pH-responsive Mannose-modified ferrocene Metal-Organic frameworks with rare earth for Tumor-targeted synchronous Chemo/Chemodynamic therapy.

The combination of chemodynamic therapy (CDT) and chemotherapy is a promising strategy to achieve enhanced anticancer effects. Metal-organic frameworks (MOFs), as multifunctional drug delivery vehicles, have received extensive attention in the biomedical field. Carbohydrate has excellent biocompatibility and targeting ability, which can be used as a targeting ligand due to a specific recognition with glycoprotein receptors that overexpress on cancer cell membranes. Herein, the pH-responsive mannose-modified ferrocene MOFs with rare earth metal were synthesized via coordination-driven self-assembly of 1,1'-Ferrocenedicarboxylic acid and ytterbium chloride. Subsequently, DOX@Fc-MOFs-Mann nanoparticles (NPs) were obtained by loading doxorubicin (DOX) and modifying mannose (Mann), where DOX@Fc-MOFs-Mann NPs were able to precisely target HepG2 cells via mannose receptor and slowly decompose in the acidic environment of tumor to release ferrocene, DOX, and Yb3+. Fe2+ in ferrocene effectively activated Fenton reaction to produce high levels of reactive oxygen species (ROS) for irreversible induction of cell apoptosis or necroptosis. Combined with the chemotherapy (CT) ability of DOX, Yb3+ further induced cell death through its own toxicity to successfully achieved the rare earth metal synergistic CDT and CT combination therapy. This synergistic CDT and CT strategy not only opens up new horizons for rare earth metals in biomedical applications but also provides new inspiration into the construction of glycosyl-modified MOFs.

A Step-by-Step Guide for the Novel Radiometal Production for Medical Applications: Case Studies with 68Ga, 44Sc, 177Lu and 161Tb.

The production of novel radionuclides is the first step towards the development of new effective radiopharmaceuticals, and the quality thereof directly affects the preclinical and clinical phases. In this review, novel radiometal production for medical applications is briefly elucidated. The production status of the imaging nuclide 44Sc and the therapeutic ß--emitter nuclide 161Tb are compared to their more established counterparts, 68Ga and 177Lu according to their targetry, irradiation process, radiochemistry, and quality control aspects. The detailed discussion of these significant issues will help towards the future introduction of these promising radionuclides into drug manufacture for clinical application under Good Manufacturing Practice (GMP).

Application of rare earth-doped nanoparticles in biological imaging and tumor treatment.

Rare earth-doped nanoparticles have been widely used in disease diagnosis, drug delivery, tumor therapy, and bioimaging. Among various bioimaging methods, the fluorescence imaging technology based on the rare earth-doped nanoparticles can visually display the cell activity and lesion evolution in living animals, which is a powerful tool in biological technology and has being widely applied in medical and biological fields. Especially in the band of near infrared (700-1700 nm), the emissions show the characteristics of deep penetration due to low absorption, low photon scattering, and low autofluorescence interference. Furthermore, the rare earth-doped nanoparticles can be endowed with the water solubility, biocompatibility, drug-loading ability, and the targeting ability for different tumors by surface functionalization. This confirms its potential in the cancer diagnosis and treatment. In this review, we summarized the recent progress in the application of rare earth-doped nanoparticles in the field of bioimaging and tumor treatment. The luminescent mechanism, properties, and structure design were also discussed.

Optimising FRET-efficiency of Nd3+-sensitised upconversion nanocomposites by shortening the emitter-photosensitizer distance.

Nd3+-Sensitised luminescent upconversion nanoparticles (UCNPs) have gained interest recently as theranostics due to their near-infrared (NIR) light excitation with a better tissue penetration depth. One example is the core/shell design NaYF4:Yb,Er@Nd,Yb. When harvesting the upconversion energy in such architectures, the long emitter-photosensitizer (i.e. Er3+-PS) distances lead to inefficient Förster resonance energy transfer (FRET). Herein, we report a new nanocomposite NaYF4:Nd,Yb@Yb@Yb,Er@Y with Nd3+ ions in the core and Er3+ ions in the shell to shorten the Er-PS distance to achieve better FRET. Furthermore, an outer non-emitting protective Y3+ shell and a conducting Yb3+ shell reduced surface quenching and Er3+-to-Nd3+ energy back transfer effects, respectively. The upconversion FRET and downshifting emission efficiencies were simultaneously optimised by adjusting the thickness of the Y3+ shell, and the FRET efficiency was at least 3.7 times that of the reference NaYF4:Yb,Er@Yb@Nd,Yb@Y in a photodynamic therapy (PDT) model.

Control synthesis, subtle surface modification of rare-earth-doped upconversion nanoparticles and their applications in cancer diagnosis and treatment.

Rare earth doped upconversion nanoparticles (UCNPs) are a new class of luminescent materials that can absorb long-wavelength near-infrared photons and emit short-wavelength UV-visible photons. UCNPs have little damage to biological tissues, have deep tissue penetration ability, have no background fluorescence noise interference, have high imaging sensitivity, and have no photobleaching effect. In the field of biomedicine, especially in the field of diagnosis and treatment of cancer, a wide range of research interests has arisen. In this paper, we briefly introduce the luminescent principle of rare-earth doped UCNPs, discuss several widely used control synthesis and modification methods, and focus on the research progress of UCNPs in detection of cancer cells, photodynamic therapy (PDT) and photothermal therapy (PTT) field. We also summarize the application of UCNPs as a diagnostic and therapeutic integrated nanoplatform in the diagnosis and treatment of cancer. At last, we explore the application challenge and prospect of UCNPs in oncology field.

Efficacy of Erbium, Chromium-doped:Yttrium, Scandium, Gallium, and Garnet Laser Irradiation Combined with Resin-based Tricalcium Silicate and Calcium Hydroxide on Direct Pulp Capping: A Randomized Clinical Trial.

INTRODUCTION: The purpose of this randomized clinical study was to evaluate the efficiency of erbium, chromium-doped:yttrium, scandium, gallium, and garnet (Er,Cr:YSGG) laser irradiation combined with a resin-based tricalcium silicate material and calcium hydroxide in direct pulp capping for a 6-month follow-up period. METHODS: A total of 60 teeth of 60 patients between the ages of 18 and 41 years were recruited for this study. Sixty permanent vital teeth without symptoms and radiographic changes were randomly assigned to the following 4 groups (n = 15): Gr CH, the exposed area was sealed with calcium hydroxide (CH) paste; Gr laser CH, the treated area was sealed with CH paste after Er,Cr:YSGG laser irradiation at an energy level of 0.5 W without water and with 45% air; Gr TheraCal, TheraCal LC (Bisco, Schaumburg, IL) was applied directly to the exposed pulp; and Gr Laser TheraCal, TheraCal LC was applied after irradiation with an Er,Cr:YSGG laser. At the 1-week and 1-, 3-, and 6-month recall examinations, the loss of vitality, spontaneous pain, reactions to thermal stimuli and percussion, and radiographic changes were considered as failure. RESULTS: The success rates in the CH and TheraCal groups were 73.3% and 66.6%, respectively. These rates did not reveal any significant difference. In both laser groups, success rates were 100%. The Er,Cr:YSGG laser-irradiated TheraCal and Er,Cr:YSGG laser-irradiated CH groups showed statistically higher success rates than the TheraCal and CH groups, respectively. CONCLUSIONS: Er,Cr:YSGG laser irradiation at 0.5 W without water combined with pulp capping agents can be recommended for direct pulp therapy.

Pm-149 DOTA bombesin analogs for potential radiotherapy. in vivo comparison with Sm-153 and Lu-177 labeled DO3A-amide-betaAla-BBN(7-14)NH(2).

Promethium-149 (149Pm) is one of only three radiolanthanides that can be prepared in no carrier added concentrations. This high specific activity radiolanthanide is thus suitable for targeting limited numbers of specific receptors found on many tumor cells. Promethium-149 is a moderate energy beta(-) emitter (1.07 MeV (95.9%)) with a half-life of 2.21 days. Pm-149 also emits a low abundance of an imageable gamma ray (286 keV (3%)) that may allow in vivo tracking of the therapeutic dose. The 149Pm and Sm complexes with the DO3A-amide chelator with zero and three carbon spacers to the bombesin peptide analog BBN(7-14)NH(2) were synthesized and characterized. The Sm complexes were synthesized for macroscopic characterization purposes (ESI-MS, in vitro cell binding) since no stable isotopes of Pm are known. The biological properties of the 149Pm, 153Sm and 177Lu-DO3A-amide-betaAla-BBN complexes were compared in normal mouse biodistribution studies.

Current and potential therapeutic uses of lanthanide radioisotopes.

In the last 25 years, diagnostic nuclear medicine has come to depend on the versatile chemistry of a single radioisotope, technetium-99m (Tc-99m). Different chelating molecules can be used to guide Tc-99m through various physiological pathways in the body to gain information about disease states. No single radioisotope similarly dominates therapeutic applications. In the field of radioisotope therapy, much discussion and debate have focused on what radioisotope might be "ideal" for treatment of malignant tumors. The ideal may not be a single radioisotope, but rather the class of very closely related radiolanthanides and lanthanide-like radioisotopes. These radioisotopes possess strikingly similar chemistries and thus all may be conjugated to biomolecules using a single chelate, the DOTA moiety (and its chemical analogs). They also provide a wide range of physical characteristics, such as half-lives and beta energies, that can be chosen to match the biological properties of the conjugated biomolecule and the malignant tumor. Thus, the radiolanthanide-DOTA bioconjugate model provides a set of physically diverse, but chemically very similar, therapeutic radiopharmaceutical agents, the individual members of which can be tailored to treat specific types of cancers.

Does perioperative outcome of transurethral holmium laser enucleation of the prostate depend on prostate size?

BACKGROUND AND PURPOSE: In conventional transurethral resection of the prostate (TURP), perioperative morbidity resulting from causes such as blood loss and TUR syndrome increases with prostate size. Therefore, TURP is restricted to small and medium-sized glands. The present study aimed to find out whether perioperative parameters of holmium laser enucleation of the prostate (HoLEP) other than operation time and weight of resected tissue were dependent on prostate size. PATIENTS AND METHODS: A total of 384 patients were treated with HoLEP (holmium:YAG laser, 2.0 J, 40 or 50 Hz, 80 or 100 W, 550-nm bare fiber) for acute removal of obstructing benign hyperplastic tissue. Among them, 111 patients (28.9%) had prostates of <40 g (group 1), 152 (39.6%) had prostates of 40 to 79 g (group 2), and 121 (31.5%) had prostates of >/=80 g (range 80-260) (group 3). The perioperative outcomes of the three groups were compared. A total of 346 patients completed the 1-month postoperative assessment. RESULTS: The mean prostate sizes were 31.8 g, 56 g, and 98.7 g for groups 1, 2, and 3 (P<0.0001 group 1 v group 2 v group 3). The mean resected tissue weight was 19.5 g v 34.4 g (P= 0.009) v 70.1 g (range 50-220) (P< 0.0001). The mean operation time was 64.3 v 84.2 (P= 0.009) v 118.4 minutes (P< 0.0001). The mean hemoglobin loss was 0.9 v 1.2 (NS) v 1.9 g/dL (P< 0.001). The overall correlation between hemoglobin loss and prostate size in all patients was very weak (r = 0.229) and just exceeded the level of significance (r = 0.2). In all three groups, the median postoperative catheter time was 1 day, and the median postoperative hospital stay was 2 days. The HoLEP resulted in an immediate and significant improvement of American Urological Association Symptom Scores, peak urinary flow rates, and postvoiding residual urine volumes (P< 0.0001) 1 month after the operation, without significant differences between the groups. The rate of complications was similar in all three groups. None of the patients needed blood transfusions. There were no perioperative deaths. CONCLUSION: In HoLEP, perioperative morbidity and postoperative micturition improvement do not depend on prostate size. Therefore, in contrast to TURP, HoLEP is equally suitable for small, medium-size, and large prostate glands.

Transurethral holmium laser enucleation of the prostate compared with transvesical open prostatectomy: 18-month follow-up of a randomized trial.

PURPOSE: This ongoing randomized study aims to find out whether transurethral holmium laser enucleation of the prostate (HoLEP) could be an alternative to open transvesical prostatectomy in patients with prostates >100 g. PATIENTS AND METHODS: A series of 120 urodynamically obstructed patients were randomized to HoLEP or open prostatectomy, 60 patients to each group. The HoLEP was performed with high-powered Ho:YAG lasers at 80 to 100 W (2.0 J, 40-50 Hz) and 550-nm bare laser fibers. The American Urological Association Symptom Scores, peak urinary flow rates, and postvoiding residual urine volumes were evaluated preoperatively and at 1, 3, 6, 12, and 18 months postoperatively. All complications were noted. RESULTS: By the Mann-Whitney test, there was no significant difference between the HoLEP and open surgery groups in patient age (69.0 years HoLEP v 71.0 years open surgery), prostate volume (115 cc [range 100-230 cc] v 113 cc [100-230 cc], or weight of resected tissue (94 g [range 57-220 g] v 96 g [range 61-220 g]). There were significant differences in the mean operative time (136 v 91 minutes; P< 0.0001), mean hemoglobin loss (1.9 v 2.8 g/dL; P< 0.0001), median catheter time (1 day v 6 days; P< 0.0001), and median hospital stay (2 days v 10 days; P< 0.0001). Both HoLEP and open prostatectomy resulted in pronounced and lasting postoperative improvements in Symptom Scores, peak urinary flow rates, and postvoiding residual volumes (P< 0.0001). The differences between HoLEP and open prostatectomy were not significant at any interval for any parameter. Blood transfusions were required in 0 HoLEP patients v 8 open surgery patients. Arterial bleeding occurred in three patients in each group. Secondary apical resection was required in two HoLEP patients and no open surgery patients. Bladder neck contracture occurred in none of the HoLEP patients and two of those having open surgery. Thus, the total number of patients having complications was 7 with HoLEP and 13 with open surgery. There were no deaths in either group. CONCLUSIONS: The HoLEP appears to be an endourologic alternative to open surgical enucleation of the prostate for large glands. It entails significantly less blood loss and a much shorter catheter time and hospital stay. The perioperative outcome strongly favors the holmium procedure. The rate of late complications is equally low with each procedure. The postoperative micturition improvement was significant and lasting and was equivalent in the two groups.

Alpha- and beta-emitting radiolanthanides in targeted cancer therapy: the potential role of terbium-149.

The efficacy of systemic cancer therapy rests on the ability of a toxin to be preferentially located in cancer cells, so that cancer cell kill is maximized and normal tissue spared. This requires that the lifetime of the toxin be less than the lifetime of the carrier in the body, effectively ruling out chemical toxins, as they remain effective until excreted from the body. The requirement of localization of dose to the cancer cell makes radioactive beta-emitting radionuclides unattractive. Alpha-emitting radionuclides are much more appropriate toxins, as their efficacy depends on the high energy and short range of the alpha particles, and terbium-149 is shown to be the most efficacious of these. However, the merit of various alpha- and beta-emitting radionuclides depends on the stage and type of cancer. Recommendations are made with respect to the matching of the target cancer with required properties of the radiolabel and carrier.

Are rare-earth nanoparticles suitable for in vivo applications?

Rare earth (RE) nanoparticles have attracted considerable attention due to their unique optical and magnetic properties associated with f-electrons. The recent accomplishments in RE nanoparticle synthesis have aroused great interest of scientists to further explore their biomedical applications. This Research News summarizes recent achievements in controlled synthesis of magnetic and luminescent RE nanoparticles, surface modification, and toxicity studies of RE nanomaterials, and highlights state-of-the-art in in vivo applications of RE nanoparticles.

Ethylene diamine tetramethylene phosphonic acid labeled with various ß(-)-emitting radiometals: labeling optimization and animal biodistribution.

Skeletal uptake of ß(-)-emitting radionuclides may be used for bone pain palliation or myeloablation. The physical characteristics of the ß(-) particles required for the two conditions are, however, different, that is, higher energies are favorable for destruction of bone marrow. In this study, the labeling conditions of ethylene diamine tetramethylene phosphonic acid (EDTMP) with three rare earth metals (90Y, 166Ho, and 177Lu) having ß(-) particles of diverse physical characteristics were optimized, and their animal biodistributions were studied and compared with 153Sm-EDTMP. All the four radiometals (X = 90Y, 166Ho, 177Lu, and 153Sm) were produced from n,γ reactions of their respective precursors (89Y, 165Ho, 176Lu, and 152Sm). They were labeled with EDTMP at varying degrees of pH and molar ratios, and labeling yields were determined by paper chromatography at each data point. The complexes with optimal labeling yields and their chloride forms (XCl3) were then studied for biodistributions in 66 Sprague-Dawley male rats at 30 minutes, 2 hours, and 24 hours after injection. All the radiopharmaceuticals gave ∼98% complex yields at pH 8. At optimum pH level, good labeling was achieved at X:EDTMP molar ratios of 1:5, 1:8, and 1:20 for 90Y, 166Ho, and 177Lu complexes, respectively. 177Lu-EDTMP showed the best biodistribution results among all the complexes, with a total skeletal uptake of 70.2% ± 2.4% at 24 hours ((153)Sm-EDTMP = 59.1% ± 2.6%). 90Y-EDTMP had skeletal accumulation significantly higher than (166)Ho-EDTMP (45.5% ± 2.9% and 27.4% ± 3.6%, respectively). Blood activity of all the agents disappeared promptly through the kidneys. This study demonstrates higher localization of 177Lu-EDTMP in skeleton than 153Sm-EDTMP and shows that the localization of 90Y-EDTMP is better among the high-energy radiometals studied.

Rare earth nanoparticles prevent retinal degeneration induced by intracellular peroxides.

Photoreceptor cells are incessantly bombarded with photons of light, which, along with the cells' high rate of oxygen metabolism, continuously exposes them to elevated levels of toxic reactive oxygen intermediates (ROIs). Vacancy-engineered mixed-valence-state cerium oxide nanoparticles (nanoceria particles) scavenge ROIs. Our data show that nanoceria particles prevent increases in the intracellular concentrations of ROIs in primary cell cultures of rat retina and, in vivo, prevent loss of vision due to light-induced degeneration of photoreceptor cells. These data indicate that the nanoceria particles may be effective in inhibiting the progression of ROI-induced cell death, which is thought to be involved in macular degeneration, retinitis pigmentosa and other blinding diseases, as well as the ROI-induced death of other cell types in diabetes, Alzheimer's disease, atherosclerosis, stroke and so on. The use of nanoceria particles as a direct therapy for multiple diseases represents a novel strategy and suggests that they may represent a unique platform technology.

[Chemical crystal aspects of remineralization of dental enamel]. / Kristallchemische Aspekte der Reimineralisation des Zahnschmelzes.

Incipient dental caries at the stage of demineralization is reversible, and remineralization can be achieved by the help of locally applied fluorides. In crystalchemical experiments, however by treating natural apatites with lanthanides Ce, La, Pr, Nd, Sm, Eu, Tb...Y, Sc, a more resistant complex could be developed. In this study extracted human molar teeth were kept for 60 days in Cerium (III)-nitrate solution, in order to investigate the incorporation of Ce3+ into human sound and carious enamel by light-microscopic-, and electronmicroprobe methods. Ce3+ was incorporated in sound enamel as well as into the incipient carious lesions, showing the histological characteristics of a remineralizing lesion. The mean values of the microprobe analysis data showed an increase in Ce3+ changing place with the Ca2+, the developing cerium-apatite being more hard an resistant from a mineralo-physical point of view.

Biodistribution and preclinical radioimmunotherapy studies using radiolanthanide-labeled immunoconjugates.

Lutetium-177 (177Lu), samarium-153 (153Sm), and yttrium-90 (90Y) are members of the family of elements known as lanthanides or rare earths. Monoclonal antibody CC49, a murine immunoglobulin (Ig) G1, which is reactive with the tumor-associated antigen TAG-72, previously has been shown to react with a wide range of human carcinomas. The authors review here the comparative biodistributions of CC49 IgG and F(ab')2 fragments labeled with 177Lu, 153Sm, and 90Y using the bifunctional chelating agent PA-DOTA. The authors also review the results of a biodistribution study comparing iodine-125-labeled and 177Lu-labeled CC49 sFv, and the use of 177Lu-CC+9 IgG in an experimental therapy model. Chelation and conjugations gave similar yields, and the labeled proteins showed similar retention of immunoreactivity regardless of the isotope used for both IgG and F(ab')2. Biodistribution data obtained in athymic mice bearing LS-174T human colon carcinoma xenografts likewise showed no differences among the three radioisotopes for both IgG and F(ab')2. Femur uptake of radioactivity was lower than previously reported for other radiolanthanide immunoconjugates. Different metabolic patterns were observed for radioiodinated versus radiometal-labeled sFv, particularly in the kidney, where localization of the latter was increased dramatically. 177Lu-CC49 was found to delay the growth of established LS-174T human colon carcinomas in athymic mice at a single dose of 50 microCi. Elimination of established tumors was demonstrated over the observation period (77 days) using single administrations of 200 or 350 microCi. Dose fractionation experiments revealed that the mice tolerated 750 microCi (3 x 250 microCi, given weekly), whereas > 50% of the mice died after receiving a single administration of approximately 500 microCi. In isotype-matched control experiments, a large differential in the therapeutic effects was observed between 177Lu-labeled control antibody and CC49.