DIAGNOSTIC AGENTS-Nanoparticles functionalized with ligands that target tumors can be cleared from the body through the kidneys if they have a hydrodynamic diameter of less than 5.5 nm. KeywordsNanotechnology; Quantum Dots; Nanoparticles; Diagnostic Imaging; Image-Guided Surgery; Biodistribution; Clearance; Fluorescence Imaging; Tumor Targeting INTRODUCTORY PARAGRAPHInorganic/organic hybrid nanoparticles are potentially useful in biomedicine but to avoid nonspecific background fluorescence and long-term toxicity, they need to be cleared from the body within a reasonable time scale. 1 Previously, we showed that rigid spherical nanoparticles such as quantum dots can be cleared by the kidneys if they had a hydrodynamic diameter less than 5.5 nm and a zwitterionic surface charge. 2 Here we show that quantum dots functionalized with high-affinity small molecule ligands that target tumors can also be cleared by the kidneys if their hydrodynamic diameter is less than this value, which sets an upper limit of 5-10 ligands per quantum dot for renal clearance. Animal models of prostate cancer and melanoma show receptor-specific imaging and renal clearance within 4 h post-injection. This study suggests a set of design rules for the clinical translation of targeted nanoparticles that can be eliminated through the kidneys.Although many classes of biocompatible, inorganic-based nanomaterials have been developed for medical diagnostics and therapeutics, 3-7 many presently available formulations require potentially toxic elements. 8 Efforts have been made to reduce toxicity by modulating the composition, particle shape, physical size, and surface coating of the nanoparticles. 9 One common strategy is to engineer nanoparticles using biocompatible and biodegradable polymeric coatings. 10-13 However, polymer coatings generally increase particle size over the * Corresponding Author: John V. Frangioni, M.D., Ph.D., Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Room SL-B05, Boston, MA 02215, Phone: 617-667-0692 Fax: 617-667-0981, jfrangio@bidmc.harvard.edu Author contributions H.S.C., W.L., F.L., K.N., and P.M. performed the experiments. H.S.C., M.G.B., and J.V.F. reviewed, analyzed, and interpreted the data. H.S.C., M.G.B., and J.V.F. wrote the paper. All authors discussed the results and commented on the manuscript. Competing financial interestsThe authors declare no competing financial interests. NIH Public Access Author ManuscriptNat Nanotechnol. Author manuscript; available in PMC 2011 January 1. Published in final edited form as:Nat Nanotechnol. [20][21][22][23] However, most of these papers fail to consider the autofluorescence of living tissue, the passive targeting caused by leaky tumor vasculature, the use of a receptor-negative tumor as a control, and the high background accumulation of nanoparticles in the RES. Indeed, most tumor targeting of nanoparticles in animals described to date is likely the result of enhanced permeability and retention, 24 and not specific targeting.To render nanoparticles vi...
To address two fundamental and unsolved problems in optical imaging (nonspecific uptake of near‐infrared fluorophores by normal tissues and organs and incomplete elimination of unbound targeted fluorophores from the body), novel zwitterionic near‐infrared fluorophores (e.g., ZW800‐1) were synthesized and their performance compared in vivo to conventional molecules (e.g., ICG) as a function of charge, charge distribution, and hydrophobicity (see picture).
Nerve damage is the major morbidity of many surgeries, resulting in chronic pain, loss of function, or both. The sparing of nerves during surgical procedures is a vexing problem because surrounding tissue often obscures them. To date, systemically administered nerve-highlighting contrast agents that can be used for nerve-sparing image-guided surgery have not been reported. In the current study, physicochemical and optical properties of 4,4’-[(2-methoxy-1,4-phenylene)di-(1E)-2,1-ethenediyl]bis-benzenamine (BMB) and a newly synthesized, red-shifted derivative 4-[(1E)-2-[4-[(1E)-2-[4-aminophenyl]ethenyl]-3-methoxyphenyl]ethenyl]-benzonitrile (GE3082) were characterized in vitro and in vivo. Both agents crossed the blood-nerve barrier and blood-brain barrier, and rendered myelinated nerves fluorescent after a single systemic injection. Although both BMB and GE3082 also exhibited significant uptake in white adipose tissue, GE3082 underwent a hypsochromic shift in adipose tissue that provided a means to eliminate the unwanted signal using hyperspectral deconvolution. Dose and kinetic studies were performed in mice to determine the optimal dose and drug-imaging interval. Results were confirmed in rat and pig, with the latter used to demonstrate, for the first time, simultaneous fluorescence imaging of blood vessels and nerves during surgery using the FLARE™ (Fluorescence-Assisted Resection and Exploration) imaging system. These results lay the foundation for the development of ideal nerve-highlighting fluorophores for image-guided surgery.
A longstanding problem in the field of image-guided surgery is the development of ideal near-infrared (NIR) fluorophores. The heptamethine NIR fluorophore indocyanine green (ICG) has been used extensively for image-guided surgery because of its clinical availability and safety. [1][2][3] However, ICG is far from ideal because it exhibits high uptake in the liver, contaminates the gastrointestinal (GI) tract, provides moderate optical properties, [4] is unstable in aqueous media, [3,5] and is unable to conjugate covalently to targeting ligands. [2] Although several classes of novel molecules have been described, [6][7][8][9][10][11][12][13] none to date exhibit simultaneous low background binding, bifunctionality, excellent optical properties, low protein binding, and high serum stability. Although it is intuitive that physicochemical properties, that is, positive/ negative charge density, hydrophilicity/lipophilicity, and charge distribution, will impact in vivo performance, chemical structures that exhibit ideal characteristics have not yet been defined.Previously, our group showed that rigid spherical nanoparticles, such as quantum dots, with a hydrodynamic diameter (HD) 5.5 nm could be rapidly cleared by the kidneys, and exhibit low background binding to normal tissues and organs, but only when the surface charge was neutral, geometrically balanced, and polyionic (referred to herein as zwitterionic for simplicity). [14][15][16][17][18][19] In this study, we explored the hypothesis that NIR fluorescent small molecules would exhibit improved in vitro and in vivo performance if synthesized with zwitterionic charges that are evenly spaced over the molecule to shield the underlying hydrophobicity of the relatively large heptamethine core.We describe two complementary molecules, termed ZW800 AE i where AE i is the charge of the conjugated targeting ligand that will render the final molecule with a net charge of zero (i.e., zwitterionic). ZW800-1 has a net charge = 0 prior to targeting ligand conjugation, and a net charge = 0 after conjugation to a targeting ligand that has a net charge of À1 (that is, a targeting ligand with a net charge of 0 prior to conjugation). ZW800-3a has a net charge = + 2 prior to conjugation, and a net charge = 0 after conjugation to a targeting ligand that has a net charge of À3 (that is, a targeting ligand with a net charge of À2 prior to conjugation). ZW800-1 and ZW800-3a were engineered for high hydrophilicity, with logD (distribution coefficient) at pH 7.4 of À3.56 and À6.95, respectively. Importantly, these molecules have also been engineered with sulfonate groups to impart negative charge and quaternary ammonium cations (quats) to impart positive charge because preliminary results showed that the weaker, more common natural analogues (carboxylic acids and primary amines, respectively) did not exhibit the desired properties.As depicted in Figure 1 a, chloro-substituted NIR fluorophores 8 and 9 were synthesized by employing quats and/or sulfonates (5 or 6) on the indocyanine backbone...
Humans and animals have a “number sense,” an innate capability to intuitively assess the number of visual items in a set, its numerosity. This capability implies that mechanisms to extract numerosity indwell the brain’s visual system, which is primarily concerned with visual object recognition. Here, we show that network units tuned to abstract numerosity, and therefore reminiscent of real number neurons, spontaneously emerge in a biologically inspired deep neural network that was merely trained on visual object recognition. These numerosity-tuned units underlay the network’s number discrimination performance that showed all the characteristics of human and animal number discriminations as predicted by the Weber-Fechner law. These findings explain the spontaneous emergence of the number sense based on mechanisms inherent to the visual system.
Given the known water exchange rate limitations of a previously reported Zn(II)-sensitive MRI contrast agent, GdDOTA-diBPEN, new structural targets were rationally designed to increase the rate of water exchange to improve MRI detection sensitivity. These new sensors exhibit fine-tuned water exchange properties and, depending on the individual structure, demonstrate significantly improved longitudinal relaxivities (r1). Two sensors in particular demonstrate optimized parameters and, therefore, show exceptionally high longitudinal relaxivities of about 50 mM−1 s−1 upon binding to Zn(II) and human serum albumin (HSA). This value demonstrates a 3-fold increase in r1 compared to that displayed by the original sensor, GdDOTA-diBPEN. In addition, this study provides important insights into the interplay between structural modifications, water exchange rate, and kinetic stability properties of the sensors. The new high relaxivity agents were used to successfully image Zn(II) release from the mouse pancreas in vivo during glucose stimulated insulin secretion.
Learning critically depends on the ability to rapidly form and store non-overlapping representations of the external world. In line with their postulated role in episodic memory, hippocampal place cells can undergo a rapid reorganization of their firing fields upon contextual manipulations. To explore the mechanisms underlying such global remapping, we juxtacellularly stimulated 42 hippocampal neurons in freely moving mice during spatial exploration. We found that evoking spike trains in silent neurons was sufficient for creating place fields, while in place cells, juxtacellular stimulation induced a rapid remapping of their place fields to the stimulus location. The occurrence of complex spikes was most predictive of place field plasticity. Our data thus indicate that plasticity-inducing stimuli are able to rapidly bias place cell activity, simultaneously suppressing existing place fields. We propose that such competitive place field dynamics could support the orthogonalization of the hippocampal map during global remapping.
Assigned from data sets measured in water at 2, 25, and 60 °C containing 13C=O NMR chemical shifts and [θ]222 ellipticities, helical propensities are reported for the twenty genetically coded amino acids, as well as for norvaline and norleucine. These have been introduced by chemical synthesis at central sites within length-optimized, spaced, solubilized Ala19 hosts. The resulting polyalanine-derived, quantitative propensity sets express for each residue its temperature-dependent but context-independent tendency to forgo a coil state and join a preexisting helical conformation. At 2 °C their rank ordering is: P ⪡ G < H < C, T, N < S < Y, F, W < V, D < K < Q < I < R, M < L < E < A; at 60 °C the rank becomes: H, P < G < C < R, K < T, Y, F < N, V < S < Q < W, D < I, M < E < A < L. The ΔΔ G values, kcal/mol, relative to alanine, for the cluster T, N, S, Y, F, W, V, D, Q, imply that at 2 °C all are strong breakers: ΔΔ Gmean = +0.63 ± 0.11, but at 60 °C their breaking tendencies are dramatically attenuated and converge toward the mean: ΔΔ Gmean = +0.25 ± 0.07. Accurate modeling of helix-rich proteins found in thermophiles, mesophiles, and organisms that flourish near 0 °C thus requires appropriately matched propensity sets. Comparisons are offered between the temperature-dependent propensity assignments of this study and those previously assigned by the Scheraga group; the special problems that attend propensity assignments for charged residues are illustrated by lysine guest data; and comparisons of errors in helicity assignments from shifts and ellipticity data show that the former provide superior precision and accuracy.
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