Treatment of acute thromboembolism in mice using heparin-conjugated carbon nanocapsules.

The unsurpassed properties in electrical conductivity, thermal conductivity, strength, and surface area-to-volume ratio allow for many potential applications of carbon nanomaterials in various fields. Recently, studies have characterized the potential of using carbon nanotubes (CNTs) as a biomaterial for biomedical applications and as a drug carrier via intravenous injection. However, most studies show that unmodified CNTs possess a high degree of toxicity and cause inflammation, mechanical obstruction from high organ retention, and other biocompatibility issues following in vivo delivery. In contrast, carbon nanocapsules (CNCs) have a lower aspect ratio compared with CNTs and have a higher dispersion rate. To investigate the possibility of using CNCs as an alternative to CNTs for drug delivery, heparin-conjugated CNCs (CNC-H) were studied in a mouse model of acute hindlimb thromboembolism. Our results showed that CNC-H not only displayed superior antithrombotic activity in vitro and in vivo but they also had the ability to extend the thrombus formation time far longer than an injection of heparin or CNCs alone. Therefore, the present study showed for the first time that functionalized CNCs can act as nanocarriers to deliver thrombolytic therapeutics.

Biosafety of non-surface modified carbon nanocapsules as a potential alternative to carbon nanotubes for drug delivery purposes.

BACKGROUND: Carbon nanotubes (CNTs) have found wide success in circuitry, photovoltaics, and other applications. In contrast, several hurdles exist in using CNTs towards applications in drug delivery. Raw, non-modified CNTs are widely known for their toxicity. As such, many have attempted to reduce CNT toxicity for intravenous drug delivery purposes by post-process surface modification. Alternatively, a novel sphere-like carbon nanocapsule (CNC) developed by the arc-discharge method holds similar electric and thermal conductivities, as well as high strength. This study investigated the systemic toxicity and biocompatibility of different non-surface modified carbon nanomaterials in mice, including multi-walled carbon nanotubes (MWCNTs), single-walled carbon nanotubes (SWCNTs), carbon nanocapsules (CNCs), and C 60 fullerene (C 60). The retention of the nanomaterials and systemic effects after intravenous injections were studied. METHODOLOGY AND PRINCIPAL FINDINGS: MWCNTs, SWCNTs, CNCs, and C 60 were injected intravenously into FVB mice and then sacrificed for tissue section examination. Inflammatory cytokine levels were evaluated with ELISA. Mice receiving injection of MWCNTs or SWCNTs at 50 µg/g b.w. died while C 60 injected group survived at a 50% rate. Surprisingly, mortality rate of mice injected with CNCs was only at 10%. Tissue sections revealed that most carbon nanomaterials retained in the lung. Furthermore, serum and lung-tissue cytokine levels did not reveal any inflammatory response compared to those in mice receiving normal saline injection. CONCLUSION: Carbon nanocapsules are more biocompatible than other carbon nanomaterials and are more suitable for intravenous drug delivery. These results indicate potential biomedical use of non-surface modified carbon allotrope. Additionally, functionalization of the carbon nanocapsules could further enhance dispersion and biocompatibility for intravenous injection.

The enhancement of endothelial cell therapy for angiogenesis in hindlimb ischemia using hyaluronan.

Growing evidence shows that injection of hyaluronan (HA) benefits ischemic injury in animals. On the other hand, cell therapy is an emerging approach to treat occlusive arterial diseases, although the low retention rate of cells after direct injection remains a major concern. Here, we tested whether injection of HA along with endothelial cells promotes the retention and growth of transplanted cells, thus improving therapeutic angiogenesis in a mouse model of hindlimb ischemia (HI). In culture, HA improved human umbilical vein endothelial cell (HUVEC) proliferation proportional to HA concentration and protected HUVECs from apoptosis. Subsequently, in immunocompromised mice HI was induced by femoral artery ligation and treatments were given 24h later. At 4 weeks, injection of HA along with HUVECs had a greater effect for restoring blood perfusion and salvaging the ischemic limb compared to injection of HA or HUVECs alone. In addition, angiogenesis and arteriogenesis were significantly increased by HA+HUVECs injection. Lastly, HA+HUVECs injection resulted in the retention of more cells than HUVECs alone, and allowed their engraftment into the vasculature of the ischemic limb. These results suggest that this combined approach can be translated into a clinical therapy for peripheral artery occlusive disease.