Higher lung accumulation of intravenously injected organic nanotubes

Abstract

The size and shape of intravenously injected particles can affect their biodistribution and is of importance for the development of particulated drug carrier systems. In this study, organic nanotubes (ONTs) with a carboxyl group at the surface, a length of approximately 2 μm and outer diameter of 70-90 nm, were injected intravenously into tumor-bearing mice. To use ONTs as drug carriers, the biodistribution in selected organs of ONTs postinjection was examined using irinotecan, as an entrapped water-soluble marker inside ONTs, and gadolinium-chelated ONT, as an ONT marker, and compared with that of a 3 μm fluorescently labeled spherical microparticle which was similar size to the length of ONTs. It was found that for irinotecan, its active metabolite and gadolinium-chelated ONTs were highly accumulated in the lung, but to a lower level in the liver and spleen. On the other hand, microparticles deposited less in the lung and more highly in the liver. Moreover, histologic examination showed ONTs distributed more in lung tissues in part, whereas microparticles were present in blood vessels postinjection. These preliminary results support the notion of using negatively charged ONTs as intravascular carriers to maximize accumulation in the lung whilst reducing sequestration by the liver and spleen. This finding suggested that ONTs are potential carriers for lung-targeting drug delivery.

Keywords: biodistribution; lung; microparticle; organic nanotube; particle shape.

Figure 1

Chemical structure of compound 1 that forms the structure of ONTs and schematic illustrations of ONT (A) and Gd-chelated ONT (Gd-ONT) (B). Note: Compound 1 consists of glycylglycine and myristic acid (molecular weight 342). Abbreviations: Gd, gadolinium; ONTs, organic nanotubes.

Figure 2

Field-emission scanning electron microscopy (FESEM) images of ONTs. Abbreviation: ONTs, organic nanotubes.

Figure 3

Effect of pH and ratio of CPT-11:ONT (w:w) on loading amount and loading efficiency of CPT-11 into ONTs at a CPT-11:ONT weight ratio of 0.25 (A) and at pH 4.0 (B) at room temperature. Note: Each value represents mean ± SD (n = 3). Abbreviations: ONTs, organic nanotubes; SD, standard deviation.

Figure 4

CPT-11 release from free CPT-11 and CPT-11/ONT in a dialysis tube in PBS at pH 5.5 and pH 7.4 at 37°C. Note: Each value represents mean ± SD (n = 3). Abbreviations: ONTs, organic nanotubes; PBS, phosphate-buffered saline; SD, standard deviation.

Figure 5

Biodistribution of free CPT-11 (4 mg/kg) and CPT-11/ONT (100 mg ONT/kg, equivalent to 2~3.5 mg CPT-11/kg) at 24 hours after a single intravenous injection into mice bearing C26 tumor. Tissue and tumor biodistribution of CPT-11 (A) and SN-38 (B). Notes: Each value represents the mean ± SE (n = 3). *P < 0.05. Abbreviations: ONTs, organic nanotubes; SE, standard error.

Figure 6

Biodistribution of Gd-ONT (50 mg ONT/kg, equivalent to 6.3 mg Gd/kg) at 3, 24, and 48 hours after a single intravenous injection into mice bearing C26 tumors. Notes: Each value represents the mean ± SD (n = 3). *P < 0.05. Abbreviations: ONTs, organic nanotubes; SD, standard deviation.

Figure 7

Biodistribution of MPs (25 mg/kg) at 3, 24 and 48 hours after a single intravenous injection into mice bearing C26 tumors. Notes: Each value represents the mean ± SD (n = 3). *P < 0.05. Abbreviations: MPs, microparticles; ONTs, organic nanotubes; SD, standard deviation.

Figure 8

Biodistribution of DXR/ONT and MPs in lung tissues at 3 hours after a single intravenous injection into mice. Notes: Fluorescence microscopy analyses confirming DXR/ONT, MPs and blood vessels (Hoechst 33342 staining) as red dots, green dots and blue fluorescence, respectively. Each saline was the control for red and green fluorescence. DXR/ONT was found outside of blood vessel in part, whereas MPs were found exclusively within the vessel lumen or associated with endothelial cells. Scale bars = 100 μm. Abbreviations: DXR, doxorubicin; MPs, microparticles; ONTs, organic nanotubes.

Figure 9

Hematoxylin and eosin-stained histological sections of lung tissue at 3 hours postinjection of saline (A) or ONTs (B). Note: Scale bars = 100 μm. Abbreviation: ONTs, organic nanotubes.