Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy

Abstract

Carbon nanotubes are promising new materials for molecular delivery in biological systems. The long-term fate of nanotubes intravenously injected into animals in vivo is currently unknown, an issue critical to potential clinical applications of these materials. Here, using the intrinsic Raman spectroscopic signatures of singlewalled carbon nanotubes (SWNTs), we measured the blood circulation of intravenously injected SWNTs and detect SWNTs in various organs and tissues of mice ex vivo over a period of three months. Functionalization of SWNTs by branched polyethyleneglycol (PEG) chains was developed, enabling thus far the longest SWNT blood circulation up to 1 day, relatively low uptake in the reticuloendothelial system (RES), and near-complete clearance from the main organs in Ϸ2 months. Raman spectroscopy detected SWNT in the intestine, feces, kidney, and bladder of mice, suggesting excretion and clearance of SWNTs from mice via the biliary and renal pathways. No toxic side effect of SWNTs to mice was observed in necropsy, histology, and blood chemistry measurements. These findings pave the way to future biomedical applications of carbon nanotubes.biodistribution ͉ blood circulation ͉ nanoparticles ͉ excretion ͉ toxicity T he utilization of novel nanomaterials for biological and biomedical applications has been an active and exciting direction of research in recent years (1-3). A wide range of nanomaterials, such as nanoparticles (4 -7), nanorods (8), nanowires (9), and nanotubes (10-12) have been investigated for their potential clinical applications in diagnosis and therapeutic treatment of diseases. The interesting structural, chemical, electrical, and optical properties of carbon nanotubes (13,14), when used in biological and medical settings, may bring new opportunities to biological detection, imaging, and therapy with high performance and efficacy. Carbon nanotube-based intercellular molecular delivery vehicles have been developed for intracellular gene (15-17) and drug delivery in vitro (18,19). Recently, research began to investigate the behavior of carbon nanotubes in animal bodies in vivo (20,21), including the finding of lack of toxicity of well PEGylated single-walled carbon nanotubes (SWNTs) in mice in a pilot study (M. L. Schipper, N. NakayamaRatchford, C.D., N. W. S. Kam, P. Chu, Z.L., X. Sun, L. C. Cork, H.D., and S. S. Gambhir, unpublished data).The biodistribution of intravenously injected carbon nanotubes in mice has been studied by using radiolabeling and isotope ratio mass spectroscopy methods (20,22). Promising result of efficient targeted tumor accumulation in vivo has been obtained by conjugating a ligand peptide to nanotubes to recognize receptors on the surface of tumor cells (20), suggesting high potential of nanotube-based drug delivery vehicles for cancer therapy. However, an important unaddressed question for carbon nanotubes and various nanomaterials in general in biomedical applications is their long term fate in vivo. It is known that most nanomaterials tend to exhibit high upt...

Photodynamic Action of Single-Walled Carbon Nanotubes

“…59 69) More importantly, the biodegraded SWNTs did not elicit a proinflammatory response in mice after pharyngeal aspiration, which was observed in previous studies for SWNTs 75) and MWNTs. 76) With regard to SWNT excretion, Liu et al used Raman microscopy to analyze the various organs of mice for up to 3 months after intravenous injection of SWNTs coated with PEG-PL conjugates.…”

“…51) In vivo studies were also performed with (6,5)-SWNTs on subcutaneous tumor-bearing mice. By detecting the intrinsic Raman G band of SWTNs after intravenous administration, 59) the blood circulation half-life of (6,5)-SWNTs coated with C 18 -PMH-mPEG was determined to be 23.95±1.49 h. 51) The authors also reported that the half-life of SWNTs was extendable up to 1 d with a branched PEG (7000) chain-PL conjugate. 59) The tumor uptake of (6,5)-SWNTs was ca.…”

“…By detecting the intrinsic Raman G band of SWTNs after intravenous administration, 59) the blood circulation half-life of (6,5)-SWNTs coated with C 18 -PMH-mPEG was determined to be 23.95±1.49 h. 51) The authors also reported that the half-life of SWNTs was extendable up to 1 d with a branched PEG (7000) chain-PL conjugate. 59) The tumor uptake of (6,5)-SWNTs was ca. 13% injected dose (ID)·g -1 , which was comparable to the 17% ID·g -1 and 12% ID·g -1 for the liver and spleen, respectively.…”

“…76) With regard to SWNT excretion, Liu et al used Raman microscopy to analyze the various organs of mice for up to 3 months after intravenous injection of SWNTs coated with PEG-PL conjugates. 59) The Raman signal intensity in the liver and spleen gradually decreased to below the detection limit (0.2 µg·mL −1 SWNTs in tissues). The biliary and renal pathways were suggested to be responsible for the excretion because the Raman signals were detected in the intestine, feces, kidney, and bladder.…”

Engineering imaging probes and molecular machines for nanomedicine

“…Amphiphilic polymers with a low critical micelle concentration (CMC), e.g., Poloxamer ® , Poloxamine ® and lipid-PEG copolymer, can form a stable coating layer around hydrophobic cores [98,114,119]. Amphiphilic polymer coated carbon nanotubes, polystyrene beads, quantum dots, and superparamagnetic iron oxide nanoparticles have been used in in vitro and in vivo applications [17,97,98,114,120,121]. This coating can be generalized for many hydrophobic nanocrystals because it does not rely on the reactivity of the crystal surface [98].…”