Encapsulation of 67Cu therapeutic radiometal in luminescent lanthanide phosphate core and core-shell nanoparticles.

Copper-67 (67Cu) has physical characteristics useful for both therapy and imaging. However, its applicability has been hindered by the complexity of obtaining large quantities of a product with high specific activity. With the advancement of 67Cu production methods, suitable radioisotope carriers are sought. Lanthanide phosphate nanoparticles have demonstrated their multifunctional characteristics for biomedical applications and, more recently, their potential in radiopharmaceuticals. Thus, we produced luminescent lanthanide phosphate nanoparticles with core and core-shell structures, incorporating 67Cu during their synthesis. The nanoparticles exhibited hexagonal crystalline structure and spherical morphology with sizes below 6 nm. The luminescent colloidal suspensions evidenced the characteristic 5D0-7FJ for Eu3+, providing the red color under UV light. A radiochemical yield of 67Cu >95% was obtained with both core and core-shell LaPO4:Eu. The core-shell nanoparticles reduced the release of 67Cu by a factor of ∼2 over that from the core, which continuously decreased with time. Multifunctional LnPO4 nanoparticles have the potential to be used as a carrier of single or multiple radioisotopes to enhance image-guided targeted nano-radiopharmaceutical therapy.

Quantitative encapsulation and retention of 227Th and decay daughters in core-shell lanthanum phosphate nanoparticles.

Targeted alpha therapy (TAT) offers great promise for treating recalcitrant tumors and micrometastatic cancers. One drawback of TAT is the potential damage to normal tissues and organs due to the relocation of decay daughters from the treatment site. The present study evaluates La(227Th)PO4 core (C) and core +2 shells (C2S) nanoparticles (NPs) as a delivery platform of 227Th to minimize systemic distribution of decay daughters, 223Ra and 211Pb. In vitro retention of decay daughters within La(227Th)PO4 C NPs was influenced by the concentration of reagents used during synthesis, in which the leakage of 223Ra was between 0.4 ± 0.2% and 20.3 ± 1.1% in deionized water. Deposition of two nonradioactive LaPO4 shells onto La(227Th)PO4 C NPs increased the retention of decay daughters to >99.75%. The toxicity of the nonradioactive LaPO4 C and C2S NP delivery platforms was examined in a mammalian breast cancer cell line, BT-474. No significant decrease in cell viability was observed for a monolayer of BT-474 cells for NP concentrations below 233.9 µg mL-1, however cell viability decreased below 60% when BT-474 spheroids were incubated with either LaPO4 C or C2S NPs at concentrations exceeding 29.2 µg mL-1. La(227Th)PO4 C2S NPs exhibit a high encapsulation and in vitro retention of radionuclides with limited contribution to cellular cytotoxicity for TAT applications.

Multifunctional GdVO4:Eu core-shell nanoparticles containing 225Ac for targeted alpha therapy and molecular imaging.

Gadolinium vanadate nanoparticles (NPs) doped with europium, in concentrations between 5-40%, were synthesized via an aqueous route to prove their multimodal imaging functionalities and their performance as radionuclide carriers for targeted alpha therapy. Core-shell Gd0.8Eu0.2VO4 NPs were doped with the α-emitting actinium-225 to assess the in vitro retention of 225Ac and its decay daughters; francium-221 and bismuth-213. Gd0.8Eu0.2VO4 core-shell NPs were obtained using a precipitation synthesis route having a tetragonal system, a spherical morphology, and a uniform particle size distribution. Gd0.8Eu0.2VO4 core-shell NPs displayed the characteristic intense emission at 618 nm (red) and paramagnetic behavior of Eu and Gd cations, respectively. Partial retention of radionuclides was obtained with Gd0.8Eu0.2VO4 core NPs, while deposition of two nonradioactive Gd0.8Eu0.2VO4 shells significantly decreased the leakage of both 225Ac and 221Fr. The luminescence and magnetic functionalities as well as radionuclide retention capabilities of Gd0.8Eu0.2VO4 core-shell NPs demonstrate their potential for biomedical applications.

Synthesis and characterization of lanthanum phosphate nanoparticles as carriers for (223)Ra and (225)Ra for targeted alpha therapy.

INTRODUCTION: Targeted alpha therapy (TAT) has the potential for killing micro-metastases with minimum collateral damage to surrounding healthy tissue. In-vivo generator radionuclides, such as(223)Ra, (225)Ra, and (225)Ac, are of special interest for radiotherapeutic applications as they emit multiple α-particles during their decay. Utilizing appropriate carriers capable of retaining both the parent radioisotope as well as daughter products is important for the effective delivery of the radioisotope to the tumor site while mitigating global in vivo radiotoxicity. In this work, LaPO4 core and core+2 shells nanoparticles (NPs) (NPs with 2 layers of cold LaPO4 deposited on the core surfaces) were synthesized containing either (223)Ra or(225)Ra/(225)Ac, and the retention of the parents and daughters within the NPs in vitro was investigated. METHODS: Core LaPO4 NPs were synthesized in aqueous solution by reacting 1 equivalent of La(NO3)3, along with few microcuries of either (223)Ra or (225)Ra/(225)Ac, with 1 equivalent of sodium tripolyphosphate (TPP) under moderate heating and purified by membrane dialysis. Core-shell NPs were also synthesized with one (core+1 shell) and two (core+2 shells) cold LaPO4 layers deposited onto the radioactive cores. The NPs were then characterized by transmission electron microscopy (TEM) and powder x-ray diffraction (XRD). Identification and quantification of radioactive parents and daughters released from the NPs in vitro were investigated using gamma-ray spectroscopy. RESULTS: XRD and TEM analysis revealed that the NPs crystallized in the rhabdophane phase with mean diameters of 3.4 and 6.3nm for core and core+2 shells, respectively. The core LaPO4 NPs retained up to 88% of (223)Ra over 35days. However, in the core+2 shells NPs, the retention of (223)Ra and its daughter, (211)Pb, was improved to >99.9% over 27days. Additionally, the retention of (225)Ra/(225)Ac parents was >99.98% and ~80% for the (221)Fr and (213)Bi daughters over 35days for the core+2 shells NPs. CONCLUSIONS: The in vitro retention of both parents and daughters results suggests that LaPO4 NPs are potentially effective carriers of radium isotopes.

Diaphragmatic activity is a determinant of postnatal lung growth.

To test the hypothesis that activity of respiratory muscles determines regional growth of lung parenchyma, we studied the effects of unilateral diaphragmatic paralysis on contralateral/ipsilateral lung growth in cats and piglets. Five 10- to 12-wk-old cats and five 8-wk-old piglets underwent unilateral diaphragmatic paralysis by thoracic and cervical phrenectomy, respectively. Five to seven weeks after surgery, when the cats were killed for studies of lung growth, gain in body weight was the same as in five sham-operated controls. At this time, mean pleural pressure ipsilateral to the paralyzed hemidiaphragm was the same as contralateral mean pleural pressure during tidal breathing, and values did not differ from controls. However overall functional residual capacity was lower in the phrenectomized cats (35 +/- 4 ml) than in the controls (55 +/- 11 ml, P less than 0.01). Growth of contralateral lungs relative to ipsilateral lungs was greater in the phrenectomized cats than in the controls, as shown by ratios of contralateral/ipsilateral wet lung weight (1.44 vs. 1.34, P less than 0.01), maximum inflation volume (1.53 vs. 1.33, P less than 0.05), and total protein content (1.45 vs. 1.26, P less than 0.05). Ratios of total protein to DNA and RNA to DNA were unchanged. One week after surgery in the piglets, the ratio of contralateral/ipsilateral wet lung weight was increased (1.61 vs. 1.29, P less than 0.01) and total weight of both lungs was reduced. We conclude that regional growth of lung parenchyma by cell proliferation depends in part on regional distribution of respiratory muscle activity.

Respiratory mechanics in adolescents with idiopathic scoliosis.

Mechanisms causing the reduction in lung capacity commonly found in adolescents with idiopathic scoliosis (IS) have not been understood. In 29 patients with typical thoracic curvatures of mild to moderate degree (less than 60 degrees), total lung capacity (TLC) was a mean 75 +/- 13% (SD) of predicted. The patients could generate only -70 +/- 26 cm H2O (SD) maximal inspiratory airway pressure at function residual capacity, as compared with -102 +/- 28 cm H2O in 21 normal control subjects (p less than 0.001). Studies of lung mechanics in 15 of the patients showed that maximal transpulmonary pressure at TLC was also reduced. Static pressure volume curves were shifted to the right, and both static and dynamic lung compliance were significantly reduced. Although both upstream conductance per TLC and anatomic dead space per TLC were abnormally high, relationships between maximal expiratory flow and static lung recoil were appropriate for age, indicating a normal growth of airway dimensions. From results of the single-breath nitrogen washout procedure, amounts of trapped nitrogen were also normal, indicating that the low lung compliance is not caused by airway closure. After a 5-min period of positive pressure (25 cm H2O) breathing, dynamic compliance increased by a mean of 34% in subjects with low TLC, and by a significantly smaller (p less than 0.05) mean increase of 14% in subjects with normal TLC. The 15 patients were restudied 1 yr after corrective surgery by the Harrington procedure.(ABSTRACT TRUNCATED AT 250 WORDS)