Self-Assembled Hybrid Nanocomposites for Multimodal Imaging-Guided Photothermal Therapy of Lymph Node Metastasis.

Multimodal imaging-guided therapy holds great potential for precise theranostics of cancer metastasis. However, imaging agents enabling the convergence of complementary modalities with therapeutic functions to achieve perfect theranostics have been less exploited. This study reports the construction of a multifunctional nanoagent (FIP-99mTc) that comprises Fe3O4 for magnetic resonance imaging, radioactive 99mTc for single-photon-emission computed tomography, and IR-1061 to serve for the second near-infrared fluorescence imaging, photoacoustic imaging, and photothermal therapy treatment of cancer metastasis. The nanoagent possessed superior multimodal imaging capability with high sensitivity and resolution attributing to the complement of all the imaging modalities. Moreover, the nanoagent showed ideal photothermal conversion ability to effectively kill tumor cells at low concentration and power laser irradiation. In the in vivo study, FIP-99mTc confirmed the fast accumulation and clear delineation of metastatic lymph nodes within 1 h after administration. Attributing to the efficient uptake and photothermal conversion, FIP-99mTc could raise the temperature of metastatic lymph nodes to 54 °C within 10 min laser irradiation, so as to facilitate tumor cell ablation. More importantly, FIP-99mTc not only played an active role in suppressing cancer growth in metastatic lymph nodes with high efficiency but also could effectively prevent further lung metastasis after resection of the primary tumor. This study proposes a simple but effective theranostic approach toward lymph node metastasis.

Synthesis and in vitro evaluation of three 99mTc-labeled hydroxamamide-based ligands as markers for hypoxic cells.

Three new hydroxamamide derivatives with different lipophilicity, N'-hydroxy-N-methyl-3-(4-nitro-1H-imidazol-1-yl)propanamidine, N-butyl-N'-hydroxy-3-(4-nitro-1H-imidazol-1-yl)propanamidine, and N'-hydroxy-3-(4-nitro-1H-imidazol-1-yl)-N-octadecylpropanamidine were easily synthesized and labeled with technetium-99m as markers for hypoxic cells. The results of in vitro experiment indicate that the accumulation of three (99m)Tc-complexes steadily increases with time in hypoxic cells, but fluctuates with time and has no fixed trend in aerobic cells; the complex with higher lipophilicity shows more uptake in cells; and the effect of lipophilicity of the (99m)Tc-complexes on the hypoxic/aerobic difference can be neglected.

Labeling efficiency and biodistribution of Technetium-99m labeled nanoparticles: interference by colloidal tin oxide particles.

The interference of colloidal tin oxides on the biodistribution of (99m)Technetium radiolabeled chitosan nanoparticles has been overcome by using sodium borohydride instead of commonly used stannous salts as reducing agent for the reduction of (99m)Tc (VII) to lower valency states. Biodistribution of radiolabeled chitosan nanoparticles prepared by using stannous chloride method revealed localization of the radioactivity mainly in the liver and spleen while that of radiolabeled chitosan nanoparticles prepared by using sodium borohydride method manifested the presence of radioactivity in blood up to an extent of 10% even after 2 h. Interestingly, the reduction of radioactivity in the latter case with the progress of time was not manifested through an increase in activity in the liver. Rather, a time dependent increased accumulation of radioactive materials was observed in the stomach. From the results it has been concluded that the biodistribution is strongly influenced by the presence of colloidal particles of tin oxides and (99m)Tc labeled chitosan nanoparticles are RES evading and long circulating in blood when Tc (VII) is reduced by sodium borohydride and not by stannous chloride during radiolabeling process.

Study of tea polyphenol as a reversal agent for carcinoma cell lines' multidrug resistance (study of TP as a MDR reversal agent).

The aim of this study was to examine MDR1 expression product P-glycoprotein (Pgp) and study the effect and mechanism of tea polyphenol (TP) in reversion of multidrug resistance (MDR) in carcinoma cell lines. Immunocytochemical method was used for qualitative detection of Pgp. A comparative study of cytotoxicity and multidrug resistance reversion effect was made by MTT assay for tea polyphenol and quinidine in MCF-7 and MCF-7/Adr cell lines. The multidrug resistance reversion effect and mechanism were studied by measuring the uptake of 99mTc-tetrofosmin in the carcinoma cell lines. (1) The Pgp overexpression in MCF-7/Adr cells was found to be strong positive, while the Pgp expression of MCF-7 was negative. (2) Although both tea polyphenol and quinidine could not remarkably change the toxicity of adriamycin to MCF-7, they could improve the sensitivity of MCF-7/Adr to adriamycin. The reversion index of tea polyphenol and quinidine was 3 and 10 respectively. (3) The cellular uptake of 99mTc-tetrofosmin was remarkably lower in MCF-7/Adr than in MCF-7. The uptake of 99mTc-tetrofosmin in MCF-7/Adr exhibited a 4, 13, 16 fold increase in the presence of 200, 400 and 500 microg/ml of tea polyphenol respectively. The uptake of 99mTc-tetrofosmin in MCF-7/Adr exhibited only a 4-fold increase in the presence of 200 microM of quinidine. Immunocytochemistry can detect P-glycoprotein expression level qualitatively. Tea polyphenol is not only an anti-tumor agent, but also a multidrug resistant modulator similar to quinidine. The multidrug resistance reversion mechanism of tea polyphenol seems to be its inhibition of the activity of P-glycoprotein. Tea polyphenol has the advantage of very low toxicity in tumor treatment.

[Preclinical pharmacological study of a novel myocardial perfusion agent: 99mTc-Q3].

In order to provide an experimental foundation for clinical study, we made a preclinical pharmacological investigation of 99mTc-Q3, a novel myocardial perfusion imaging agent, technetium-99m-N,N'-ethylenebis (acetylace-toneiminato) bis (tris (3-methoxy-1-proply) phosphine). After the preparation of this compound, the kinetics of blood clearance in rabbits, biodistribution in mice, measurement of plasma protein binding rate, and myocardial perfusion imaging in dog were carried out. The labelling efficiency and radiochemical purity measured were over 99%, and the stability (in vitro) was good and stable up to 6 hr of testing at room temperature. The pharmacokinetics met the two-compartment model with 0.23 +/- 0.09 ml/min of excellent blood clearance, an initial half-time of 1.5979 +/- 0.4182 min, and a late half-time of 203 +/- 25.83 min. The biodistribution as shown in myocardial accumulation was earlier, the radioactive value was higher, and once extracted, it remained relatively constant in the myocardium for at least 4 hr. The tracer was rapidly cleared from the blood, lung and the liver. The scintigraphy imaging in dog demonstrated that it was rapidly cleared from the lung, and the radioactive concentration approached that of background 1 hr after injection. At 15 min after injection, the myocardial imaging displayed clearly up to 3 hr. In vitro protein binding rate was low (7.13 +/- 0.42%). The tolerance of this drug in mice was 500 times as much as in humans. In conclusion, 99mTc-Q3 exhibits favorable stability, biological property and safety, so clinical study of this preparation as a myocardial perfusion imaging agent is worthwhile.