Large scale synthesis of AuNP RGD using Au
Large scale synthesis of 198AuNP-RGD using 198Au produced in the Dhruva reactor.
aAmount of Au foil irradiated (mg)
nanoparticles in these healthy Lactacystin is one of the major chal-lenges towards clinical translation of this class of agents for use in cancer imaging and therapy . When a high dose (equivalent to 20–25 mg/kg of body weight of mice) of c(RGDfK) was administered in mice along with 198AuNP-RGD, the uptake of radioactivity in the tumor was signif-icantly reduced to 2.9 ± 0.8%ID/g at 4 h p.i. (Fig. 11). Further, when non-targeted 198Au nanoparticles were administered, the uptake of radioactivity in the tumor was significantly low (3.0 ± 0.9%ID/g) at 4 h p.i. (Fig. 11). These studies established that the enhanced uptake of targeted 198AuNP-RGD was indeed receptor mediated.
3.8. Tumor regression studies
In order to elucidate the therapeutic efficacy of 198AuNP-RGD in effecting retardation of tumor growth, a group of melanoma tumor bearing C57BL/6 mice were intravenously administered with 3 different doses (18.5 MBq, 37.0 MBq and 55.5 MBq) of the radiolabeled agent and TGI and BWI were monitored over a period of 15 d (Fig. 12). Tumor growth was significantly retarded in treated mice and the deceleration in the growth was enhanced with the increasing dose of 198AuNP-RGD. One time injection of 18.5 MBq 198AuNP-RGD resulted in limited tumor growth delay as compared with mice injected with normal saline or non-radioactive AuNP-RGD as controls (Fig. 12A). For mice treated with 37.0 MBq or 55.5 MBq of 198AuNP-RGD, significant reduction in TGI was observed. Over this period of time, there was no signif-
Fig. 5. Representative γ-ray spectra of 198AuNP-RGD.
Overall, this study indicated that a single dose of 37.0 MBq of 198AuNP-RGD was most effective for targeted tumor therapy in melanoma tumor bearing mice.
The biodistribution studies described above showed high accumula-tion of radiolabeled nanoparticles occurred in healthy organs such as kidney, liver and spleen. Despite, high uptake of radiolabeled nanopar-ticles in these organs, no adverse effect (in terms of changes in normal behavior of animals and significant weight loss) was observed in the
Radioactivity eluted (%) 50
Volume of PBS (mL) Number of nanoparticles bound to cells (X 1015)
Binding in excess of c(RGDfK)
Fig. 7. Size exclusion chromatographic pattern of 198AuNP-RGD developed using a PD-10 column. Fig. 9. In vitro cell binding and inhibition studies with 198AuNP-RGD in melanoma cells.
group of animals treated with optimal radioactive dose (37.0 MBq) of 198AuNP-RGD over the 15 days period of study.
A simple and efficient single step methodology for clinical scale syn-thesis of intrinsically radiolabeled 198AuNP-RGD has been developed for use in targeted cancer therapy. Well dispersed 198AuNP-RGD could be synthesized with excellent colloidal and radiochemical stability and good biocompatibility. The binding affinity and specificity of 198AuNP-RGD towards integrin αvβ3 expression could be demonstrated by in vitro studies in melanoma cells. The therapeutic efficacy of 198AuNP-RGD was established by tumor regression studies in C57BL/6 mice bearing melanoma tumors. The promising results obtained in this study would potentially advance this class of intrinsically radiolabeled nanoparticles towards future clinical use. This strategy can also be explored for synthesis of Au nanoparticles conjugated with new biological vectors, which in turn would expand the utility of this approach for targeting wide variety of tumors expressing other receptors.