Plasmon-Triggered Upconversion Emissions and Hot Carrier Injection for Combinatorial Photothermal and Photodynamic Cancer Therapy.

Despite the unique ability of lanthanide-doped upconversion nanoparticles (UCNPs) to convert near-infrared (NIR) light to high-energy UV-vis radiation, low quantum efficiency has rendered their application unpractical in biomedical fields. Here, we report anatase titania-coated plasmonic gold nanorods decorated with UCNPs (Au NR@aTiO2@UCNPs) for combinational photothermal and photodynamic therapy to treat cancer. Our novel architecture employs the incorporation of an anatase titanium dioxide (aTiO2) photosensitizer as a spacer and exploits the localized surface plasmon resonance (LSPR) properties of the Au core. The LSPR-derived near-field enhancement induces a threefold boost of upconversion emissions, which are re-absorbed by neighboring aTiO2 and Au nanocomponents. Photocatalytic experiments strongly infer that LSPR-induced hot electrons are injected into the conduction band of aTiO2, generating reactive oxygen species. As phototherapeutic agents, our hybrid nanostructures show remarkable in vitro anticancer effect under NIR light [28.0% cancer cell viability against Au NR@aTiO2 (77.3%) and UCNP@aTiO2 (98.8%)] ascribed to the efficient radical formation and LSPR-induced heat generation, with cancer cell death primarily following an apoptotic pathway. In vivo animal studies further confirm the tumor suppression ability of Au NR@aTiO2@UCNPs through combinatorial photothermal and photodynamic effect. Our hybrid nanomaterials emerge as excellent multifunctional phototherapy agents, providing a valuable addition to light-triggered cancer treatments in deep tissue.

Clemizole and La3+ salts ameliorate angiotensin II-induced glomerular hyperpermeability in vivo.

Angiotensin II (Ang II) induces marked, dynamic increases in the permeability of the glomerular filtration barrier (GFB) in rats. After binding to its receptor, Ang II elicits Ca2+ influx into cells, mediated by TRPC5 and TRPC6 (transient receptor potential canonical type 5 and 6). Clemizole and La3+ salts have been shown to block TRPC channels in vitro, and we therefore tested their potential effect on Ang II-induced glomerular hyperpermeability. Anesthetized male Sprague-Dawley rats were infused with Ang II (80 ng kg-1  min-1 ) alone, or together with clemizole or low-dose La3+ (activates TRPC5, blocks TRPC6) or high-dose La3+ (blocks both TRPC5 and TRPC6). Plasma and urine samples were taken during baseline and at 5 min after the start of the infusions and analyzed by high-performance size-exclusion chromatography for determination of glomerular sieving coefficients for Ficoll 10-80 Å (1-8 nm). Ang II infusion evoked glomerular hyperpermeability to large Ficolls (50-80 Å), which was ameliorated by clemizole, having no significant effect on glomerular filtration rate (GFR) or Ang II-mediated increase in mean arterial pressure (ΔMAP). In contrast, high- and low-dose La3+ significantly lowered ΔMAP and reduced Ang II-induced hyperpermeability. Combined, clemizole and low-dose La3+ were less effective at ameliorating Ang II-induced glomerular hyperpermeability than low-dose La3+ alone. In conclusion, our data show that both clemizole and La3+ are effective against Ang II-induced glomerular hyperpermeability, with differential effects on blood pressure. Further research using more specific blockers of TRPC5 and TRPC6 should be performed to reveal the underlying mechanisms.

Delivery of drugs, proteins, and nucleic acids using inorganic nanoparticles.

Inorganic nanoparticles provide multipurpose platforms for a broad range of delivery applications. Intrinsic nanoscopic properties provide access to unique magnetic and optical properties. Equally importantly, the structural and functional diversity of gold, silica, iron oxide, and lanthanide-based nanocarriers provide unrivalled control of nanostructural properties for effective transport of therapeutic cargos, overcoming biobarriers on the cellular and organismal level. Taken together, inorganic nanoparticles provide a key addition to the arsenal of delivery vectors for fighting disease and improving human health.

Ln3+-doped nanoparticles with enhanced NIR-II luminescence for lighting up blood vessels in mice.

Probes functioning in the second near-infrared window (1000-1700 nm, NIR-II) exhibit higher resolution and diminished auto-fluorescence compared to those in the traditional NIR region (700-950 nm). Here, we designed and synthesized rare earth ion doped probes with core/shell/shell structures and bright luminescence in the NIR-II region excited at 808 nm. With the doping of Ce3+ ions, the emission intensity of Er3+ at 1530 nm increased 10 times, while the upconversion luminescence decreased to less than 1%. After being modified with polyacrylic acid and polyethylene glycol, the as-obtained water-soluble probe exhibits continuous high-resolution for distinguishing 0.25 mm blood vessels even 10 h after injection. Noteworthily, the imaging of tumors was achieved by injecting the probe, indicating that the designed NIR-II probe has sufficient brightness and the ability to passively target tumor tissue.

Investigation on Anti-Autofluorescence, Osteogenesis and Long-Term Tracking of HA-Based Upconversion Material.

Hydroxyapatite (HA) material will be long-standing once implanted in bone tissue of the body. It should be considered to endow the osteogenic HA material with traceable fluorescence to realize a lifelong in vivo tracking. We prepared and utilized lanthanides-doped HA upconversion material, and revealed for the first time that the lanthanides (ytterbium (Yb) and holmium (Ho)) co-doped HA upconversion material was suitable for long-term or lifelong in vivo tracking, the lanthanide ions doped in the HA matrix would not affect the biocompatibility and osteogenesis, and the tissue autofluorescence could be effectively avoided by the HA:Yb/Ho upconversion material. Also the distribution in bone and osteointegration with bone of the HA:Yb/Ho material could be clearly discriminated by its bright fluorescence under NIR irradiation. The upconversion characteristic of the HA:Yb/Ho material provides a feasibility and promising prospect for lifelong in vivo tracking, and has an advantage in revealing the material-tissue interrelation. The material has important clinical application value in addition to its usefulness for scientific investigation.

Intensely red-emitting luminescent upconversion nanoparticles for deep-tissue multimodal bioimaging.

Nowadays, in order to improve the diagnostic accuracy of the disease, more and more contrast agents have been applied in the clinical imaging modalities. A combination of nanotechnology with optical, computed X-ray tomography (CT), and magnetic resonance imaging (MRI) has great potential to improve disease diagnosis and therapy. Herein, we developed a novel multimodal contrast agent for deep-tissue bioimaging based on PEGylated Mn2+ doped NaLuF4:Yb/Er nanoparticles (PEG-UCNPs). The multimodal nanoprobes have revealed the intensely red upconversion luminescence emission for deep-tissue upconversion luminescence (UCL) imaging. Moreover, Owing to the high longitudinal relaxivity, the PEG-UCNPs can be used as T1-weighted MRI contrast agents. Additionally, with the high X-ray mass absorption coefficient of Lu3+, the novel nanoprobes are appropriate for CT imaging. With integration the high paramagnetic property, superior X-ray mass absorption coefficient and excellent upconversion luminescence in one system, the multimodal nanoprobes can provide a unique opportunity for MRI, CT and UCL imaging. More importantly, modification with PEG endows the novel nanoprobes with high biocompatibility, which would bring more opportunities for the biomedical applications in clinic.

Near infrared-assisted Fenton reaction for tumor-specific and mitochondrial DNA-targeted photochemotherapy.

The strong dependence on oxygen level, low ultraviolet/visible (UV/vis) light penetration depth and the extremely short lifetime of reactive oxygen species (ROS) are the major challenges of photodynamic therapy (PDT) for tumors. Fenton reaction can produce abundant ROS such as reactive hydroxyl radicals (OH) with significantly higher oxidation performance than singlet oxygen (1O2), which, however, has been rarely used in biomedical fields due to strict reaction conditions (favorably in pH range of 3-4, mostly under UV/vis light catalysis). Herein we propose and demonstrate a photochemotherapy (PCT) strategy of cancer therapy using near-infrared (NIR)-assisted tumor-specific Fenton reactions. NIR light-upconverted UV/vis light by upconversion nanoparticles (UCNPs) catalyze the intra-mitochondrial Fenton reaction between the delivered Fe2+ and H2O2 species over-expressed in cancer cell's mitochondria to in-situ kill the cancer cells. The intra-mitochondrial ROS generation of enabled by directly targeting the mitochondrial DNA (mtDNA) helix minimized the distance between the ROS and mtDNA molecules, thus the present PCT strategy showed much enhanced and tumor-specific therapeutic efficacy, as demonstrated by the intratumoral-accelerated OH burst and elevated cytotoxicity. Following the direct intratumoral injection, the PCT revealed marked tumor regression effect in vivo. This constructed PCT-agent is the first paradigm of NIR-upconversion catalyzed intra-mitochondrial Fenton reaction in response to tumoral microenvironment, establishing a novel photochemotherapy strategy for efficient cancer therapy.

Inhibition of lanthanide nanocrystal-induced inflammasome activation in macrophages by a surface coating peptide through abrogation of ROS production and TRPM2-mediated Ca(2+) influx.

Lanthanide-based nanoparticles (LNs) hold great promise in medicine. A variety of nanocrystals, including LNs, elicits potent inflammatory response through activation of NLRP3 inflammasome. We have previously identified an LNs-specific surface coating peptide RE-1, with the sequence of 'ACTARSPWICG', which reduced nanocrystal-cell interaction and abrogated LNs-induced autophagy and toxicity in both HeLa cells and liver hepatocytes. Here we show that RE-1 coating effectively inhibited LNs-induced inflammasome activation, mostly mediated by NLRP3, in mouse bone marrow derived macrophage (BMDM) cells, human THP-1 cells and mouse peritoneal macrophages and also reduced LNs-elicited inflammatory response in vivo. RE-1 coating had no effect on cellular internalization of LNs in BMDM cells, in contrast to the situation in HeLa cells where cell uptake of LNs was significantly inhibited by RE-1. To elucidate the molecular mechanism underlying the inflammasome-inhibiting effect of RE-1, we assessed several parameters known to influence nanocrystal-induced NLRP3 inflammasome activation. RE-1 coating did not reduce potassium efflux, which occurred after LNs treatment in BMDM cells and was necessary but insufficient for LNs-induced inflammasome activation. RE-1 did decrease lysosomal damage induced by LNs, but the inhibitor of cathepsin B did not affect LNs-elicited caspase 1 activation and IL-1ß release, suggesting that lysosomal damage was not critically important for LNs-induced inflammasome activation. On the other hand, LNs-induced elevation of intracellular reactive oxygen species (ROS), critically important for inflammasome activation, was largely abolished by RE-1 coating, with the reduction on NADPH oxidase-generated ROS playing a more prominent role for RE-1's inflammasome-inhibiting effect than the reduction on mitochondria-generated ROS. ROS generation further triggered Ca(2+) influx, an event that was mediated by Transient Receptor Potential M2 (TRPM2) and was necessary for inflammasome activation, and this event was completely inhibited by RE-1 coating. We conclude from these studies that inhibition of ROS production, and the subsequent abrogation of TRPM2-mediated Ca(2+) influx, is the primary mechanism underlying RE-1's inhibitory effect on LNs-induced inflammasome activation. The ability of regulating the inflammatory response of nanocrystals through peptide surface coating may be of great value for in vivo applications of LNs and other engineered nanomaterials.

An anion-induced hydrothermal oriented-explosive strategy for the synthesis of porous upconversion nanocrystals.

Rare-earth (RE)-doped upconversion nanocrystals (UCNCs) are deemed as the promising candidates of luminescent nanoprobe for biological imaging and labeling. A number of methods have been used for the fabrication of UCNCs, but their assembly into porous architectures with desired size, shape and crystallographic phase remains a long-term challenging task. Here we report a facile, anion-induced hydrothermal oriented-explosive method to simultaneously control size, shape and phase of porous UCNCs. Our results confirmed the anion-induced hydrothermal oriented-explosion porous structure, size and phase transition for the cubic/hexagonal phase of NaLuF4 and NaGdF4 nanocrystals with various sizes and shapes. This general method is very important not only for successfully preparing lanthanide doped porous UCNCs, but also for clarifying the formation process of porous UCNCs in the hydrothermal system. The synthesized UCNCs were used for in vitro and in vivo CT imaging, and could be acted as the potential CT contrast agents.

LnPO4 nanoparticles doped with Ac-225 and sequestered daughters for targeted alpha therapy.

For targeted alpha therapy (TAT) with 225Ac, daughter radioisotopes from the parent emissions should be controlled. Here, we report on a second-generation layered nanoparticle (NP) with improved daughter retention that can mediate TAT of lung tumor colonies. NPs of La3+, Gd3+, and 225Ac3+ ions were coated with additional layers of GdPO4 and then coated with gold via citrate reduction of NaAuCl4. MAb 201b, targeting thrombomodulin in lung endothelium, was added to a polyethylene glycol (dPEG)-COOH linker. The NPs:mAb ratio was quantified by labeling the mAb with 125I. NPs showed 30% injected dose/organ antibody-mediated uptake in the lung, which increased to 47% in mice pretreated with clodronate liposomes to reduce phagocytosis. Retention of daughter 213Bi in lung tissue was more than 70% at one hour and about 90% at 24 hours postinjection. Treatment of mice with lung-targeted 225Ac NP reduced EMT-6 lung colonies relative to cold antibody competition for targeting or phosphate-buffered saline injected controls. We conclude that LnPO4 NPs represent a viable solution to deliver the 225Ac as an in vivo α generator. The NPs successfully retain a large percentage of the daughter products without compromising the tumoricidal properties of the α-radiation.

Lanthanide-loaded erythrocytes as highly sensitive chemical exchange saturation transfer MRI contrast agents.

Chemical exchange saturation transfer (CEST) agents are a new class of frequency-encoding MRI contrast agents with a great potential for molecular and cellular imaging. As for other established MRI contrast agents, the main drawback deals with their low sensitivity. The sensitivity issue may be tackled by increasing the number of exchanging protons involved in the transfer of saturated magnetization to the "bulk" water signal. Herein we show that the water molecules in the cytoplasm of red blood cells can be exploited as source of exchangeable protons provided that their chemical shift is properly shifted by the intracellular entrapment of a paramagnetic shift reagent. The sensitivity of this system is the highest displayed so far among CEST agents (less than 1 pM of cells), and the natural origin of this system makes it suitable for in vivo applications. The proposed Ln-loaded RBCs may be proposed as reporters of the blood volume in the tumor region.

Access to a novel near-infrared photodynamic therapy through the combined use of 5-aminolevulinic acid and lanthanide nanoparticles.

BACKGROUND: There have been considerable efforts to develop photodynamic therapy (PDT) for cancer, in which photoirradiation of a sensitizer delivered near cancer cells results in the conversion of oxygen into active species, causing cell destruction. Aiming at the best cancer selectivity, one PDT method employed protoporphyrin IX (PPIX), which selectively accumulated in cancer cells after oral administration of 5-aminolevulinic acid (ALA). The drawback, however, is that blue incident lights are required to excite PPIX, resulting in low tissue penetrability, and therefore limiting its application to surface cancers. METHODS: To overcome the low penetrability of the incident light, we employed a light energy upconverter, lanthanide nanoparticle (LNP), which, upon irradiation with highly penetrative near-infrared (NIR) radiation, emits visible light within the Q-band region of PPIX absorbance allowing its sensitization. To discover the optimum conditions for the LNP-assisted PDT, the cytotoxicity and PPIX-sensitizability of LNPs were first studied. Then, the LNP-assisted PDT was validated using the MKN45 cell line: cells were pretreated with ALA and LNP, irradiated with a 975-nm diode laser, and subjected to MTT assay to measure cell viability. RESULTS: The singlet oxygen generation on NIR-irradiation of the PPIX-LNP mixture was proved, indicating that the emission from LNP could excite the PPIX sensitizer. An intermittent NIR-irradiation for 32 min of MKN45, pretreated with LNP (1mg/mL) and ALA (2mM), caused 87% cell destruction. CONCLUSIONS: The potential applicability of the NIR-irradiation PDT with ALA- and LNP-pretreated cancer cells was demonstrated.

Direct visualization of gastrointestinal tract with lanthanide-doped BaYbF5 upconversion nanoprobes.

Nanoparticulate contrast agents have attracted a great deal of attention along with the rapid development of modern medicine. Here, a binary contrast agent based on PAA modified BaYbF5:Tm nanoparticles for direct visualization of gastrointestinal (GI) tract has been designed and developed via a one-pot solvothermal route. By taking advantages of excellent colloidal stability, low cytotoxicity, and neglectable hemolysis of these well-designed nanoparticles, their feasibility as a multi-modal contrast agent for GI tract was intensively investigated. Significant enhancement of contrast efficacy relative to clinical barium meal and iodine-based contrast agent was evaluated via X-ray imaging and CT imaging in vivo. By doping Tm(3+) ions into these nanoprobes, in vivo NIR-NIR imaging was then demonstrated. Unlike some invasive imaging modalities, non-invasive imaging strategy including X-ray imaging, CT imaging, and UCL imaging for GI tract could extremely reduce the painlessness to patients, effectively facilitate imaging procedure, as well as rationality economize diagnostic time. Critical to clinical applications, long-term toxicity of our contrast agent was additionally investigated in detail, indicating their overall safety. Based on our results, PAA-BaYbF5:Tm nanoparticles were the excellent multi-modal contrast agent to integrate X-ray imaging, CT imaging, and UCL imaging for direct visualization of GI tract with low systemic toxicity.

Lanthanide-doped upconverting luminescent nanoparticle platforms for optical imaging-guided drug delivery and therapy.

Lanthanide-doped upconverting luminescent nanoparticles (UCNPs) are promising materials for optical imaging-guided drug delivery and therapy due to their unique optical and chemical properties. UCNPs absorb low energy near-infrared (NIR) light and emit high-energy shorter wavelength photons. Their special features allow them to overcome various problems associated with conventional imaging probes and to provide versatility for creating nanoplatforms with both imaging and therapeutic modalities. Here, we discuss several approaches to fabricate and utilize UCNPs for traceable drug delivery and therapy.

Oxidative stress in the liver of mice caused by intraperitoneal injection with lanthanoides.

In order to study the mechanisms underlying the effects of lanthanoid (Ln) on the liver, ICR mice were injected with LaCl3, CeCl3, and NdCl3 at a dose of 20 mg/kg BW into the abdominal cavity daily for 14 days. We then examined oxidative stress-mediated responses in the liver. The increase of lipid peroxide in the liver produced by Ln suggested an oxidative attack that was activated by a reduction of antioxidative defense mechanisms as measured by analyzing the activities of superoxide dismutase, catalase, and ascorbate peroxidase, as well as antioxidant levels such as glutathione and ascorbic acid, which were greatest in Ce(3+) treatment, medium in Nd(3+), and least in La(3+). Our results also implied that the oxidative stress in the liver caused by Ln likely is Ce(3+) > Nd(3+) >La(3+), but the mechanisms need to be further studied in future.

Effects of diagnostic contrast-enhanced ultrasound on permeability of placental barrier: a primary study.

OBJECTIVE: To evaluate the effects of contrast-enhanced ultrasound (CEU) on the permeability of placental barrier primarily. METHODS: A total of 60 pregnant Sprague Dawley (SD) rats were divided into 10 groups, including six groups of microbubbles-enhanced ultrasound (varied mechanical index (MI) of 0.13, 1.0 and 1.4 with continuous and intermittent insonation respectively) (US+MB), two groups of ultrasound insonation only (continuous and intermittent insonation respectively) (US), the group of microbubbles only (MB) and the control group. Evans blue (EB), as the tracer, was intravenously injected before treatment. The EB in placenta and fetus was observed under fluorescence microscope and analyzed quantitatively. The EB amount was compared between groups and between placenta and fetus. Lanthanum nitrate-tracing transmission electron microscope examination was performed to observe the distribution of lanthanum in the placenta and fetus. RESULTS: Observed by naked eye, the plancenta was dyed into deep blue while there was no sign of dyeing to the fetus in all groups. Under fluorescence microscope, the red fluorescence radiated by EB was observed in placenta but not in fetus. The EB amount in placenta, insonated by microbubbles-enhanced ultrasound of varied MI, was higher significantly than that in MB, US and control group (all P<0.01) while there was no difference between the latter three groups. And in each group, EB amount was much higher in placenta than that in fetus (P<0.01). The lanthanum particles deposited in the intercellular space in the syntrophoblast while there was no lanthanum presented in the cytotrophoblast in all groups. CONCLUSION: Our findings suggest that diagnostic CEU with SonoVue will not increase the permeability of placenta to the macromolecules larger than albumin, although it may affect placenta.

Lanthanide-loaded liposomes for multimodality imaging and therapy.

UNLABELLED: Many advanced molecular imaging agents are currently being investigated preclinically. Especially, liposomes, have proven to be very promising carrier systems for diagnostic agents for use in single-photon emission computed tomography (SPECT) or magnetic resonance imaging (MRI), as well as for therapeutic agents to treat diseases such as cancer. In this study, nanosized liposomes were designed and labeled with the radionuclides, holmium-166 (both a beta- and gamma-emitter and also highly paramagnetic) or technetium-99m, and coloaded with paramagnetic gadolinium allowing multimodality SPECT and MR imaging and radionuclide therapy with one single agent. METHODS: Diethylenetriaminepentaacetic acid bisoctadecylamide (an amphiphilic molecule with a chelating group suitable for labeling with radionuclides) and gadoliniumacetylacetonate (GdAcAc) (a small lipophilic paramagnetic molecule) were incorporated in liposomes. The liposomes were characterized by measuring their mean size and size distribution, gadolinium content, and radiochemical stability after incubation in human serum at 37 degrees C. The MRI properties (in vitro) were determined by use of relaxivity measurements at 1.5 and 3.0 Tesla in order to evaluate their potency as imaging agents. RESULTS: The liposomes were successfully labeled with holmium-166, resulting in a high labeling efficiency (95% +/- 1%) and radiochemical stability (> 98% after 48 hours of incubation), and coloaded with GdAcAc. Labeling of liposomes with technetium-99m was somewhat less efficient (85% +/- 2%), although their radiochemical stability was sufficient (95% +/- 1% after 6 hours of incubation). MRI measurements showed that the incorporation of GdAcAc had a strong effect on the MRI relaxivity. CONCLUSIONS: The synthesized liposomes allow for multimodality imaging and therapy, which makes these new agents highly attractive for future applications.

Selective mineral elements concentration of the intestinal mucosa role of the lysosomes of duodenal enterocytes in the handling of mineral elements after intragastric administration.

Intragastric administration to rats of four soluble lanthanides cerium, lanthanum, europium, thulium and of three soluble elements of group IIIA aluminium, indium and gallium has been shown in previous studies. In this work two new rare earths gadolinium and terbium were studied using the same protocols and the same methods (transmission electron microscopy and ion microanalysis). among the previously studied elements, some of them were administered simultaneously on the one hand aluminium and indium, and on the other hand, lanthanum and cerium. These metals were looked for in intestinal mucosa, liver and kidney. The results showed: a) gadolinium and terbium were selectively concentrated in lysosomes of duodenal enterocytes, precipitated as non-soluble phosphate salts and eliminated with the cell's turn-over in less than 48 hr; b) Administered simultaneously, they precipitated in the same lysosome. c/ none of them was observed in the liver or kidney even with high dose. This study brings up to nine the number of elements forming a non-soluble phosphate salts, explaining their precipitation in lysosomes. None of them have a physiological role, two are toxic (aluminium and indium). This rapid intralysosomal concentration is an efficient mechanism which limits the diffusion of the foreign substances through the digestive barrier, then permits their elimination along with the cytoptose phenomenon in the intestinal lumen.

Lanthanide bearing microparticulate systems for multi-modality imaging and targeted therapy of cancer.

The rapid developments of high-resolution imaging techniques are offering unique possibilities for the guidance and follow up of recently developed sophisticated anticancer therapies. Advanced biodegradable drug delivery systems, e.g. based on liposomes and polymeric nanoparticles or microparticles, are very effective tools to carry these anticancer agents to their site of action. Elements from the group of lanthanides have very interesting physical characteristics for imaging applications and are the ideal candidates to be co-loaded either in their non-radioactive or radioactive form into these advanced drug delivery systems because of the following reasons: Firstly, they can be used both as magnetic resonance imaging (MRI) and computed tomography (CT) contrast agents and for single photon emission computed tomography (SPECT). Secondly, they can be used for radionuclide therapies which, importantly, can be monitored with SPECT, CT, and MRI. Thirdly, they have a relatively low toxicity, especially when they are complexed to ligands. This review gives a survey of the currently developed lanthanide-loaded microparticulate systems that are under investigation for cancer imaging and/or cancer therapy.

Analytical microscopy observations of rat enterocytes after oral administration of soluble salts of lanthanides, actinides and elements of group III-A of the periodic chart.

The behavior in the intestinal barrier of nine elements (three of the group III-A, four lanthanides and two actinides), absorbed as soluble salts, has been studied by two microanalytical methods: electron probe X-ray micro analysis (EPMA) and secondary ion mass spectrometry (SIMS). It has been shown that the three elements of group III-A, aluminium, gallium and indium; and the four lanthanides, lanthanum, cerium, europium and thulium, are selectively concentrated and precipitated as non-soluble form in enterocytes of proximal part of the intestinal tract. SIMS microscopy has shown that these elements are concentrated as a number of submicroscopic precipitates, most of them localized in the apical part of the duodenum enterocytes, where they are observed from one hour to 48 hr after a single intragastric administration. No precipitate is observed after three days. It is suggested that this mechanism of local concentration limits the diffusion of these elements through the digestive barrier, some of them being toxic and none of them having a recognized physiological role. Additionally, the precipitation in duodenal enterocytes, the life time of which is on the order of 2-3 days, allows the elements absorbed as soluble form to be eliminated as a non-soluble form in the digestive lumen along with the desquamation of the apoptotic enterocytes. The intracytoplasmic localization of the precipitates are supposed to be the lysosomes although no direct evidence could be given here due to the very small sizes of the lysosomes of enterocytes. The same results were not observed with the two studied actinides. After administration of thorium, only some very sparse microprecipitates could be observed in intestinal mucosa and, after administration of uranium, no precipitates were observed with the exception of some in the conjunctive part of the duodenal villi.