Tissue Penetration Of Light Research Articles

Fiber Optic Devices for Diagnostics and Therapy in Photomedicine

AbstractPhotonic technologies have made enormous impacts on modern medicine, advancing disease diagnostics and treatments as well as health monitoring. A long‐standing challenge in the use of light and its widespread effects in photomedicine is the finite penetration of light in tissues. However, judiciously engineered optical fibers helped overcome this challenge and advance light delivery to deep tissues with spatial precision and desired accessibility. In recent years, the development of photonic technologies including optical biomaterials, fiber functionalization, and biomedical device innovations has greatly expanded the scope of light‐based healthcare. Here, the fundamentals and materials of fiber optics to endow themselves with biocompatibility, flexibility, and diverse functionalities required for long‐term implantation are overviewed. The design strategies of lab‐on‐fiber techniques, operation requirements to construct fiber optic sensors, and their health monitoring applications as wearable and implantable devices are presented. The use of fiber optics in major light‐based therapeutic modalities including optogenetics, photodynamic therapy, photobiomodulation, photochemical cross–linking, and photothermal therapy is illustrated to enhance their effectiveness, specificity, and feasibility. In short, a comprehensive review is provided on the fiber optic techniques and the latest photonic devices, which are envisioned to evolve photomedicine in clinical and point‐of‐care practices.

Photoresponsive Drug Delivery Systems: Challenges and Progress

AbstractPhotoresponsive drug delivery systems (PDDSs) have emerged as a promising toolbox for drug delivery, offering precise control over the site, duration, and dosage of light‐triggered medication. It allows controlled drug release, photo‐triggered targeting, diagnosis, and treatment, improving the precision and efficacy of therapies for various diseases. Despite progress in designing different PDDSs, clinical translation has been limited due to various obstacles. Herein, this review article focuses on three critical challenges of PDDSs: 1) accumulation at diseased lesions, 2) precision of light irradiation, and 3) penetration of light in tissues. Also, this article summarizes and discusses current advancements and strategies to address these challenges. Overall, it emphasizes the need to clarify the current challenges from bench to bedside and develop strategies to enhance therapeutic outcomes, increase compatibility and patient compliance, and unlock the possibilities in different clinical therapies.

System for Self-excited Targeted Photodynamic Therapy Based on the Multimodal Protein DARP-NanoLuc-SOPP3.

Despite the significant potential of photodynamic therapy (PDT) as a minimally invasive treatment modality, the use of this method in oncology has remained limited due to two serious problems: 1) limited penetration of the excitation light in tissues, which makes it impossible to affect deep-seated tumors and 2) use of chemical photosensitizers that slowly degrade in the body and cause photodermatoses and hyperthermia in patients. To solve these problems, we propose a fully biocompatible targeted system for PDT that does not require an external light source. The proposed system is based on bioluminescent resonance energy transfer (BRET) from the oxidized form of the luciferase substrate to the photosensitizing protein SOPP3. The BRET-activated system is composed of the multimodal protein DARP-NanoLuc-SOPP3, which contains a BRET pair NanoLuc-SOPP3 and a targeting module DARPin. The latter provides the interaction of the multimodal protein with tumors overexpressing tumor-associated antigen HER2 (human epidermal growth factor receptor type II). In vitro experiments in a 2D monolayer cell culture and a 3D spheroid model have confirmed HER2-specific photo-induced cytotoxicity of the system without the use of an external light source; in addition, experiments in animals with subcutaneous HER2-positive tumors have shown selective accumulation of DARP-NanoLuc-SOPP3 on the tumor site. The fully biocompatible system for targeted BRET-induced therapy proposed in this work makes it possible to overcome the following limitations: 1) the need to use an external light source and 2) the side phototoxic effect from aberrant accumulation of chemical photosensitizers. The obtained results demonstrate that the fully protein-based self-excited BRET system has a high potential for targeted PDT.

Polydimethylsiloxane as a more biocompatible alternative to glass in optogenetics

Optogenetics is highly useful to stimulate or inhibit defined neuronal populations and is often used together with electrophysiological recordings. Due to poor penetration of light in tissue, there is a need for biocompatible wave guides. Glass wave guides are relatively stiff and known to cause glia reaction that likely influence the activity in the remaining neurons. We developed highly flexible micro wave guides for optogenetics that can be used in combination with long-lasting electrophysiological recordings. We designed and evaluated polydimethylsiloxane (PDMS) mono-fibers, which use the tissue as cladding, with a diameter of 71 ± 10 µm and 126 ± 5 µm. We showed that micro PDMS fibers transmitted 9–33 mW/mm2 light energy enough to activate channelrhodopsin. This was confirmed in acute extracellular recordings in vivo in which optogenetic stimulation through the PDMS fibers generated action potentials in rat hippocampus with a short onset latency. PDMS fibers had significantly less microglia and astrocytic activation in the zone nearest to the implant as compared to glass. There was no obvious difference in number of adjacent neurons between size matched wave guides. Micro PDMS wave guide demonstrates in vivo functionality and improved biocompatibility as compared to glass. This enables the delivery of light with less tissue damage.

Non-invasive in vivo imaging of human corneal microstructures with optical coherence microscopy.

Non-invasive imaging systems with cellular-level resolution offer the opportunity to identify biomarkers of the early stage of corneal diseases, enabling early intervention, monitoring of disease progression, and evaluating treatment efficacy. In this study, a non-contact polarization-dependent optical coherence microscope (POCM) was developed to enable non-invasive in vivo imaging of human corneal microstructures. The system integrated quarter-wave plates into the sample and reference arms of the interferometer to enable deeper penetration of light in tissues as well as mitigate the strong specular reflection from the corneal surface. A common-path approach was adopted to enable control over the polarization in a free space configuration, thus alleviating the need for a broadband polarization-maintained fiber. The POCM achieved volumetric imaging of corneal microstructures, including endothelial cells over a field of view 0.5 × 0.5 mm2 with an almost isotropic resolution of ∼2.2 µm and a volume (500 × 500 × 2048 voxels) rate of 1 Hz. A self-interference approach between the corneal surface and underlying layers was also developed to lessen the corneal curvature and axial motion artifacts, thus enabling high-resolution imaging of microstructures in the anterior cornea, including squamous epithelial cells, wing epithelial cells, basal epithelial cells, sub-basal nerve plexus, and stromal keratocytes.

Potential Application of Photosensitizers With High-Z Elements for Synergic Cancer Therapy

The presence of heavy elements in photosensitizers (PS) strongly influences their electronic and photophysical properties, and hence, conjugation of PS with a suitable element is regarded as a potential strategy to improve their photodynamic properties. Moreover, PS conjugated to metal ion or metal complex and heavy atoms such as halogen have attracted considerable attention as promising agents for multimodal or synergistic cancer therapy. These tetrapyrrole compounds depending on the type and nature of the inorganic elements have been explored for photodynamic therapy (PDT), chemotherapy, X-ray photon activation therapy (PAT), and radiotherapy. Particularly, the combination of metal-based PS and X-ray irradiation has been investigated as a promising novel approach for treating deep-seated tumors, which in the case of PDT is a major limitation due to low light penetration in tissue. This review will summarize the present status of evidence on the effect of insertion of metal or halogen on the photophysical properties of PS and the effectiveness of various metal and halogenated PS investigated for PDT, chemotherapy, and PAT as mono and/or combination therapy.

Photostability investigation of a near-infrared-II heptamethine cyanine dye

The development of small-molecule organic fluorophores in the second near-infrared region (NIR-II, 1000–1700 nm) has recently received immense attention due to deep tissue light penetration and reduced autofluorescence. Polymethine cyanine dyes as important building blocks are frequently used to design NIR-II light-activated fluorophores. However, applications of these fluorophores were restricted by their poor photostability. Herein, we synthesized a NIR-II heptamethine cyanine dye 4 as the model compound to investigate its photostability and identify its photoproducts. Compound 4 shows improved photostability compared to ICG, and remains relatively stable even under sunlight irradiation. The cyanine scaffold’s good photostability promoted its stable photothermal properties. The effective photothermal activity of cyanine dye 4 and the low toxicity of its one major photoproduct demonstrated its potential for further photo-therapeutic applications. This work would pave the way for the development of NIR-II cyanines with photostability through delicate structure design.

Probing the mechanisms of sonodynamic therapy

Drugs that can be activated by a physical stimulus at a target site offer great potential for limiting toxic side effects, e.g., in cancer therapy. In photodynamic therapy, light is used as the stimulus, but clinical applications are limited due to the poor penetration of light in tissue. Multiple studies have demonstrated that ultrasound can also be used to activate some light-responsive drugs. This potentially extends the range of therapeutic applications considerably, but the mechanisms underpinning drug activation, dubbed sonodynamic therapy (SDT), remain unclear. It was recently demonstrated that multi-bubble sonoluminescence could be detected from a suspension of microbubble ultrasound contrast agents when exposed to ultrasound under conditions similar to those used in SDT. Moreover, the addition of an SDT drug produced a reduction in optical emissions at the wavelength corresponding to its activation. Numerous questions, however, remain and the aim of this talk is to review recent studies of SDT and new evidence for the roles of sonoluminescence, sonoporation, and other phenomena hypothesized to play a role in its mechanism of action.

Sonochemical Internalization of Bleomycin Inhibits Adenocarcinoma Breast Tumor Development in an Orthotopic Rat Model.

One approach to reducing post-operative tumor recurrence and alleviate debilitating side effects of systemic chemotherapy, is work centered on the development of drug activation by focused and targeted externally applied physical energy thus providing site and temporal specificity. One such technique, light mediated photochemical internalization (PCI), has been shown to be a method to obtain enhanced chemotherapy efficacy for a wide variety of anti-cancer agents. A related technology, sonochemical internaization (SCI), is an extension of the PCI concept developed to overcome the limitations of poor light penetration in tissue. SCI utilizes ultrasonic energy, to activate sonosensitizers, co-administered with anti cancer agents. The purpose of the study reported here was to evaluate the inhibitory effects of SCI of bleomycin (BLM), both in vitro and in vivo, on the adenocarcinoma breast tumor rat cell line Mat B III. In vitro, the two aspects of sonication, sonoporation (SP) and sonochemical internalization (SCI) of BLM were examined. In vivo, BLM-SCI significantly inhibited tumor development, following Mat B III implantation, in an orthotopic breast tumor animal model using Fisher rats.

Photothermal properties of stable aggregates of gold nanorods

Aggregation of the nanoparticles is a natural phenomena due to various biological and physical parameters but these aggregates are highly unstable. If aggregates would have been stable then it might be useful for some biomedical applications. To study the optical properties and photothermal heat generation of stable aggregates of the metal nanoparticles, we present a forced synthesis of aggregates of small gold nanorods in a mixture of Dulbecco’s Modified Eagle’s medium (DMEM) and Bovine Serum Albumin (BSA). We synthesized hexadecyltrimethylammonium bromide (CTAB) coated gold nanorods and then prepared the stable aggregates to study the optical characteristics of these aggregates. Absorption spectra of aggregates show the redshift compared to the monodispersive gold nanorods and confirm that the shape and size of aggregate depend on the amount of BSA in DMEM as well as on the concentration of CTAB in the stock solution of the gold nanorods suspension. The higher concentration of the BSA in DMEM and lower concentration of CTAB of monodispersive gold nanorod suspension causes greater redshift. We tuned the well defined plasmonic absorption resonance peaks of the aggregates of gold nanorods up to the second biological therapeutic window. We studied the stability of the synthesized aggregates of gold nanorods for up to one week and found that the aggregates were stable for at least one week. A photothermal study of these aggregates was also carried out using high power broadband near-infrared light source. Aggregates were also photothermally stable which warrants their repeated use for such applications. The photothermal conversion efficiency of these stable gold nanorod aggregates were higher than its monodispersive form of the nanorods. The present study on the optical and photothermal properties of stable aggregates could be useful for biomedical therapeutic applications, sensing, deep tissue light penetration for imaging and other scientific applications to redshift the plasmonic absorption resonance peak and enhance the photothermal effect.

Abstract 1318: Mechanochemical dynamic therapy for focal cancer treatment

Abstract This study proposes a new cancer drug delivery modality that allows for spatiotemporal control over activation of the therapeutic. Current standard cancer therapies of surgery, chemotherapy, and radiation therapy have their limitations, such as invasiveness and systemic toxicities. Developing a new modality that is localized and triggerable is becoming increasingly advantageous. Currently, photodynamic therapy (PDT) has been shown to be clinically effective but is limited by poor tissue penetration of light. Sonodynamic therapy (SDT) bypasses this pitfall with increased tissue penetration depth of ultrasound. However, PDT has limitations as it relies on the potentially damaging ultrasound cavitation effect and requires sonosensitizers or nanoparticles that have issues with bioavailability, biostability, and biosafety. In this study, we propose a novel ultrasound-based cancer treatment modality called mechanochemical dynamic therapy (MDT). In MDT, high intensity focused ultrasound (HIFU) delivers mechanical forces to force-responsive moieties of azo mechanophores that are embedded into biocompatible polyethylene glycol (PEG) hydrogel polymers. Upon focal sonication with HIFU, these mechanophores generate highly reactive free radicals (FRs) that are converted to reactive oxygen species (ROSs). The sonicated gels are then placed into in vitro cultures, allowing for the diffusion of ROSs into the cells to induce oxidative cytotoxicity and eventually cell death. Cell proliferation is monitored at 24-hour intervals, and by 72 hours, the sonicated gels produced cell killing effects comparable to lethal doses of H2O2 in both in vitro mouse melanoma (B16F10) and breast cancer (E0771) models. Sonication of control hydrogels that did not contain mechanophores showed minimal cytotoxicity. This study shows the potential of MDT as a drug delivery platform that overcomes the limitations of PDT and SDT and has the potential to be applied synergistically with other current cancer treatments. This is the first demonstration of using HIFU-activated mechanophores to non-invasively deliver cancer therapies with spatiotemporal control. Citation Format: Gun Kim, Qiong Wu, James L. Chu, Emily J. Smith, Michael L. Oelze, King C. Li, Jeffrey S. Moore. Mechanochemical dynamic therapy for focal cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1318.

A Photoresponsive Nanozyme for Synergistic Catalytic Therapy and Dual Phototherapy.

Dual phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has shown a great prospect in cancer treatment. However, its therapeutic effect is restricted by the depth of light penetration in tissue and tumor hypoxia environment. Herein, inspired by the specific response of nanozymes to the tumor microenvironment (TME), a simple and versatile nanozyme-mediated synergistic dual phototherapy nanoplatform (denoted as FePc/HNCSs) is constructed using hollow nitrogen-doped carbon nanospheres (HNCSs) and iron phthalocyanine (FePc). FePc/HNCSs simultaneously exhibit peroxidase (POD)- and catalase (CAT)-like activities, which not only can convert endogenous hydrogen peroxide (H2 O2 ) into highly toxic hydroxyl radicals (•OH) for catalytic therapy, but also decompose H2 O2 to oxygen (O2 ) to enhance O2 -dependent PDT. In addition, their enzyme-like activities are significantly enhanced under light irradiation. Combining with the excellent photothermal effect, FePc/HNCSs realize a high tumor inhibition rate of 96.3%. This strategy opens a new horizon for exploring a more powerful tumor treatment nanoplatform.

Near‐Infrared Light Triggered Silk Fibroin Scaffold for Photothermal Therapy and Tissue Repair of Bone Tumors

AbstractSilk fibroin (SF) has attracted great interest in bone tissue engineering due to its extraordinary characteristics in terms of mechanical properties, biocompatibility, and biodegradability. SF scaffolds are assembled by biocompatible polydopamine nanoparticles at mesoscopic scale, which endows the scaffolds with a near‐infrared (NIR) light response for the treatment of bone tumors. The functionalized SF scaffold not only enhances the significant structure and performance of native SF scaffold for bone treatment and reconstruction, such as primary and mesoscopic structure, multi‐level pores, and biodegradation, as well as biocompatibility but also have excellent photothermal effect leading a significant cytotoxicity to MG63 cancer cells after NIR laser irradiation. Moreover, the penetration of NIR light in tissue is improved using an optical fiber, which demonstrates the obtained scaffolds’ great potential in the application of photothermal therapy.

NIR-II window tracking of hyperglycemia induced intracerebral hemorrhage in cerebral cavernous malformation deficient mice.

Second near infrared (NIR-II) window fluorescence imaging between 1000 and 1700 nm with reduced scattering and autofluorescence and deep tissue light penetration allows early and non-invasive determination of vascular pathologies. Here, we demonstrate in vivo NIR-II imaging techniques for tracking hyperglycaemia-induced Intracerebral Hemorrhage (ICH) and Blood Brain Barrier (BBB) hyperpermeability in Cerebral Cavernous Malformation (CCM) deficient mice (CCM1+/-). We synthesised PEGylated Ag2S quantum dots (QDs) with a bright fluorescent emission peak centred at 1135 nm under an 808 nm NIR light for dynamic imaging of cerebral vasculature in mice and determined the development of ICH and BBB impairment in hyperglycaemic CCM1+/- mice. In vivo optical imaging was conducted with micro-CT (including k-mean cluster analysis) as well as in vivo permeability assays using FITC-dextran perfusion and IgG staining, respectively. The increased BBB permeability in CCM1+/- mice was further demonstrated to be associated with a high-glucose-caused decrease of CCM1 expressions. This study validates that deep-penetrating NIR-II QDs can be used for the tracking of ICH and BBB hyperpermeability in transgenic mice models of cerebral vascular anomalies.

Modelling Optogenetic Subthreshold Effects.

We develop a system-level approach to modelling optogenetic-neurons firing behaviour in in-vivo conditions. This approach contains three sub-modules: 1) a Mie/Rayleigh scattering mode of light penetration in tissue; 2) a classic likelihood Poisson spiking train model; 3) a 4-state model of the Channelrhodopsin-2 (ChR2) channel added to a CA3 neuron Hodgkin-Huxley model. We first investigate opto-neurons lightto-spike mechanisms in an in-vivo model: the background noise (synaptic currents) play a dominant role in generating spikes rather than light intensities as for in-vitro conditions (Typically the required light intensity is less than 0.3 mW/mm2 for in-vivo). Then the spiking fidelity is analyzed for different background noise levels. Next, by combining light penetration profiles, we show how neuron firing rates decay as tissue distance increases, for a 2D dimensional cross-section. This preliminary data clearly demonstrate that at given light stimulation protocol, the maximum effected distance in-vivo is 250 μm with small frequency decay rates, while for in-vitro is 50μm with considerable frequency decay rates. Therefore, the developed model can be used for designing sensible light stimulation strategies in-vivo and opto-electronics systems.

Nanostructure Endows Neurotherapeutic Potential in Optogenetics: Current Development and Future Prospects.

Optogenetics have evolved as a promising tool to control the processes at a cellular level via photons. Specially, it confers a specific control over cellular function through real-time cytomodulation even in freely moving animals. Neuronal stimulation is prerequisite for deep tissue light penetration or insertion of optrode for light illumination to the neurons that have been proven to be compromised due to poor light penetration and invasiveness of the procedure, respectively. In this review, the application of nanotechnology is being elaborated by the use of metal nanoparticles (AuNPs), upconversion nanocrystals (UCNPs), and quantum dots (CdSe) for targeting particular organs or tissues, and their potential to emit a specific light on excitation to overcome the limitations associated with earlier methods has been elucidated. The optothermal and magnetothermal properties, photoluminescence, and higher photostability of nanomaterials are explored in context of therapeutic applicability of optogenetics. The nanostructure characteristics and specific ion channel targeting have shown promising therapeutic potential against neurodegenerative disorders (Alzheimer's, Parkinson's, Huntington's), epilepsy, and blindness. This review compiles mechanical and optical characteristics of nanomaterials that endow superior optogenetic therapeutic potentials to cure immedicable infirmities.

Near Infrared Photoimmunotherapy with Combined Exposure of External and Interstitial Light Sources.

Near infrared photoimmunotherapy (NIR-PIT) is a new target-cell-specific cancer treatment that induces highly selective necrotic/immunogenic cell death after systemic administration of a photoabsorber antibody conjugate and subsequent NIR light exposure. However, the depth of NIR light penetration in tissue (approximately 2 cm) with external light sources limits the therapeutic effects of NIR-PIT. Interstitial light exposure using cylindrical diffusing optical fibers can overcome this limitation. The purpose in this study was to compare three NIR light delivery methods for treating tumors with NIR-PIT using a NIR laser system at an identical light energy; external exposure alone, interstitial exposure alone, and the combination. Panitumumab conjugated with the photoabsorber IRDye-700DX (pan-IR700) was intravenously administered to mice with A431-luc xenografts which are epithelial growth factor receptor (EGFR) positive. One and 2 days later, NIR light was administered to the tumors using one of three methods. Interstitial exposure alone and in combination with external sources showed the greatest decrease in bioluminescence signal intensity. Additionally, the combination of external and interstitial NIR light exposure showed significantly greater tumor size reduction and prolonged survival after NIR-PIT compared to external exposure alone. This result suggested that the combination of external and interstitial NIR light exposure was more effective than externally applied light alone. Although external exposure is the least invasive means of delivering light, the combination of external and interstitial exposures produces superior therapeutic efficacy in tumors greater than 2 cm in depth from the tissue surface.

Brain Photobiomodulation Therapy: a Narrative Review.

Brain photobiomodulation (PBM) therapy using red to near-infrared (NIR) light is an innovative treatment for a wide range of neurological and psychological conditions. Red/NIR light is able to stimulate complex IV of the mitochondrial respiratory chain (cytochrome c oxidase) and increase ATP synthesis. Moreover, light absorption by ion channels results in release of Ca2+ and leads to activation of transcription factors and gene expression. Brain PBM therapy enhances the metabolic capacity of neurons and stimulates anti-inflammatory, anti-apoptotic, and antioxidant responses, as well as neurogenesis and synaptogenesis. Its therapeutic role in disorders such as dementia and Parkinson's disease, as well as to treat stroke, brain trauma, and depression has gained increasing interest. In the transcranial PBM approach, delivering a sufficient dose to achieve optimal stimulation is challenging due to exponential attenuation of light penetration in tissue. Alternative approaches such as intracranial and intranasal light delivery methods have been suggested to overcome this limitation. This article reviews the state-of-the-art preclinical and clinical evidence regarding the efficacy of brain PBM therapy.

The comparative effect of wrapping solid gold nanoparticles and hollow gold nanoparticles with doxorubicin-loaded thermosensitive liposomes for cancer thermo-chemotherapy.

Since conventional chemotherapy is a systemic treatment that affects the body globally and will not concentrate inside the tumor, it causes adverse side effects to patients. In this study, doxorubicin (DOX) together with solid gold nanoparticles (GNPs) or hollow gold nanoparticles (HGNPs), respectively, is loaded inside thermosensitive liposomes (GNPs&DOX-TLs and HGNPs&DOX-TLs), where the GNPs and HGNPs act as a "nanoswitch" for killing tumor cells directly by hyperthermia and triggering DOX release from TLs in the tumor quickly by near infrared laser (NIR) illumination. In addition, this study investigated the photothermal transformation ability, NIR triggered drug release behavior, and the intracellular uptake and cytotoxicity of breast tumor cells and the thermo-chemotherapy mediated by the co-delivery of GNPs&DOX-TLs and HGNPs&DOX-TLs. GNPs and HGNPs had very different light-to-heat transduction efficiencies, while the hollow HGNPs had the advantage of NIR surface plasmon tunability, resulting in the photothermal ablation of tumors with 800 nm light penetration in tissue. The prepared HGNPs&DOX-TLs exhibited a spherical shape with a diameter of 190 nm and a ξ potential of -29 mV, which were steadily dispersed for at least one month. The co-encapsulated DOX was released under hyperthermia caused by NIR-responsive HGNPs and the local drug concentration increased along with the disintegration of the liposomal membrane. This co-delivery of HGNPs&DOX-TLs produced a synergistic cytotoxicity response, thereby enhancing anticancer efficacy 8-fold and increasing the survival time compared to GNPs&DOX-TLs. This work suggested that the co-delivery of HGNPs&DOX-TLs followed by burst-release of DOX using NIR-responsive HGNPs sensitized cancer cells to the chemotherapeutic compound, which provided a novel concept for the combination strategy of chemotherapy and photothermal therapy. These results suggest that the markedly improved therapeutic efficacy and decreased systemic toxicity of the NPs presented in this study hold significant potential for future cancer treatment.

Shortwave Infrared in Vivo Imaging with Gold Nanoclusters.

The use of visible/NIR-emitting gold nanoclusters (Au NCs), previously proposed for in vivo imaging, has been limited to some extent by low quantum yields (QYs) and the limited penetration of visible light in tissue. Here we report short wavelength infrared (SWIR, λ = 1-2 μm) emitting Au NCs with a good photoluminescence QY for this wavelength range (0.6% to 3.8% for λem = 1000 to 900 nm) and excellent stability under physiological conditions. We show that surface ligand chemistry is critical to achieving these properties. We demonstrate the potential of these SWIR-emitting Au NCs for in vivo imaging in mice. The Au NCs have a hydrodynamic diameter that is small (∼5 nm) enough that they exhibit a rapid renal clearance, and images taken in the SWIR region show better resolution of the blood vessels than in the NIR region.