Amelioration of Tumor Targeting and In Vivo Biodistribution of 99mTc-Methotrexate-Gold Nanoparticles (99mTc-Mex-AuNPs).

Gold nanoparticles (AuNPs) represent very attractive and promising drug delivery carriers due to their unique dimensions, adjustable surface functions, and controllable drug release. Therefore, AuNPs are used to overcome the limitations of conventional chemotherapy, for example methotrexate (Mex), one of the first-generation chemotherapy drugs for cancer treatment, whose usefulness has been restricted due to drug resistance and dose-dependent side effects. In the present study, the AuNPs drug delivery system was synthesized and loaded with technetium-99 m radiolabeled Methotrexate (99mTc-Mex) to produce new potential nanoradiopharmaceutical for tumor targeting and further imaging. The Methotrexate loaded gold nanoparticles (Mex-AuNPs) successfully prepared in small spherical particle size (20.3 nm), polydispersity index PDI (< 0.5) and a zeta potential (-17.6 mV) with loading efficiency% (93 ± 1.2%) of methotrexate at 30 min as an optimum stirring time and showed strong absorption peak for Mex-AuNPs at λmax, 525 nm. The in vitro release profile of Mex-AuNPs showed high release percent of methotrexate at pH 5; the Q0.5 h and Q8h were 21.2 ± 1.5% and 92.9 ± 3.4%, respectively. The in vitro cytotoxicity was investigated at different concentrations (0.024-50 µl/100 µl) of Mex-AuNPs (1 mg/ml) against MCF-7 (Michigan Cancer Foundation-7) breast cancer cells by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay technique. Mex-AuNPs showed higher anticancer activity with low inhibitory concentration (IC50 = 0.098 µl/100 µl) that was three times lower than the inhibitory concentration (IC50) of methotrexate (IC50 = 0.3 µl/100 µl). 99mTc-Mex complex prepared by direct reduction method at maximum radiochemical yield (RCY)% Ì´ 98.3 ± 1.09 % was loaded in AuNPs to form 99mTc-Mex-AuNPs with loading efficiency% (93 ± 1.2 %) at 30 min of stirring time. 99mTc-Mex-AuNPs showed convenient in vitro stability in mice serum up to 24 h with RCY% > 90 %. The preclinical biodistribution studies of 99mTc-Mex-AuNPs were performed in 3 experimental groups A (intravenous (I.V.) injected normal mice), B and C (I.V. and intratumor (I.T.) injected tumor bearing mice, respectively). The 99mTc-Mex-AuNPs achieved highest tumor uptake (93 ± 0.39 %ID/g) and highest Target/NonTarget (T/NT) ratio (58.1 ± 0.91) with high Tumor/Blood (T/B) ratio (25.8 ± 0.11) at 10 min post I.T. injection and retained high tumor uptake (79 ± 0.65 %ID/g) up to 60 min post I.T. injection before escaping into blood stream. Consequently, 99mTc-Mex-AuNPs can be considered as new potential nanoradiopharmaceutical in tumor diagnosis.

Biodistribution of 99mTc-sunitinib as a potential radiotracer for tumor hypoxia imaging.

Tyrosine kinases are groups of enzymes, which are over-expressed in solid tumor cells, representing good targets for different drugs such as sunitinib (N-[2-(diethylamino)ethyl]-5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxamide). The aim of this work was to design and synthesize (99m)Tc-sunitinib radiotracer and to study its tumor binding specificity as a novel selective radiopharmaceutical for tumor hypoxia imaging. The in vivo biodistribution of (99m)Tc-sunitinib in tumor bearing mice showed high target/non-target (T/NT) ratio (T/NT ~ 3 at 60 min post injection). This preclinical high biological accumulation in tumor cells suggests that (99m)Tc-sunitinib is ready to go through the clinical trials as a potential selective radiotracer able to image tumor hypoxia.