless&#44; lymph nodes were not evident&#59; as abdominal activity masks the lymphatic abdominal chains &#40;<a class="elsevierStyleCrossRef" href="#f0020">Fig&#46; 4B</a>&#41;&#46;</p><elsevierMultimedia ident="f0020"></elsevierMultimedia><p id="p0160" class="elsevierStylePara elsevierViewall">Following MIRD<a class="elsevierStyleCrossRef" href="#fn0020"><span class="elsevierStyleSup">4</span></a> rules and applying the absorbed fraction method to calculate the absorbed dose&#44; the obtained values are similar to those used in conventional nuclear medicine routine studies&#44; to evaluate alveolar-capillary permeability with aerosols&#46;<a class="elsevierStyleCrossRefs" href="#bb0195"><span class="elsevierStyleSup">39&#44;40</span></a></p></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Discussion</span><p id="p0165" class="elsevierStylePara elsevierViewall">Pulmonary lymphatic network is crucial for alveolar and interstitial clearance&#44; being responsible for removal of many substances&#44; particles&#44; dusts&#44; or pathogenic agents&#46; Preferential lymphatic drainage correlates with certain specific surface components&#44; such as those present in microorganisms&#46;</p><p id="p0170" class="elsevierStylePara elsevierViewall">This paper describes the obtained results of the <span class="elsevierStyleItalic">in vivo</span> animal studies in normal baboons&#44; using the referred formulation &#40;<span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes&#41;&#44; administered as an aerosol as a diagnostic imaging agent to visualize the deep lung lymphatic drainage&#46;</p><p id="p0175" class="elsevierStylePara elsevierViewall">This carrier could be used both for visualization and therapy&#44; whether it encapsulates an imaging agent or a therapeutic drug&#44; respectively&#46; Since anionic compounds are quickly removed by the lymphatic network negatively charged small calibrated unilamellar liposomes were produced by extrusion through polycarbonate membranes of 100<span class="elsevierStyleHsp" style=""></span>nm pore size&#46;<a class="elsevierStyleCrossRef" href="#bb0205"><span class="elsevierStyleSup">41</span></a></p><p id="p0180" class="elsevierStylePara elsevierViewall">Since <span class="elsevierStyleSup">99m</span>Tc has 6 hours of half-life&#44; labelling the liposome aqueous phase&#44; after their formation&#44; was done immediately prior to administration&#46;<a class="elsevierStyleCrossRefs" href="#bb0035"><span class="elsevierStyleSup">7&#44;11&#44;18&#44;23&#44;24&#44;34&#44;42</span></a> Extrusion under moderate pressures was done&#44; as liposome inhalation implied absence of organic solvents or detergents in the solution&#44; to avoid possible allergic reactions&#46;<a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a></p><p id="p0185" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In vivo</span> stability of liposomes may change and be altered by complement aggression&#44; depending on the lipidic composition of the membrane&#46;<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a> To evaluate these disruptive effects&#44; <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes stability was tested <span class="elsevierStyleItalic">in vitro</span>&#44; by incubation with saline&#44; fresh human&#58; serum&#44; plasma and serum albumin solution &#40;4<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#41;&#44; as previously described&#46; Results showed a statistically significant increase of labelling efficiency in presence of human serum and plasma for the studied formulation &#40;t &#61; 3&#46;2&#59; <span class="elsevierStyleItalic">p</span> &#61; &#46;01&#41;&#46; This shows that biological fluids do not induce liposome aqueous content leakage&#46; Stability to ultrasonication was determined analysing the labelling efficiency after 2&#46;7<span class="elsevierStyleHsp" style=""></span>MHz US action&#46; Results do not show statistically significant differences for labelling efficiencies pre- and post-US action&#44; as previously mentioned by other authors&#46;<a class="elsevierStyleCrossRefs" href="#bb0185"><span class="elsevierStyleSup">37&#44;41&#8211;45</span></a></p><p id="p0190" class="elsevierStylePara elsevierViewall">Liposomal stability was also studied in terms of entrapped content loss &#40;<a class="elsevierStyleCrossRef" href="#f0005">Fig&#46; 1B</a>&#41;&#44; during 5&#46;5 hours&#46; Results showed a progressive increase of aqueous content loss&#44; probably depending on the lipidic composition&#46;</p><p id="p0195" class="elsevierStylePara elsevierViewall">The inhaled thin liposomal aerosol duly reached the lung alveolar-capillary membrane&#46; The vesicles could either be cleared by crossing the alveolar surface to lung interstitium after phagocytosis by alveolar macrophages&#44; or directly through intercellular spaces or mucociliary escalator&#46; Those&#44; which crossed the interstitium&#44; were eliminated by lymphatic drainage to the lymph nodes and subsequently to blood capillaries&#46;<a class="elsevierStyleCrossRefs" href="#bb0230"><span class="elsevierStyleSup">46&#8211;48</span></a></p><p id="p0200" class="elsevierStylePara elsevierViewall">Anatomically&#44; pulmonary lymphatics can be grouped into two interconnected networks&#58; the superficial pleural one&#44; running in the connective tissue of the visceral pleura&#44; and a deep intrapulmonary network forming the peribronchovascular lymphatics&#44; located in the connective tissue sheets of the pulmonary bronchial and vascular trees&#46; Several lymphatic capillaries can be seen in juxta-alveolar areas&#44; in contiguity with the alveolar wall and separated from the alveolar lumen only by the alveolar epithelium and supporting connective tissue &#40;usually very thin and richly vascularized&#41;&#46; Pulmonary lymphatics can also be found in the loose connective tissue supporting more peripheral pleural cells and covering the pulmonary lobes&#44; interalveolar septa and perivascular sheets&#46;<a class="elsevierStyleCrossRefs" href="#bb0015"><span class="elsevierStyleSup">3&#8211;5&#44;41&#44;49</span></a></p><p id="p0205" class="elsevierStylePara elsevierViewall">The clearance mechanism also depends on physicochemical characteristics and particle size&#46; Only submicronic sizes &#40;&#60; 50<span class="elsevierStyleHsp" style=""></span>nm &#216;&#41; can be deposited on the alveolar surface&#44; being drained afterwards by the lymphatic system&#46;<a class="elsevierStyleCrossRef" href="#bb0250"><span class="elsevierStyleSup">50</span></a> After reaching the alveolar surface&#44; the <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes cross into the lymphatic capillaries of juxta-alveolar areas through intercellular gaps and are engulfed by alveolar macrophages&#44; migrating then to the hilar lymph nodes&#46;<a class="elsevierStyleCrossRefs" href="#bb0015"><span class="elsevierStyleSup">3&#8211;5&#44;41&#44;49&#44;51</span></a> In our animal model&#44; the rather high radioactive dose deposited in the lungs&#44; did not help to identify these nodes&#46; Nevertheless&#44; the main lymphatic drainage route of the whole organ is linked to the mediastinal and abdominal periaortic lymph nodes&#44; therefore their visualization in the images agrees with the anatomical data &#40;<a class="elsevierStyleCrossRef" href="#f0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bb0005"><span class="elsevierStyleSup">1&#8211;5&#44;41&#44;49&#44;51</span></a> There is a fast infra-abdominal lymphatic drainage&#44; post-inhalation&#44; confirmed by indirect lymphoscintigraphy&#46; This clearance can possibly explain distant metastasis of lung cancer appearing in unexpected sites&#46;</p></span><span id="s0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Conclusions</span><p id="p0210" class="elsevierStylePara elsevierViewall">Aerosols of specially tailored <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes proved to be an interesting approach to study deep lung lymphatic drainage&#46; The physiological behaviour of these drug carriers&#44; mimicking some properties of micro-organisms&#44; allowed visualization of a descendant lymphatic pathway to the abdominal aortic chain nodes&#44; confirmed by indirect lymphoscintigraphy&#46; Images of these chains could give highly relevant information for staging lung tumours&#44; as well as to evaluate other pathologies with important pulmonary lymphatic contribution&#46; In addition&#44; this methodology may play an important role in targeted lung delivery of other pharmaceuticals&#44; e&#46;g&#46; cytotoxic drugs&#46;</p><p id="p0215" class="elsevierStylePara elsevierViewall">Taking into account the promising obtained results in the tested animal models&#44; the production of a tracer&#44; for inhaled administration&#44; providing information on the degree of pulmonary invasion and metastization through functional images&#44; is in perspective&#46;</p></span><span id="s0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Conflict of interest</span><p id="p0220" class="elsevierStylePara elsevierViewall">Authors declare that they don&#39;t have any conflict of interest&#46;</p></span></span>"
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              "titulo" => "Liposome preparation"
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              "titulo" => "Labelling procedures"
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              "identificador" => "s0030"
              "titulo" => "Liposome size and surface-charge measurements"
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              "titulo" => "Stability studies"
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              "titulo" => "Aerosol production and administration"
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              "titulo" => "Statistical methods"
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          "titulo" => "Results"
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            1 => "Lymphatic drainage"
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        "resumen" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">Deep lymphatic drainage plays an important role in the lung&#44; as it removes foreign materials laying on the airways surface&#44; such as pathogenic microorganisms&#46; This drainage is also associated with lung tumour dissemination route&#46; Liposomes with a specially tailored membrane were used as foreign particles to be removed by the lung lymphatics&#46; We aim to obtain images of deep lung lymphatics in baboons using liposomes encapsulating <span class="elsevierStyleSup">99m</span>Tc-HMPAO&#44; as aerosols&#46; Axillary lymph nodes were visualized 30 min post-inhalation&#44; becoming more evident 1 hour after&#44; when abdominal aortic and inguinal lymph nodes were also observed&#46; Late images added no additional information&#46; ROI&#39;s and their time-activity curves were drawn to obtain biokinetic information&#46; In conclusion&#44; we can say that the proposed technique enables visualization of the deep lymphatic lung network and lymph nodes&#46; This methodology may be an important tool for targeted lung delivery of cytotoxic drugs&#46;</p>"
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        "resumen" => "<p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">A drenagem linf&#225;tica profunda desempenha um papel importante no pulm&#227;o&#44; uma vez que remove materiais estranhos depositados sobre a superf&#237;cie das vias respirat&#243;rias&#44; tais como microrganismos patog&#233;nicos&#46; Esta drenagem est&#225; igualmente associada &#224;s vias de dissemina&#231;&#227;o tumoral&#46; Liposomas com uma membrana especificamente desenhada foram usados para simular part&#237;culas estranhas a ser removidas pelos linf&#225;ticos pulmonares&#46; Pretendem obter-se imagens dos linf&#225;ticos profundos em babu&#237;nos usando liposomas que encapsulam <span class="elsevierStyleSup">99m</span>Tc-HMPAO sob a forma de aerossol&#46; Observaram-se g&#226;nglios linf&#225;ticos axilares 30 min p&#243;s-inala&#231;&#227;o&#44; que se tornaram mais evidentes 1 hora ap&#243;s&#44; quando os g&#226;nglios abdominais e a&#243;rticos tamb&#233;m se tornaram vis&#237;veis&#46; Imagens tardias n&#227;o acrescentaram informa&#231;&#227;o relevante&#46; Foram desenhadas ROI&#39;s &#40;regi&#245;es de interesse&#41;&#44; bem como as correspondentes curvas de actividade-tempo para obter informa&#231;&#227;o acerca da biocin&#233;tica&#46; Em conclus&#227;o&#44; pode dizer-se que a t&#233;cnica proposta torna poss&#237;vel a visualiza&#231;&#227;o da rede linf&#225;tica profunda do pulm&#227;o e os g&#226;nglios linf&#225;ticos&#46; Esta metodolog&#237;a poder&#225; vir a ser importante na liberta&#231;&#227;o pulmonar controlada de f&#225;rmacos citot&#243;xicos&#46;</p>"
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          "es" => "<p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Animal controls&#46; A&#41; Dynamic image sequence of the indirect lymphoscintigraphy obtained during the first 30<span class="elsevierStyleHsp" style=""></span>min after interdigital feet <span class="elsevierStyleSup">99m</span>Tc-Re<span class="elsevierStyleInf">2</span>S<span class="elsevierStyleInf">7</span> injection&#44; as well as static images at 60&#44; 90 and 120<span class="elsevierStyleHsp" style=""></span>min&#46; The observed lymphatic abdominal drainage corresponds to the visualized areas with liposomes labelled with <span class="elsevierStyleSup">99m</span>Tc-exametazime&#46; B&#41; <span class="elsevierStyleSup">99m</span>Tc-exametazime biodistribution is a control and does not visualize the lymph nodes or lymphatic abdominal chains&#44; only thoracic and abdominal activity uptake&#46;</p>"
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ORIGINAL ARTICLE
Visualization of deep lung lymphatic network using radioliposomes
Visualização da rede linfática profunda usando radioliposomas
M.F. Botelhoa,
Corresponding author
filomena@ibili.uc.pt

Corresponding author.
, J.J.P. de Limaa, I.C. Dormehlb, M. Fontes Baganhac, C.M. Gomesa, A.C. Santosa, J.N. Moreirad, E. Kilianb
a Instituto Biofísica/Biomatemática, IBILI, Faculdade de Medicina, Azinhaga de Santa Comba, Coimbra, Portugal
b Institute for Life Sciences, Pretoria University, Pretoria, South Africa
c Centro de Pneumologia da Universidade de Coimbra, Coimbra, Portugal
d Centro de Neurociências e Biologia Celular de Coimbra, Faculdade de Farmácia, Coimbra, Portugal
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They can be administered by several routes such as aerosols&#46; Based upon the pathophysiology of <span class="elsevierStyleItalic">Bacillus tuberculosis</span> pulmonary infection&#44; specific liposomes can be modulated&#46; They can be made to mimick the membrane composition of the <span class="elsevierStyleItalic">Bacillus subtilis</span> spores &#40;a respiratory tract saprophyte microorganism&#41; in order to be captured by pulmonary lymphatics&#46;<a class="elsevierStyleCrossRefs" href="#bb0040"><span class="elsevierStyleSup">8&#44;9</span></a></p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0010">Materials and methods</span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015">Chemicals<a class="elsevierStyleCrossRef" href="#fn0005"><span class="elsevierStyleSup">1</span></a></span><p id="p0015" class="elsevierStylePara elsevierViewall">Distearoylphosphatidylcholine &#40;DSPC&#41; was selected as the main phospolipid &#40;transition temperature 56<span class="elsevierStyleHsp" style=""></span>&#176;C&#41;&#44; enabling the production of stable liposomes in presence of biological fluids&#46;<a class="elsevierStyleCrossRefs" href="#bb0030"><span class="elsevierStyleSup">6&#44;7&#44;10</span></a> Phosphatidylglycerol &#40;PG&#41; was chosen as a negatively charge phospholipid<a class="elsevierStyleCrossRefs" href="#bb0055"><span class="elsevierStyleSup">11&#44;12</span></a> and glutamic acid &#40;GA&#41; acts as a residue&#44; being present in the internal layer and in the dense outer layer&#46; <a class="elsevierStyleCrossRefs" href="#bb0065"><span class="elsevierStyleSup">13&#44;14</span></a> DSPC&#44; PG&#44; GA and GSH were obtained from Sigma &#40;St&#46; Louis&#44; MO&#44; USA&#41;&#44; and Sephadex G-25 from Pharmacia &#40;Upsala&#44; Sweden&#41;&#46; For anaesthesia&#44; Ketalar&#174; &#40;Parke Davis&#44; Cape Town&#44; S&#46;A&#46;&#41; and Sagatal &#40;Kyron Laboratories Pty&#46; Ltd&#46;&#44; Benrose&#44; S&#46;A&#46;&#41; were used&#46; <span class="elsevierStyleSup">99m</span>Tc was obtained from a commercial <span class="elsevierStyleSup">99</span>Mo&#47;<span class="elsevierStyleSup">99m</span>Tc generator &#40;NECSA&#44; South Africa&#41;&#46; Exametazime &#40;Ceretec&#8482;&#41; was purchased from G&#46;E&#46; Healthcare &#40;UK&#41;&#46; For labelling efficiency and radiochemical purity determination&#44; strips of ITLC-SG &#40;Gelman Sciences Inc&#46;&#44; Ann Arbor&#44; USA&#41; and Whatman no&#46; 1 paper were used&#46;</p></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020">Liposome preparation</span><p id="p0020" class="elsevierStylePara elsevierViewall">The designed liposomal formulation is composed of DSPC&#58;PG&#58;GA&#44; respectively 8&#58;1&#58;1&#44; in molar ratio&#46; The lipidic mixture with a 50<span class="elsevierStyleHsp" style=""></span>mg&#47;mL concentration was dissolved in 2<span class="elsevierStyleHsp" style=""></span>mL of chloroform in a round-bottom flask&#46; Then it was evaporated at room temperature&#44; under reduced pressure and inert atmosphere&#44; for 2 hours&#44; to form a thin lipid film&#44; which was dried overnight in <span class="elsevierStyleItalic">vacuum</span>&#46;<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a> 100<span class="elsevierStyleHsp" style=""></span>mM reduced GSH in 0&#46;9 &#37; saline was added to the films by energetic vortex mixing&#46;<a class="elsevierStyleCrossRefs" href="#bb0080"><span class="elsevierStyleSup">16&#8211;19</span></a> The flask was placed in a water bath at 65<span class="elsevierStyleHsp" style=""></span>&#176;C for 10<span class="elsevierStyleHsp" style=""></span>min&#44; to hydrate the lipidic film&#46;</p><p id="p0025" class="elsevierStylePara elsevierViewall">The produced multilamellar liposomes were then extruded at 70<span class="elsevierStyleHsp" style=""></span>&#176;C through two stacked polycarbonate filters &#40;Nucleopore&#44; CA&#44; USA&#41; of 100<span class="elsevierStyleHsp" style=""></span>nm pore size&#44; mounted in a mini-extruder &#40;LiposoFast&#8482;&#44; Avestin&#44; Canada&#41; fitted with two 0&#46;5<span class="elsevierStyleHsp" style=""></span>mL Hamilton syringes &#40;Hamilton&#44; NV&#44; USA&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bb0100"><span class="elsevierStyleSup">20&#8211;22</span></a> In order to obtain unilamellar liposomes&#44; with small polydispersity index&#44; they were passed through the filters 20 times&#46;<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a></p><p id="p0030" class="elsevierStylePara elsevierViewall">To remove any remaining extravesicular GSH&#44; the vesicle suspension &#40;500 &#956;L at a time&#41; was eluted through a Sephadex G-25 gel molecular exclusion chromatography minicolumn at room temperature&#44; plugged with a Durapore&#174; membrane filter &#40;Millipore&#44; Ireland&#41; of 0&#46;45<span class="elsevierStyleHsp" style=""></span>&#956;m pore size&#46; <a class="elsevierStyleCrossRefs" href="#bb0115"><span class="elsevierStyleSup">23&#8211;26</span></a> The columns were washed with 0&#46;9 &#37; saline&#44; pH &#61; 7&#46;4&#44; with a flow of &#177; 21<span class="elsevierStyleHsp" style=""></span>mL&#47;h&#46;<a class="elsevierStyleCrossRefs" href="#bb0075"><span class="elsevierStyleSup">15&#44;22&#44;27</span></a></p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Labelling procedures</span><p id="p0035" class="elsevierStylePara elsevierViewall">Liposome labelling was done according to Phillips et al&#46; <a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a> Ceretec&#174; kits&#44; containing 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg exametazime&#44; 7&#46;6<span class="elsevierStyleHsp" style=""></span>&#956;g SnCl<span class="elsevierStyleInf">2</span> and 4&#46;5<span class="elsevierStyleHsp" style=""></span>mg NaCl were reconstituted with 740<span class="elsevierStyleHsp" style=""></span>MBq &#40;20<span class="elsevierStyleHsp" style=""></span>mCi&#41; 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Germany&#41;&#44; generating US &#40;ultrasound&#41; of 2&#46;7<span class="elsevierStyleHsp" style=""></span>MHz frequency<a class="elsevierStyleCrossRef" href="#fn0010"><span class="elsevierStyleSup">2</span></a>&#46;</p><p id="p0080" class="elsevierStylePara elsevierViewall">The obtained heterodispersed aerosol was administered directly into a intratracheal tube inserted in the baboons&#39; trachea &#40;4 adult males&#44; 25&#8211;27<span class="elsevierStyleHsp" style=""></span>kg&#41;&#44; until about 2000 Kcounts&#47;min in the total field of view of the gamma camera were recorded &#40;&#177; 3<span class="elsevierStyleHsp" style=""></span>min&#41;&#46; Animals were anaesthetised throughout the study&#46; To induce anaesthesia Ketalar&#174; &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;Kg&#44; i&#46;m&#46;&#41; was used&#44; immediately followed by a controlled infusion of Sagatal&#174; &#40;25&#8211;30<span class="elsevierStyleHsp" style=""></span>mg&#47;kg at 30<span class="elsevierStyleHsp" style=""></span>mL&#47;h&#44; i&#46;v&#46;&#41;&#46;</p><p id="p0085" class="elsevierStylePara elsevierViewall">The urinary bladder of all animals was catheterized throughout the study&#44; to drain the urine and enabling better pelvic image acquisition&#46;</p><p id="p0090" class="elsevierStylePara elsevierViewall">The effectively inhaled radioactivity dose &#40;74 to 148<span class="elsevierStyleHsp" style=""></span>MBq&#41; was determined using a calibrator &#40;Capintec&#41; and measuring the remaining labelled solution in the nebulizer after aerosolisation&#46;</p><p id="p0095" class="elsevierStylePara elsevierViewall">The protocol for the <span class="elsevierStyleItalic">in vivo</span> studies was approved by the Ethics Committee of the University of Pretoria&#44; according to the guidelines of the national Code for Animal Use in Research&#44; Education&#44; Diagnosis and Testing of Drugs and Related Substances in South Africa&#46;<a class="elsevierStyleCrossRef" href="#fn0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Biodistribution studies</span><p id="p0100" class="elsevierStylePara elsevierViewall">Biodistribution studies were performed in four baboons <span class="elsevierStyleItalic">&#40;Papio ursinus&#41;</span> placed in dorsal <span class="elsevierStyleItalic">decubitus</span>&#44; over the gamma camera &#40;Siemens Orbiter&#44; Siemens&#44; Erlangen&#44; Germany&#41;&#44; following preliminary results obtained in <span class="elsevierStyleItalic">Sus scrofa</span>&#46;<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a> For dynamic acquisition &#40;64 &#215; 64 matrix&#44; 1 frame&#47;min for 30<span class="elsevierStyleHsp" style=""></span>min&#41; the collimator was placed under the thorax&#46; The acquisition was synchronized with <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposome inhalation&#46; A series of static images &#40;128 &#215; 128 matrix&#44; 2<span class="elsevierStyleHsp" style=""></span>min&#47;frame&#41; of thorax and pelvis was acquired at 30&#44; 60&#44; 90 and 120<span class="elsevierStyleHsp" style=""></span>min post-inhalation&#46;</p><p id="p0105" class="elsevierStylePara elsevierViewall">Indirect lymphoscintigraphy was done in one baboon&#44; to confirm the inguinal lymph nodes localization&#46; 18&#46;5<span class="elsevierStyleHsp" style=""></span>MBq of <span class="elsevierStyleSup">99m</span>Tc- Re<span class="elsevierStyleInf">2</span>S<span class="elsevierStyleInf">7</span> were injected into the first interdigital space of both feet to perform a 30<span class="elsevierStyleHsp" style=""></span>min dynamic acquisition &#40;64 &#215; 64 matrix&#44; 1 frame&#47;min&#41; of the pelvis&#46; Immediately after a pelvic static image &#40;128 &#215; 128 matrix&#41; was acquired&#44; doing passive movements of both feet&#46;</p><p id="p0110" class="elsevierStylePara elsevierViewall">As a control&#44; one baboon inhaled a <span class="elsevierStyleSup">99m</span>Tc-exametazime aerosol&#46; Dynamic acquisition followed the previously referred protocol&#44; as well as the static images&#46; These images were used as background for subtraction in the <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposome images&#46;</p><p id="p0115" class="elsevierStylePara elsevierViewall">ROIs were drawn over lung&#44; heart&#44; axillary lymph nodes&#44; liver&#44; kidney&#44; and bladder dynamic images&#46; In order to obtain biokinetic information&#44; time-activity curves were plotted&#46;</p></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Statistical methods</span><p id="p0120" class="elsevierStylePara elsevierViewall">Data are reported as mean &#177; standard deviation&#46; A t-Student analysis was applied to the means&#44; being the accepted probability for a significant statistical difference <span class="elsevierStyleItalic">p</span> &#60; &#46;05&#46;</p></span></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Results</span><p id="p0125" class="elsevierStylePara elsevierViewall">The used methodology enabled production of unilamellar vesicles &#40;mean diameter 50&#8211;100<span class="elsevierStyleHsp" style=""></span>nm&#41; with a small polydispersity index &#40;0&#46;17&#44; n &#61; 3&#41;&#44; and a surface charge of &#8211;45&#46;8<span class="elsevierStyleHsp" style=""></span>mV &#40;n &#61; 3&#41;&#44; confirmed by zeta potential and by photon correlation spectroscopy determination&#46;</p><p id="p0130" class="elsevierStylePara elsevierViewall">The labelling efficiency of the liposome formulation was tested by ascendant instant thin layer microchromatography &#40;ITLC-SG&#41; with saline&#46; The average labelling efficiency obtained for <span class="elsevierStyleSup">99m</span>Tc-exametazime was 74&#46;1 &#177; 13&#46;9 &#37; &#40;n &#61; 12&#41;&#46; The previously referred <span class="elsevierStyleItalic">in vitro</span> stability studies are shown in <a class="elsevierStyleCrossRef" href="#f0005">Figure 1A</a>f&#46; Labelling efficiency of <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes was good&#44; but the most important feature was that <span class="elsevierStyleItalic">in vitro</span> stability in the presence of human serum&#44; human plasma and albumin solution was higher than in the presence of blood fraction&#46;</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0135" class="elsevierStylePara elsevierViewall">The liposomal formulation was administered as an aerosol&#44; and its labelling efficiency &#40;after 3<span class="elsevierStyleHsp" style=""></span>min of US action&#41; was not significantly different from the values determined pre- and post-US exposure&#46; Study of liposomal aqueous core content loss&#44; during 5&#46;5 hours after the second ITLC&#44; showed a good stability before and after ultrasonication &#40;<a class="elsevierStyleCrossRef" href="#f0005">Fig&#46; 1B</a>&#41;&#46;</p><p id="p0140" class="elsevierStylePara elsevierViewall">Dynamic scintigraphic studies&#44; both of <span class="elsevierStyleSup">99m</span>Tc-exametazime and <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes aerosol inhalation&#44; showed a good deposition in the lung&#44; confirming that the produced liposomes reached the small airways and&#44; hence&#44; the alveolar surface&#46;</p><p id="p0145" class="elsevierStylePara elsevierViewall">Axillary lymph nodes were visualized 30<span class="elsevierStyleHsp" style=""></span>min post-inhalation&#46; 1 hour post-inhalation they became more evident&#44; and abdominal aortic and inguinal lymph nodes were also observed&#46; Later images did not give additional information&#44; although activity is observed in abdominal organs &#40;<a class="elsevierStyleCrossRef" href="#f0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0150" class="elsevierStylePara elsevierViewall">The mean activity&#47;pixel in each ROI&#44; after background and decay correction&#44; was used to plot regional time-activity curves&#44; showing the radiotracer biokinetics variations in certain target areas during the study &#40;<a class="elsevierStyleCrossRef" href="#f0015">Fig&#46; 3</a>&#41;&#46; Total activity was measured in the lungs post-inhalation&#44; as well as clearance rate &#40;t1&#47;2 &#61; 77<span class="elsevierStyleHsp" style=""></span>min&#41; &#40;<a class="elsevierStyleCrossRef" href="#f0015">Fig&#46; 3A</a>&#41;&#46; An increase of activity was simultaneously observed in axillary lymph nodes&#44; reaching maximum activity values for axillary and inguinal nodes &#177; 60<span class="elsevierStyleHsp" style=""></span>min &#40;<a class="elsevierStyleCrossRef" href="#f0015">Fig&#46; 3B-D</a>&#41;&#46;</p><elsevierMultimedia ident="f0015"></elsevierMultimedia><p id="p0155" class="elsevierStylePara elsevierViewall">Promoting passive movement of the feet&#44; after <span class="elsevierStyleSup">99m</span>Tc-Re<span class="elsevierStyleInf">2</span>S<span class="elsevierStyleInf">7</span> injection&#44; the left inguinal node was visualized at 45<span class="elsevierStyleHsp" style=""></span>min&#44; corresponding to the area visualized with <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes &#40;<a class="elsevierStyleCrossRef" href="#f0020">Fig&#46; 4A</a>&#41;&#46; In a control animal&#44; <span class="elsevierStyleSup">99m</span>Tc-exametazime biodistribution showed a lung fast clearance through alveolar-capillary permeability&#44; which enabled a quick visualization of several organs &#40;liver&#44; gallbladder&#44; spleen&#44; kidneys and the ascending and transverse colon &#40;Product datasheet&#44; Ceretec&#174;&#44; 2001&#41;&#46; Nevertheless&#44; lymph nodes were not evident&#59; as abdominal activity masks the lymphatic abdominal chains &#40;<a class="elsevierStyleCrossRef" href="#f0020">Fig&#46; 4B</a>&#41;&#46;</p><elsevierMultimedia ident="f0020"></elsevierMultimedia><p id="p0160" class="elsevierStylePara elsevierViewall">Following MIRD<a class="elsevierStyleCrossRef" href="#fn0020"><span class="elsevierStyleSup">4</span></a> rules and applying the absorbed fraction method to calculate the absorbed dose&#44; the obtained values are similar to those used in conventional nuclear medicine routine studies&#44; to evaluate alveolar-capillary permeability with aerosols&#46;<a class="elsevierStyleCrossRefs" href="#bb0195"><span class="elsevierStyleSup">39&#44;40</span></a></p></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Discussion</span><p id="p0165" class="elsevierStylePara elsevierViewall">Pulmonary lymphatic network is crucial for alveolar and interstitial clearance&#44; being responsible for removal of many substances&#44; particles&#44; dusts&#44; or pathogenic agents&#46; Preferential lymphatic drainage correlates with certain specific surface components&#44; such as those present in microorganisms&#46;</p><p id="p0170" class="elsevierStylePara elsevierViewall">This paper describes the obtained results of the <span class="elsevierStyleItalic">in vivo</span> animal studies in normal baboons&#44; using the referred formulation &#40;<span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes&#41;&#44; administered as an aerosol as a diagnostic imaging agent to visualize the deep lung lymphatic drainage&#46;</p><p id="p0175" class="elsevierStylePara elsevierViewall">This carrier could be used both for visualization and therapy&#44; whether it encapsulates an imaging agent or a therapeutic drug&#44; respectively&#46; Since anionic compounds are quickly removed by the lymphatic network negatively charged small calibrated unilamellar liposomes were produced by extrusion through polycarbonate membranes of 100<span class="elsevierStyleHsp" style=""></span>nm pore size&#46;<a class="elsevierStyleCrossRef" href="#bb0205"><span class="elsevierStyleSup">41</span></a></p><p id="p0180" class="elsevierStylePara elsevierViewall">Since <span class="elsevierStyleSup">99m</span>Tc has 6 hours of half-life&#44; labelling the liposome aqueous phase&#44; after their formation&#44; was done immediately prior to administration&#46;<a class="elsevierStyleCrossRefs" href="#bb0035"><span class="elsevierStyleSup">7&#44;11&#44;18&#44;23&#44;24&#44;34&#44;42</span></a> Extrusion under moderate pressures was done&#44; as liposome inhalation implied absence of organic solvents or detergents in the solution&#44; to avoid possible allergic reactions&#46;<a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a></p><p id="p0185" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In vivo</span> stability of liposomes may change and be altered by complement aggression&#44; depending on the lipidic composition of the membrane&#46;<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a> To evaluate these disruptive effects&#44; <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes stability was tested <span class="elsevierStyleItalic">in vitro</span>&#44; by incubation with saline&#44; fresh human&#58; serum&#44; plasma and serum albumin solution &#40;4<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#41;&#44; as previously described&#46; Results showed a statistically significant increase of labelling efficiency in presence of human serum and plasma for the studied formulation &#40;t &#61; 3&#46;2&#59; <span class="elsevierStyleItalic">p</span> &#61; &#46;01&#41;&#46; This shows that biological fluids do not induce liposome aqueous content leakage&#46; Stability to ultrasonication was determined analysing the labelling efficiency after 2&#46;7<span class="elsevierStyleHsp" style=""></span>MHz US action&#46; Results do not show statistically significant differences for labelling efficiencies pre- and post-US action&#44; as previously mentioned by other authors&#46;<a class="elsevierStyleCrossRefs" href="#bb0185"><span class="elsevierStyleSup">37&#44;41&#8211;45</span></a></p><p id="p0190" class="elsevierStylePara elsevierViewall">Liposomal stability was also studied in terms of entrapped content loss &#40;<a class="elsevierStyleCrossRef" href="#f0005">Fig&#46; 1B</a>&#41;&#44; during 5&#46;5 hours&#46; Results showed a progressive increase of aqueous content loss&#44; probably depending on the lipidic composition&#46;</p><p id="p0195" class="elsevierStylePara elsevierViewall">The inhaled thin liposomal aerosol duly reached the lung alveolar-capillary membrane&#46; The vesicles could either be cleared by crossing the alveolar surface to lung interstitium after phagocytosis by alveolar macrophages&#44; or directly through intercellular spaces or mucociliary escalator&#46; Those&#44; which crossed the interstitium&#44; were eliminated by lymphatic drainage to the lymph nodes and subsequently to blood capillaries&#46;<a class="elsevierStyleCrossRefs" href="#bb0230"><span class="elsevierStyleSup">46&#8211;48</span></a></p><p id="p0200" class="elsevierStylePara elsevierViewall">Anatomically&#44; pulmonary lymphatics can be grouped into two interconnected networks&#58; the superficial pleural one&#44; running in the connective tissue of the visceral pleura&#44; and a deep intrapulmonary network forming the peribronchovascular lymphatics&#44; located in the connective tissue sheets of the pulmonary bronchial and vascular trees&#46; Several lymphatic capillaries can be seen in juxta-alveolar areas&#44; in contiguity with the alveolar wall and separated from the alveolar lumen only by the alveolar epithelium and supporting connective tissue &#40;usually very thin and richly vascularized&#41;&#46; Pulmonary lymphatics can also be found in the loose connective tissue supporting more peripheral pleural cells and covering the pulmonary lobes&#44; interalveolar septa and perivascular sheets&#46;<a class="elsevierStyleCrossRefs" href="#bb0015"><span class="elsevierStyleSup">3&#8211;5&#44;41&#44;49</span></a></p><p id="p0205" class="elsevierStylePara elsevierViewall">The clearance mechanism also depends on physicochemical characteristics and particle size&#46; Only submicronic sizes &#40;&#60; 50<span class="elsevierStyleHsp" style=""></span>nm &#216;&#41; can be deposited on the alveolar surface&#44; being drained afterwards by the lymphatic system&#46;<a class="elsevierStyleCrossRef" href="#bb0250"><span class="elsevierStyleSup">50</span></a> After reaching the alveolar surface&#44; the <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes cross into the lymphatic capillaries of juxta-alveolar areas through intercellular gaps and are engulfed by alveolar macrophages&#44; migrating then to the hilar lymph nodes&#46;<a class="elsevierStyleCrossRefs" href="#bb0015"><span class="elsevierStyleSup">3&#8211;5&#44;41&#44;49&#44;51</span></a> In our animal model&#44; the rather high radioactive dose deposited in the lungs&#44; did not help to identify these nodes&#46; Nevertheless&#44; the main lymphatic drainage route of the whole organ is linked to the mediastinal and abdominal periaortic lymph nodes&#44; therefore their visualization in the images agrees with the anatomical data &#40;<a class="elsevierStyleCrossRef" href="#f0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bb0005"><span class="elsevierStyleSup">1&#8211;5&#44;41&#44;49&#44;51</span></a> There is a fast infra-abdominal lymphatic drainage&#44; post-inhalation&#44; confirmed by indirect lymphoscintigraphy&#46; This clearance can possibly explain distant metastasis of lung cancer appearing in unexpected sites&#46;</p></span><span id="s0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Conclusions</span><p id="p0210" class="elsevierStylePara elsevierViewall">Aerosols of specially tailored <span class="elsevierStyleSup">99m</span>Tc-exametazime-liposomes proved to be an interesting approach to study deep lung lymphatic drainage&#46; The physiological behaviour of these drug carriers&#44; mimicking some properties of micro-organisms&#44; allowed visualization of a descendant lymphatic pathway to the abdominal aortic chain nodes&#44; confirmed by indirect lymphoscintigraphy&#46; Images of these chains could give highly relevant information for staging lung tumours&#44; as well as to evaluate other pathologies with important pulmonary lymphatic contribution&#46; In addition&#44; this methodology may play an important role in targeted lung delivery of other pharmaceuticals&#44; e&#46;g&#46; cytotoxic drugs&#46;</p><p id="p0215" class="elsevierStylePara elsevierViewall">Taking into account the promising obtained results in the tested animal models&#44; the production of a tracer&#44; for inhaled administration&#44; providing information on the degree of pulmonary invasion and metastization through functional images&#44; is in perspective&#46;</p></span><span id="s0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Conflict of interest</span><p id="p0220" class="elsevierStylePara elsevierViewall">Authors declare that they don&#39;t have any conflict of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Materials and methods"
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              "titulo" => "Chemicals"
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              "titulo" => "Liposome preparation"
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              "titulo" => "Labelling procedures"
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            3 => array:2 [
              "identificador" => "s0030"
              "titulo" => "Liposome size and surface-charge measurements"
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              "titulo" => "Stability studies"
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              "titulo" => "Aerosol production and administration"
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              "titulo" => "Biodistribution studies"
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              "titulo" => "Statistical methods"
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          "titulo" => "Results"
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            1 => "Drenagem linf&#225;tica"
            2 => "Cintigrafia"
            3 => "Liberta&#231;&#227;o pulmonar controlada"
            4 => "Estudos <span class="elsevierStyleItalic">in vivo</span>"
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        "titulo" => "Abstract"
        "resumen" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">Deep lymphatic drainage plays an important role in the lung&#44; as it removes foreign materials laying on the airways surface&#44; such as pathogenic microorganisms&#46; This drainage is also associated with lung tumour dissemination route&#46; Liposomes with a specially tailored membrane were used as foreign particles to be removed by the lung lymphatics&#46; We aim to obtain images of deep lung lymphatics in baboons using liposomes encapsulating <span class="elsevierStyleSup">99m</span>Tc-HMPAO&#44; as aerosols&#46; Axillary lymph nodes were visualized 30 min post-inhalation&#44; becoming more evident 1 hour after&#44; when abdominal aortic and inguinal lymph nodes were also observed&#46; Late images added no additional information&#46; ROI&#39;s and their time-activity curves were drawn to obtain biokinetic information&#46; In conclusion&#44; we can say that the proposed technique enables visualization of the deep lymphatic lung network and lymph nodes&#46; This methodology may be an important tool for targeted lung delivery of cytotoxic drugs&#46;</p>"
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        "resumen" => "<p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">A drenagem linf&#225;tica profunda desempenha um papel importante no pulm&#227;o&#44; uma vez que remove materiais estranhos depositados sobre a superf&#237;cie das vias respirat&#243;rias&#44; tais como microrganismos patog&#233;nicos&#46; Esta drenagem est&#225; igualmente associada &#224;s vias de dissemina&#231;&#227;o tumoral&#46; Liposomas com uma membrana especificamente desenhada foram usados para simular part&#237;culas estranhas a ser removidas pelos linf&#225;ticos pulmonares&#46; Pretendem obter-se imagens dos linf&#225;ticos profundos em babu&#237;nos usando liposomas que encapsulam <span class="elsevierStyleSup">99m</span>Tc-HMPAO sob a forma de aerossol&#46; Observaram-se g&#226;nglios linf&#225;ticos axilares 30 min p&#243;s-inala&#231;&#227;o&#44; que se tornaram mais evidentes 1 hora ap&#243;s&#44; quando os g&#226;nglios abdominais e a&#243;rticos tamb&#233;m se tornaram vis&#237;veis&#46; Imagens tardias n&#227;o acrescentaram informa&#231;&#227;o relevante&#46; Foram desenhadas ROI&#39;s &#40;regi&#245;es de interesse&#41;&#44; bem como as correspondentes curvas de actividade-tempo para obter informa&#231;&#227;o acerca da biocin&#233;tica&#46; Em conclus&#227;o&#44; pode dizer-se que a t&#233;cnica proposta torna poss&#237;vel a visualiza&#231;&#227;o da rede linf&#225;tica profunda do pulm&#227;o e os g&#226;nglios linf&#225;ticos&#46; Esta metodolog&#237;a poder&#225; vir a ser importante na liberta&#231;&#227;o pulmonar controlada de f&#225;rmacos citot&#243;xicos&#46;</p>"
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ISSN: 21735115
Original language: Spanish
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Pulmonology

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