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...

Drug delivery by nanocarriers (NCs) has long been stymied by dominant liver uptake and limited target organ deposition, even when NCs are targeted using affinity moieties. Here we report a universal solution: red blood cell (RBC)-hitchhiking (RH), in which NCs adsorbed onto the RBCs transfer from RBCs to the first organ downstream of the intravascular injection. RH improves delivery for a wide range of NCs and even viral vectors. For example, RH injected intravenously increases liposome uptake in the first downstream organ, lungs, by ~40-fold compared with free NCs. Intra-carotid artery injection of RH NCs delivers >10% of the injected NC dose to the brain, ~10× higher than that achieved with affinity moieties. Further, RH works in mice, pigs, and ex vivo human lungs without causing RBC or end-organ toxicities. Thus, RH is a clinically translatable platform technology poised to augment drug delivery in acute lung disease, stroke, and several other diseases.

Red blood cells (RBCs) constitute a unique drug delivery system as a biologic or hybrid carrier capable of greatly enhancing pharmacokinetics, altering pharmacodynamics (for example, by changing margination within the intravascular space), and modulating immune responses to appended cargoes. Strategies for RBC drug delivery systems include internal and surface loading, and the latter can be performed both ex vivo and in vivo. A relatively new avenue for RBC drug delivery is their application as a carrier for nanoparticles. Efforts are also being made to incorporate features of RBCs in nanocarriers to mimic their most useful aspects, such as long circulation and stealth features. RBCs have also recently been explored as carriers for the delivery of antigens for modulation of immune response. Therefore, RBC-based drug delivery systems represent supercarriers for a diverse array of biomedical interventions, and this is reflected by several industrial and academic efforts that are poised to enter the clinical realm.

BackgroundThe potential medical applications of nanomaterials are shaping the landscape of the nanobiotechnology field and driving it forward. A key factor in determining the suitability of these nanomaterials must be how they interface with biological systems. Single walled carbon nanotubes (CNT) are being investigated as platforms for the delivery of biological, radiological, and chemical payloads to target tissues. CNT are mechanically robust graphene cylinders comprised of sp2-bonded carbon atoms and possessing highly regular structures with defined periodicity. CNT exhibit unique mechanochemical properties that can be exploited for the development of novel drug delivery platforms. In order to evaluate the potential usefulness of this CNT scaffold, we undertook an imaging study to determine the tissue biodistribution and pharmacokinetics of prototypical DOTA-functionalized CNT labeled with yttrium-86 and indium-111 (86Y-CNT and 111In-CNT, respectively) in a mouse model.Methodology and Principal FindingsThe 86Y-CNT construct was synthesized from amine-functionalized, water-soluble CNT by covalently attaching multiple copies of DOTA chelates and then radiolabeling with the positron-emitting metal-ion, yttrium-86. A gamma-emitting 111In-CNT construct was similarly prepared and purified. The constructs were characterized spectroscopically, microscopically, and chromatographically. The whole-body distribution and clearance of yttrium-86 was characterized at 3 and 24 hours post-injection using positron emission tomography (PET). The yttrium-86 cleared the blood within 3 hours and distributed predominantly to the kidneys, liver, spleen and bone. Although the activity that accumulated in the kidney cleared with time, the whole-body clearance was slow. Differential uptake in these target tissues was observed following intraveneous or intraperitoneal injection.ConclusionsThe whole-body PET images indicated that the major sites of accumulation of activity resulting from the administration of 86Y-CNT were the kidney, liver, spleen, and to a much less extent the bone. Blood clearance was rapid and could be beneficial in the use of short-lived radionuclides in diagnostic applications.

The field of clinical nanomaterials is enlarging steadily, with more than a billion US dollars of funding allocated to research by US government agencies in the past decade. The first generation of anti-cancer agents using novel nanomaterials has successfully entered widespread use. Newer nanomaterials are garnering increasing interest as potential multifunctional therapeutic agents; these drugs are conferred novel properties, by virtue of their size and shape. The new features of these agents could potentially allow increased cancer selectivity, changes in pharmacokinetics, amplification of cytotoxic effects, and simultaneous imaging capabilities. After attachment to cancer target reactive-ligands, which interact with cell-surface antigens or receptors, these new constructs can deliver cytolytic and imaging payloads. The molecules also introduce new challenges for drug development. While nanoscale molecules are of a similar size to proteins, the paradigms for how cells, tissues and organs of the body react to the non-biological materials are not well understood, because most cellular and metabolic processes have evolved to deal with globular, enzyme degradable molecules. We discuss examples of different materials to illustrate interesting principles for development and future applications of these nanomaterial medicines with emphasis on the possible pharmacologic and safety hurdles for accomplishing therapeutic goals.