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Background: Gold nanoshells are excellent agents for photothermal ablation cancer therapy and are currently under clinical trial for solid tumors. Previous studies showed that passive delivery of gold nanoshells through intravenous administration resulted in limited tumor accumulation, which represents a major challenge for this therapy. In this report, the impact of direct intratumoral administration on the pharmacokinetics and biodistribution of the nanoshells was systematically investigated. Methods: The gold nanoshells were labeled with the radionuclide, copper-64 ( 64 Cu). Intratumoral infusion of 64 Cu-nanoshells and two controls, ie, 64 Cu-DOTA (1,4,7,10-tetraazaciclododecane-1,4,7,10-tetraacetic acid) and 64 Cu-DOTA-PEG (polyethylene glycol), as well as intravenous injection of 64 Cu-nanoshells were performed in nude rats, each with a head and neck squamous cell carcinoma xenograft. The pharmacokinetics was determined by radioactive counting of serial blood samples collected from the rats at different time points post-injection. Using positron emission tomography/computed tomography imaging, the in vivo distribution of 64 Cu-nanoshells and the controls was monitored at various time points after injection. Organ biodistribution in the rats at 46 hours was analyzed by radioactive counting and compared between the different groups. Results:The resulting pharmacokinetic curves indicated a similar trend between the intratumorally injected agents, but a significant difference with the intravenously injected 64 Cu-nanoshells. Positron emission tomography images and organ biodistribution results on rats after intratumoral administration showed higher retention of 64 Cu-nanoshells in tumors and less concentration in other healthy organs, with a significant difference from the controls. It was also found that, compared with intravenous injection, tumor concentrations of 64 Cu-nanoshells improved substantially and were stable at 44 hours post-injection. Conclusion: There was a higher intratumoral retention of 64 Cu-nanoshells and a lower concentration in other healthy tissues, suggesting that intratumoral administration is a potentially better approach for nanoshell-based photothermal therapy.

Intriguing patterns of periodic, concentric, layered, mineral microstructure are present in nature and organisms, yet they have elusive geneses. We hypothesize temperature oscillation can be an independent factor that causes the self-assembly of such patterns in mineral phases synthesized in solution. Static experiments verify that rhythmic concentric multi-layered magnesium carbonate microhemispheres can be synthesized from bicarbonate solution by temperature oscillation, without use of a chemical template, additive or gel-diffusion system. Appropriate reactant concentration and initial pH value can restrain the competitive growth of other mineral generations. Polarized light microscopy images indicate the microhemispheres are crystalline and the crystallinity increases with incubation time. The thickness of a single mineral layer of microhemisphere in microscale is precisely controlled by the waveform parameters of the temperature oscillation, while the layer number, which can reach tens to about one hundred, is constrained by the temperature oscillation period number. FT-IR spectra show that these microhemispheres synthesized under different conditions can be identified as the basic form of magnesium carbonate, hydromagnesite (Mg5(CO3)4(OH)2⋅4H2O). SEM images exhibit the characteristic microscopic texture of the alternating dark and light rings of these microhemispheres. TEM images and ED patterns suggest the nanoflakes of microhemispheres are present in polycrystalline form with some degree of oriented assembly. The temperature oscillation modulated self-assembly may offer a new mechanism to understand the formation of layered microstructure of minerals in solution, and provide a non-invasive and programmable means to synthesize hierarchically ordered materials.