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A simple and novel electrostatic coupling method is reported, which provides a hyaluronic acid-quantum dot conjugate (HA-QD) that is colloidally stable and size-tunable from 50 to 120 nm. The HA-QDs show cancer targeting efficiency, which suggests diagnostic and imaging applications. The conjugates are also demonstrated for the fluorescence staining capability for lymphatic vessels in vitro and in vivo. Using the HA-QDs in a small animal model, lymphatic vessels are visualized real-time in vivo for days. Comprehensive cytotoxicity evaluations are made for the conjugates and the unconjugated counterpart. The HA-QDs showcase the potentials toward cancer imaging and real-time visualization of changes in lymphatic vessels such as lymphangiogenesis.
ACS Nano 2009 Jun 23
PMID:Hyaluronic acid-quantum dot conjugates for in vivo lymphatic vessel imaging. 1947 39

The central nervous system (CNS) coordinates all aspects of life, autonomic and sentient, though how it has evolved to contend with pathogenic infections remains, to a great degree, a mystery. The skull and cerebrospinal fluid (CSF) provide protection from blunt force contacts, and it was once thought that the blood-brain barrier (BBB) was a fortress that restricted pathogen entry and limited inflammation. Recent studies, however, have caused a revision of this viewpoint: the CNS is monitored by blood-borne lymphocytes, but can use alternative strategies to prevent or resolve many pathogenic challenges. In this Review, we discuss emerging principles that indicate how the CNS is immunologically unique from peripheral tissues. We focus on developments that include glymphatics, recently characterized brain lymphatic vessels, distinctions in innate and adaptive immune strategies, novel points of entry for neurotropic viruses, and, finally, how the periphery can influence CNS homeostasis and immune responses within the brain. Collectively, these attributes demand a re-evaluation of immunity in the brain: not privileged, but distinct.
ACS Chem Neurosci 2016 Apr 20
PMID:Get It through Your Thick Head: Emerging Principles in Neuroimmunology and Neurovirology Redefine Central Nervous System "Immune Privilege". 2685 33

A novel dual imaging probe for in vivo magnetic resonance imaging (MRI) and optical imaging was developed by combining gadolinium (Gd)-chelating MR probe and a near-infrared (NIR) fluorophore, aza-BODIPY (AB; BODIPY = boron-dipyrromethene). This aza-BODIPY-based bimodal contrast agent (AB-BCA) showed a significant fluorescence emission around the NIR range and an enhanced longitudinal relaxivity in MR modality. The probe was easily delivered to phagocytic cells of the innate immune system, together with macrophages and dendritic cells (DCs), and presented high-performance fluorescence and MR imaging without obvious cytotoxicity. For in vivo visualization of AB-BCA using MRI and optical imaging, bone marrow-derived DCs were labeled and injected into the footpad of mice, and labeled DCs were tracked in vivo. We observed the migration of AB-BCA-labeled DCs into the lymph nodes via lymphatic vessels using NIR fluorescence and T1-weighted MR images. This dual-modality imaging probe was used for noninvasive monitoring of DC migration into lymph nodes and could be useful for investigating advanced cellular immunotherapy.
ACS Appl Mater Interfaces 2016 04 27
PMID:In Vivo Tracking of Phagocytic Immune Cells Using a Dual Imaging Probe with Gadolinium-Enhanced MRI and Near-Infrared Fluorescence. 2705 3

It has been widely accepted that lymph nodes (LNs) are critical targets of cancer vaccines because antigen presentation and initiation of T-cell-mediated immune responses occur primarily at these locations. In this study, amphiphilic diblock copolymer poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (PEOz-PLA) combined with carboxylterminated-Pluronic F127 was used to construct mixed micelles [carboxylated-nanoparticles (NPs)] for codelivery of antigen ovalbumin (OVA) and Toll-like receptor-7 agonist CL264 (carboxylated-NPs/OVA/CL264) to the LN-resident dendritic cells (DCs). The results showed that the small, sub-60 nm size of the self-assembled mixed micelles enables them to rapidly penetrate into lymphatic vessels and reach draining lymph nodes after subcutaneous injection. Furthermore, the surface modification with carboxylic groups imparted the carboxylated-NPs with endocytic receptor-targeting ability, allowing for DC internalization of carboxylated-NPs/OVA/CL264 via the scavenger receptor-mediated pathway. Because stimulation of CL264 in early endosomes will lead to a more effective immune response than that in late endo/lysosomes, the mass ratio of PEOz-PLA to carboxylated-Pluronic F127 in the mixed micelles was adjusted to release the encapsulated CL264 to the early endosome, resulting in increased expression of costimulatory molecules and secretion of stimulated cytokines by DCs. Moreover, the incorporation of PEOz outside the micellar shell effectively augmented MHC I antigen presentation through facilitating endosome escape and cytosolic release of antigens. This in turn evoked potent immune responses in vivo, including activation of antigen-specific T-cell responses, production of antigen-specific IgG antibodies, and generation of cytotoxic T-lymphocyte responses. Finally, immunization with the codelivery system in E.G7-OVA tumor-bearing mice could not only significantly inhibit tumor growth but also markedly prolong the survival of tumor-bearing mice. Taken together, carboxylated-NPs/OVA/CL264 have demonstrated great potential for clinical applications as an effective antitumor vaccine for further immunotherapy.
ACS Appl Mater Interfaces 2018 Jan 24
PMID:Synthetic Polymeric Mixed Micelles Targeting Lymph Nodes Trigger Enhanced Cellular and Humoral Immune Responses. 2928 34

The absorption of dietary fat requires complex neuroendocrine-mediated regulation of chylomicron trafficking through enterocytes and intestinal lymphatic vessels. Calcitonin-receptor-like receptor (Calcrl) is a G protein-coupled receptor that can bind either a lymphangiogenic ligand adrenomedullin, with coreceptor RAMP2, or the neuropeptide CGRP, with coreceptor RAMP1. The extent to which this common GPCR controls lipid absorption via lymphatics or enteric innervation remains unclear. We used conditional and inducible genetic deletion of Calcrl in lymphatics to elucidate the pathophysiological consequences of this receptor pathway under conditions of high-fat diet. Inefficient absorption of dietary fat coupled with altered lymphatic endothelial junctions in Calcrl fl/fl /Prox1-CreER T2 mice results in excessive, transcellular lipid accumulation and abnormal enterocyte chylomicron processing and failure to gain weight. Interestingly, Calcrl fl/fl /Prox1-CreER T2 animals show reduced and disorganized mucosal and submucosal innervation. Consistently, mice with genetic loss of the CGRP coreceptor RAMP1 also displayed mucosal and submucosal innervation deficits, substantiating the CGRP-biased function of Calcrl in the neurolymphocrine axis. Thus, the common Calcrl receptor is a critical regulator of lipid absorption through its cell-specific functions in neurolymphocrine crosstalk.
ACS Pharmacol Transl Sci 2019 Apr 12
PMID:Calcitonin-Receptor-Like Receptor Signaling Governs Intestinal Lymphatic Innervation and Lipid Uptake. 3221 16

Indocyanine green (ICG) is a fluorescent dye with a strong emission in the near-infrared spectral range that allows deep signal penetration and minimal interference of tissue autofluorescence. It has been employed in clinics for different applications, among which the more interesting is certainly near-infrared fluorescence image-guided surgery. This technique has found wide application in surgical oncology for lymph node mapping or for laparoscopic surgery. Despite ICG being useful for tracking loco-regional lymph nodes, it does not provide any information about cancer involvement of such lymph nodes or lymphatic vessels, lacking any tumor-targeting specificity. However, the clinical need in surgical oncology is not only a specific tracking of metastatic nodes but also the intraoperative detection of micrometastatic deposits. Here, we have exploited a nanotechnological solution to improve ICG usefulness by its encapsulation in H-ferritin (HFn) nanocages. They are natural protein-based nanoparticles that exhibit some very interesting features as delivery systems in oncological applications because they display specific tumor homing. We show that HFn loaded with ICG exhibits specific uptake into different cancer cell lines and is able to deliver ICG to the tumor more efficiently than the free dye in an in vivo model of TNBC. Our results pave the way for the application of ICG-loaded HFn in fluorescence image-guided surgery of cancer.
ACS Omega 2020 Jun 02
PMID:Development of Tumor-Targeted Indocyanine Green-Loaded Ferritin Nanoparticles for Intraoperative Detection of Cancers. 3254 82