Paradoxical glomerular filtration of carbon nanotubes

Abstract

The molecular weight cutoff for glomerular filtration is thought to be 30-50 kDa. Here we report rapid and efficient filtration of molecules 10-20 times that mass and a model for the mechanism of this filtration. We conducted multimodal imaging studies in mice to investigate renal clearance of a single-walled carbon nanotube (SWCNT) construct covalently appended with ligands allowing simultaneous dynamic positron emission tomography, near-infrared fluorescence imaging, and microscopy. These SWCNTs have a length distribution ranging from 100 to 500 nm. The average length was determined to be 200-300 nm, which would yield a functionalized construct with a molecular weight of ∼350-500 kDa. The construct was rapidly (t 1/2 ∼ 6 min) renally cleared intact by glomerular filtration, with partial tubular reabsorption and transient translocation into the proximal tubular cell nuclei. Directional absorption was confirmed in vitro using polarized renal cells. Active secretion via transporters was not involved. Mathematical modeling of the rotational diffusivity showed the tendency of flow to orient SWCNTs of this size to allow clearance via the glomerular pores. Surprisingly, these results raise questions about the rules for renal filtration, given that these large molecules (with aspect ratios ranging from 100:1 to 500:1) were cleared similarly to small molecules. SWCNTs and other novel nanomaterials are being actively investigated for potential biomedical applications, and these observations-that high aspect ratio as well as large molecular size have an impact on glomerular filtration-will allow the design of novel nanoscalebased therapeutics with unusual pharmacologic characteristics.multimodal imaging | nanotechnology | renal C arbon nanotubes (CNTs) have interesting properties and have been proposed as novel components of drugs and devices in pharmaceutical and biomedical applications (1). CNTs have unique intrinsic physical, chemical, electronic, thermal, and optical properties and can be chemically modified (with, e.g., targeting ligands, magnetic, radioactive, fluorescent, and chemotherapeutic moieties) to exhibit additional extrinsic properties (2-4). Pharmacokinetic (PK) studies of covalently functionalized single-wall CNTs (SWCNTs) (5-9) and multiwall (MWCNTs) (10-12) have reported a short blood compartment half-life (1-3 h) and limited tissue (kidneys, liver, and spleen) accumulation and renal excretion. Clearance via renal mechanisms is significant (13), because it provides the opportunity for the host to eliminate SWCNTs, allowing potential therapeutic and diagnostic applications in vivo. The elimination of noncovalently modified SWCNTs has been reported to favor the hepatobiliary route, with evidence of a minor role for the renal route (14).Renal clearance of solutes occurs through a combination of glomerular filtration, active tubular secretion, and passive tubular reabsorption (15). In previous work, we reported radioactivity in the renal cortex and in the urine within 1 h of administration of radiolabeled...

Perturbation of physiological systems by nanoparticles

“…For example, within one minute after intravenous injection, SWCNTs (0.8-1.2 nm in diameters and 100-500 nm in length) were found in the bladders of mice. 245 After intravenous injection to mice, 50% of a preparation of SWCNTs was excreted in urine within 24 hours. 246 After intraperitoneal injection, SWCNTs were also detected in mice urine after 18 days.…”

Self-assembled, aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics

“…Recent biotechnological advancements have led to a variety of targeted drug transport (TDT) strategies based on aptamer-drug conjugates or aptamer-nanomaterial assemblies (11,12,(18)(19)(20)(21)27). However, these strategies have unique limitations that could hamper the transition to clinical application, including (i) complicated design, laborious and uneconomical bulky preparation of myriad ssDNA as building blocks to construct sophisticated nucleic acid-based nanomaterials, or laborious and inefficient preparation of aptamer-drug conjugates (9,11,14,15,17,18); (ii) limited drug payload capacity and the attendant high cost, hampering production scale-up (9,11,14,15,17,18,20,27); (iii) poor biodegradability, causing chronic accumulation of nanomaterials in vivo (28,29); and (iv) limited universality by the requirement of specific aptamer for drug loading (20).…”

Dialytic Separation of Bundled, Functionalized Carbon Nanotubes from Carbonaceous Impurities

“…The in vivo bundling of unmodified SWCNTs has been observed as aggregates in discrete organs and cell types [25,26]. Following solubilization through functionalization (Scheme S1), if SWCNTs are lyophilized to a powder [13], they require extensive sonication to resolubilize. This phenomenon is attributed to bundling properties of even functionalized SWCNTs as they engage in longitudinal pi-stacking and other non-covalent attractive interactions powerful enough to overcome the repulsive forces of sometimes ionized adducts and the entropic advantages of true solubilization.…”

“…The products of this simultaneous functionalization of both starting materials-fullerene and carbonaceous impurity-are of similar solubility, and are not easily separated by solubility-and filtration-based separations [22,23]. Until recently, our laboratory used a short C18 column to separate the more polar modified amorphous carbon from the less polar modified carbon nanotubes [13]. The baseline gap between amorphous carbons and SWCNT peaks in C18 High-performance liquid chromatography (HPLC) analysis mirrors the preparatory potential for separation with C18 columns (Figure 1).…”

“…While unmodified spheroid fullerenes have been established as non-toxic in a wide variety of delivery methods, including inhalation into the lung [4], pristine separating functionalized single-wall carbon nanotubes (SWCNT) toxicity has raised concern [5,6]. Functionalization allows the attachment of fluorophores, radioisotopes, pharmaceuticals, and other ligands to carbon nanotubes and spheroid fullerenes [7][8][9], which, when solubilized, with variation due to adduct properties, become non-toxic [10,11], non-immunogenic [11,12], and rapidly excretable [13] substrates with a unique anisotropy and durability [14]. The intrinsic properties of the carbon nanomaterial in combination with the manner and degree in which it is functionalized allows for a vast array of potential constructs, bringing versatility to construction and application [15,16].…”