Significant size-charge effects on the biodistribution of nanocomposites in a mouse tumor model system Free

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Background: Nanocomposite (Guest-Host Nanodevices) are a well studied class of nanodevices with several potential medical uses. In particular, they hold great promise for the improvement of cancer imaging and therapy (Balogh L, et al, Chemistry Today 20: 35-40 (2002); Balogh L, et al, PharmaChem 2: 94-99 (2003)). The design of these nanodevices permits the host and guest properties to be individually modified and optimized. The host component consists of Poly(amidoamine) dendrimers that can be made with discrete sizes, and differing surface charges. The guest component consists in this case of elemental gold (Au). Purpose: This study determines, in the first detailed quantitative analysis, the significant effects that the manipulation of the size and surface charge of nanodevices cause on their biodistribution in a mouse melanoma tumor model system. This understanding is critical for the rational design of these devices for use in cancer imaging and treatment. Experimental Procedures: Au nanodevices were fabricated using amine and partially substituted acetamide terminated PAMAM dendrimers with gold incorporation. The gold carrying nanodevices tested include: 5 nm positive surface, and 5 nm negative surface, and 12 nm negative surface nanodevices. One million B16F10 tumor cells were injected s.c. into the dorsal surface of 8-10 week old C57BL/6J mice, and the tumors grown to greater than 500 mm³. Three tumor bearing mice were then injected with each type of nanodevices in PBS, pH 7.2. Mice were euthanized at 1 hour, and 1, 4 days post-injection, and the organs/tissues (blood, lung, heart, liver, kidney, spleen, pancreas, muscle, tumor, and brain) were weighed and collected, lyophilized, and gold quantitation analysis done. Activation of Au nanodevices into Au-198 was achieved by direct neutron irradiation in aqueous solutions. Results: Charge had a significant, but different, effect on Au-Nanocomposite (guest and host) biodistribution, as it did in previous dendrimer (host only) studies (Nigavekar S et al, Pharm. Res. 21: 476-83 (2004)). 5 nm positive surface Au-nanodevice showed significantly high kidney accumulation even out to 4 days. The 5 nm negative surface Au-nanodevice showed significantly high accumulation in the liver and spleen out to 4 days. Size also had a strongly significant effect on biodistribution, with the 5nm negative surface Au nanodevice having longer blood clearance time. The 12 nm negative surface nanodevice, in comparison, showed significantly high levels in the spleen and liver over 4 days. Conclusions: Our studies show that both the size and charge of nanodevices greatly affect their biodistribution patterns in a mouse tumor model system. This has great significance for the design of all nanodevices, targeted and nontargeted, being considered for cancer imaging and therapy.