Luminescent Gold Nanoparticles Research Articles

Intrarenal pH-Responsive Self-Assembly of Luminescent Gold Nanoparticles for Diagnosis of Early Kidney Injury.

Metabolic acidosis-induced kidney injury (MAKI) is asymptomatic and lack of clinical biomarkers in early stage, but rapidly progresses to severe renal fibrosis and ultimately results in end-stage kidney failure. Therefore, developing rapid and noninvasive strategies direct responsive to renal tubular acidic microenvironment rather than delayed biomarkers are essential for timely renoprotective interventions. Herein, we develop pH-responsive luminescent gold nanoparticles (p-AuNPs) in the second near-infrared emission co-coated with 2,3-dimethylaleic anhydride conjugated β-mercaptoethylamine and cationic 2-diethylaminoethanethiol hydrochloride, which showed sensitive pH-induced charge reversal and intrarenal self-assembly for highly sensitive and long-time (~24 h) imaging of different stages of MAKI. By integrating advantages of pH-induced intrarenal self-assembly and enhanced interactions between pH-triggered positively charged p-AuNPs and renal tubular cells, the early- and late-stage MAKI could be differentiated rapidly within 10 min post-injection (p.i.) with contrast index (CI) of 3.5 and 4.3, respectively. The corresponding maximum CI could reach 5.1 and 9.2 at 12 h p.i., respectively. Furthermore, p-AuNPs were demonstrated to effectively real-time monitor progressive recovery of kidney injury in MAKI mice after therapy, and also exhibit outstanding capabilities for drug screening. This pH-responsive strategy showed great promise for feedback on kidney dysfunction progression, opening new possibilities for early-stage diagnosis of pH-related diseases.

Intrarenal pH‐Responsive Self‐Assembly of Luminescent Gold Nanoparticles for Diagnosis of Early Kidney Injury

Metabolic acidosis‐induced kidney injury (MAKI) is asymptomatic and lack of clinical biomarkers in early stage, but rapidly progresses to severe renal fibrosis and ultimately results in end‐stage kidney failure. Therefore, developing rapid and noninvasive strategies direct responsive to renal tubular acidic microenvironment rather than delayed biomarkers are essential for timely renoprotective interventions. Herein, we develop pH‐responsive luminescent gold nanoparticles (p‐AuNPs) in the second near‐infrared emission co‐coated with 2,3‐dimethylaleic anhydride conjugated β‐mercaptoethylamine and cationic 2‐diethylaminoethanethiol hydrochloride, which showed sensitive pH‐induced charge reversal and intrarenal self‐assembly for highly sensitive and long‐time (~24 h) imaging of different stages of MAKI. By integrating advantages of pH‐induced intrarenal self‐assembly and enhanced interactions between pH‐triggered positively charged p‐AuNPs and renal tubular cells, the early‐ and late‐stage MAKI could be differentiated rapidly within 10 min post‐injection (p.i.) with contrast index (CI) of 3.5 and 4.3, respectively. The corresponding maximum CI could reach 5.1 and 9.2 at 12 h p.i., respectively. Furthermore, p‐AuNPs were demonstrated to effectively real‐time monitor progressive recovery of kidney injury in MAKI mice after therapy, and also exhibit outstanding capabilities for drug screening. This pH‐responsive strategy showed great promise for feedback on kidney dysfunction progression, opening new possibilities for early‐stage diagnosis of pH‐related diseases.

Renal-clearable luminescent gold nanoparticles incorporating active and bio-orthogonal tumor-targeting for drug delivery and controlled release

The use of ultrasmall gold nanoparticles (AuNPs) as drug delivery systems (DDSs) represents certain challenges, including limited targeting efficiency, uncontrolled drug release, and off-target drug toxicity. Herein, we synthesize a series of second near-infrared (NIR-II) region emitting AuNPs by incorporating both c(RGDfC) peptide and cucurbit[7]uril (CB[7]) for active and bio-orthogonal tumor-targeting, respectively. The CB[7]/c(RGDfC)-AuNPs exhibited rapid tumor accumulation and prolonged retention, which were utilized as nanocarriers to load oxaliplatin (OX) to afford OX@CB[7]/c(RGDfC)-AuNPs for targeted drug delivery and tumor chemotherapy. The mice treated with OX@CB[7]/c(RGDfC)-AuNPs achieved superior therapeutic outcomes compared to three times the dose of OX treatment (H-OX group). Meanwhile, the AuNPs showed excellent biosafety as opposed to obvious hepatotoxicity and severe hepatorenal toxicity observed in the mice treated with low dose of OX and H-OX, respectively. This renal-clearable DDS holds promise for precise drug delivery and controlled release, offering new perspectives and methods for clinical cancer treatment.

Transcytosis-Based Renal Tubular Reabsorption of Luminescent Gold Nanoparticles for Enhanced Tumor Imaging.

Transcytosis-based tubular reabsorption of endogenous proteins is a well-known energy-saving pathway that prevents nutrient loss. However, utilization of this well-known reabsorption pathway for the delivery of exogenous nanodrugs remains a challenge. In this study, using the surface mimic strategy of a specific PEPT1/2-targeted Gly-Sar peptide as a ligand, renal-clearable luminescent gold nanoparticles (P-AuNPs) were developed as protein mimics to investigate the transcytosis-based tubular reabsorption of exogenous substances. By regulating the influential factors (H+ content in tubular lumens and PEPT1/2 transporter counts in tubular cells) of Gly-Sar-mediated transcytosis, the specific and efficient interaction between P-AuNPs and renal tubular cells was demonstrated both in vitro and in vivo. Efficient transcellular transportation significantly guided the reabsorption of P-AuNPs back into the bloodstream, which enhanced the blood concentration and bioavailability of nanoparticles, contributing to high-contrast tumor imaging.

Transcytosis‐Based Renal Tubular Reabsorption of Luminescent Gold Nanoparticles for Enhanced Tumor Imaging

AbstractTranscytosis‐based tubular reabsorption of endogenous proteins is a well‐known energy‐saving pathway that prevents nutrient loss. However, utilization of this well‐known reabsorption pathway for the delivery of exogenous nanodrugs remains a challenge. In this study, using the surface mimic strategy of a specific PEPT1/2‐targeted Gly−Sar peptide as a ligand, renal‐clearable luminescent gold nanoparticles (P−AuNPs) were developed as protein mimics to investigate the transcytosis‐based tubular reabsorption of exogenous substances. By regulating the influential factors (H+ content in tubular lumens and PEPT1/2 transporter counts in tubular cells) of Gly−Sar‐mediated transcytosis, the specific and efficient interaction between P−AuNPs and renal tubular cells was demonstrated both in vitro and in vivo. Efficient transcellular transportation significantly guided the reabsorption of P−AuNPs back into the bloodstream, which enhanced the blood concentration and bioavailability of nanoparticles, contributing to high‐contrast tumor imaging.

Luminescent Gold Nanoparticles with Discrete DNA Valences for Precisely Controlled Transport at the Subcellular Level.

Ultrasmall luminescent gold nanoparticles (AuNPs) with excellent capabilities to cross biological barriers offer great promise in designing intelligent model nanomedicines for investigating structure-property relationships at the subcellular level. However, the strict surface controllability of ultrasmall AuNPs is challenging because of their small size. Herein, we report a facile in situ method for precisely controlling DNA aptamer valences on the surface of luminescent AuNPs with emission in the second near-infrared window using a phosphorothioate-modified DNA aptamer, AS1411, as a template. The discrete DNA aptamer number of AS1411-functionalized AuNPs (AS1411-AuNPs, ≈1.8 nm) with emission at 1030 nm was controlled in one aptamer (V1), two aptamers (V2), and four aptamers (V4). It was then discovered that not only the tumor-targeting efficiencies but also the subcellular transport of AS1411-AuNPs were precisely dependent on valences. A slight increase in valence from V1 to V2 increased tumor-targeting efficiencies and resulted in higher nucleus accumulation, whereas a further increase in valence (e.g., V4) significantly increased tumor-targeting efficiencies and led to higher cytomembrane accumulation. These results provide a basis for the strict surface control of nanomedicines in the precise regulation of in vivo transport at the subcellular level and their translation into clinical practice in the future.

Luminescent Gold Nanoparticles with Discrete DNA Valences for Precisely Controlled Transport at the Subcellular Level

AbstractUltrasmall luminescent gold nanoparticles (AuNPs) with excellent capabilities to cross biological barriers offer great promise in designing intelligent model nanomedicines for investigating structure–property relationships at the subcellular level. However, the strict surface controllability of ultrasmall AuNPs is challenging because of their small size. Herein, we report a facile in situ method for precisely controlling DNA aptamer valences on the surface of luminescent AuNPs with emission in the second near‐infrared window using a phosphorothioate‐modified DNA aptamer, AS1411, as a template. The discrete DNA aptamer number of AS1411‐functionalized AuNPs (AS1411‐AuNPs, ≈1.8 nm) with emission at 1030 nm was controlled in one aptamer (V1), two aptamers (V2), and four aptamers (V4). It was then discovered that not only the tumor‐targeting efficiencies but also the subcellular transport of AS1411‐AuNPs were precisely dependent on valences. A slight increase in valence from V1 to V2 increased tumor‐targeting efficiencies and resulted in higher nucleus accumulation, whereas a further increase in valence (e.g., V4) significantly increased tumor‐targeting efficiencies and led to higher cytomembrane accumulation. These results provide a basis for the strict surface control of nanomedicines in the precise regulation of in vivo transport at the subcellular level and their translation into clinical practice in the future.

Exploration of surface chemistry effects on the biodistribution and pharmacokinetics of dual-ligand luminescent gold nanoparticles

Understanding how surface chemistry influences gold nanoparticle (AuNP) biodistribution and pharmacokinetics is critical for the design of Au-based nanoprobes for in vivo sensing and imaging. AuNPs prepared using a single surface ligand have been widely studied; however, limited work has been reported for luminescent AuNPs decorated with multiple surface ligands. Herein, we describe the synthesis and characterization of four dual-ligand luminescent AuNPs prepared using a combination of four thiol-containing ligands (GSH, MUA, tDK, tDY). The impact of surface chemistry on in vivo biodistribution and pharmacokinetics was then investigated for each dual-ligand AuNP type using a mouse model. Our results indicate that variation of one of the two surface ligands can exert a significant influence on the pharmacokinetics and biodistribution of the AuNPs. Interestingly, we observed changes in biodistribution in the lung and digestive organs, as well as blood circulation time. These results are expected to inform the future de novo design of dual-ligand luminescent AuNPs for in vivo applications.

Glutathione-Activated Emission of Ultrasmall Gold Nanoparticles in the Second Near-Infrared Window for Imaging of Early Kidney Injury.

Biomarker-activatable luminescent probes with high sensitivity and specificity show great promise in advanced bioimaging applications. However, the lack of stable biomarkers at an early stage is currently a major obstacle for sensitive early disease imaging. Herein, we develop a facile in vivo ligand exchange strategy to achieve renal-clearable activatable luminescent gold nanoparticles (AuNPs), which are independent of biomarkers for sensitive and long-time imaging of early kidney injury. Significantly activated emission in the second near-infrared region (∼1026 nm) is realized from the ligand exchange of triphenylphosphine-3,3',3″-trisulfonic acid (TPPTS)-coated AuNPs (∼1.4 nm, TPPTS-AuNPs) with quantitative amounts of glutathione (GSH). The abundant GSH in cells, particularly in liver sinusoids, is then demonstrated successfully to activate the emission of TPPTS-AuNPs with an extremely low background for both cell imaging and in vivo visualization of visceral organs (e.g., liver and kidneys). In addition, the in vivo GSH-exchanged TPPTS-AuNPs show enhanced interactions with acidic renal tubular epithelial cells, resulting in sensitive (contrast index, ∼3.9) and long-time (>6.5 h) noninvasive monitoring of acidosis-induced early kidney injury. This facile ligand exchange strategy opens new possibilities for designing activatable luminescent probes independent of biomarkers for earlier disease diagnosis and treatment.

Highly Controllable Nanoassemblies of Luminescent Gold Nanoparticles with Abnormal Disassembly-Induced Emission Enhancement for In Vivo Imaging Applications.

Assembly-induced emission enhancement has been widely observed for luminophors but it causes emission decrease after disassembly. The construction of unique nanoassemblies with disassembly-induced emission enhancement (DIEE) is demanded. Herein, by taking advantages of alterable siloxane bridge crosslinking states, we report a facile strategy to fabricate water-soluble nanoassemblies of luminescent gold nanoparticles (AuNPs) with abnormal DIEE. The fabricated AuNP nanoassemblies with dominant interparticle crosslinking showed a redshifted emission at ≈1070 nm with quantum yields (QYs) of 1.8 %. After disassembly, the nanoassemblies with increased intraparticle crosslinking exhibited a unique DIEE (>6 folds, QYs, 12 %) due to the enhanced ligand-to-metal charge transition. Besides, the disassembly facilitated renal clearance of AuNPs to reduce nonspecific retention in the body, opening new possibilities for designing highly emissive renal-clearable nanostructures toward more bioapplications.

Highly Controllable Nanoassemblies of Luminescent Gold Nanoparticles with Abnormal Disassembly‐Induced Emission Enhancement for In Vivo Imaging Applications

AbstractAssembly‐induced emission enhancement has been widely observed for luminophors but it causes emission decrease after disassembly. The construction of unique nanoassemblies with disassembly‐induced emission enhancement (DIEE) is demanded. Herein, by taking advantages of alterable siloxane bridge crosslinking states, we report a facile strategy to fabricate water‐soluble nanoassemblies of luminescent gold nanoparticles (AuNPs) with abnormal DIEE. The fabricated AuNP nanoassemblies with dominant interparticle crosslinking showed a redshifted emission at ≈1070 nm with quantum yields (QYs) of 1.8 %. After disassembly, the nanoassemblies with increased intraparticle crosslinking exhibited a unique DIEE (>6 folds, QYs, 12 %) due to the enhanced ligand‐to‐metal charge transition. Besides, the disassembly facilitated renal clearance of AuNPs to reduce nonspecific retention in the body, opening new possibilities for designing highly emissive renal‐clearable nanostructures toward more bioapplications.

Luminescent Gold Nanoparticles with Controllable Hydrophobic Interactions.

The construction of luminescent gold nanoparticles (AuNPs) with highly redshifted emission in the second near-infrared window (NIR-II) and good biocompatibility is still challenging. Herein, using an amphiphilic block copolymer (ABC) template with controllable hydrophobic interactions in the diverse forms of unimers and micelles, we report a facile strategy for redshifting the emission and enhancing the biological interactions of luminescent AuNPs. While the uniform clusters of NIR-II AuNPs are formed in situ inside the hydrophobic cores of ABC micelles with strong interparticle hydrophobic interactions and enhanced emission at 1080 nm with a high quantum yield (QY) of 1.6%, the rigid NIR-II AuNPs are generated with strong intraparticle hydrophobic interactions as ABC unimers on the surface, leading to a redshifted emission of 1280 nm with a QY of 0.25% and enhancing the affinities toward injured intestinal mucosa in colitis imaging. These findings open new possibilities for the design of highly redshifted luminescent AuNPs with enhanced biological interactions.

Surface-regulated injection dose response of ultrasmall luminescent gold nanoparticles.

With the rapid growth of the use of renal-clearable nanomedicines in disease targeting and therapy, a fundamental understanding of their injection dose responses is of great importance for future translation to clinical settings. Using glutathione-coated gold nanoparticles (GS-AuNPs) as a renal-clearable nanomedicine model for the construction of ultrasmall AuNPs with different serum protein binding abilities, we discover that the concentration-dependent serum protein binding capabilities endow GS-AuNPs with a more sensitive response to injection dose than NPs resistant to serum protein binding, resulting in greatly improved tumor-targeting efficiencies during both single and repeated low-dose injections; the performance is also distinct from nonrenal-clearable AuNPs coated with serum protein, which show decreased tumor-targeting efficiency with a decrease in the injection dose.

Enhanced Ultrasound Contrast of Renal‐Clearable Luminescent Gold Nanoparticles

AbstractRenal‐clearable nanoparticles are typically fast eliminated through the free glomerular filtration, which show weak interaction with the renal compartments and negligible ultrasound signals, raising challenges in direct imaging of kidney diseases. Here, we report the ultrasmall renal‐clearable luminescent gold nanoparticles (AuNPs) with both pH‐induced charge reversal and aggregation properties, and discover that enhanced ultrasound contrast could be facilely acquired through the increased tubular reabsorption and in situ aggregation of AuNPs in renal tubule cells in injured kidneys. The tuning elimination pathway of the renal‐clearable luminescent AuNPs is further demonstrated to provide a synergistical fluorescence and ultrasound imaging strategy for diagnosing early kidney injury with precise anatomical information.

Enhanced Ultrasound Contrast of Renal-Clearable Luminescent Gold Nanoparticles.

Renal-clearable nanoparticles are typically fast eliminated through the free glomerular filtration, which show weak interaction with the renal compartments and negligible ultrasound signals, raising challenges in direct imaging of kidney diseases. Here, we report the ultrasmall renal-clearable luminescent gold nanoparticles (AuNPs) with both pH-induced charge reversal and aggregation properties, and discover that enhanced ultrasound contrast could be facilely acquired through the increased tubular reabsorption and in situ aggregation of AuNPs in renal tubule cells in injured kidneys. The tuning elimination pathway of the renal-clearable luminescent AuNPs is further demonstrated to provide a synergistical fluorescence and ultrasound imaging strategy for diagnosing early kidney injury with precise anatomical information.

Growth regulation of luminescent gold nanoparticles directed from amphiphilic block copolymers: highly-controlled nanoassemblies toward tailored in-vivo transport

The understanding of amphiphilic block copolymers (ABC) in encapsulation and transport of inorganic nanomedicines is highly desired. Still, it remains limited due to the challenges in the fabrication of nanoassemblies (NAs) with highly-controlled shape and loading of nanoparticles. Herein, through growth regulation of luminescent gold nanoparticles (AuNPs) by different reductants with ABC pluronic F127 as a template, a straightforward strategy is reported for in-situ fabrication of three well-controlled gold NAs (AuNAs) that display tunable shapes from spherical to elongated nanostructures and controllable surface chemistry and loading of AuNPs with distinct emissions but identical individual AuNP size. The three AuNAs exhibit tailored in-vivo transport behaviours: those with spherical shape and more hydrophilic surface show longer blood retention with higher tumor-targeting efficiency (∼25.3% injection dose/g) and excellent long-term near-infrared tumor imaging even after 96 h post-injection. These findings provide a useful guidance in designing specific nanostructures for future nanomedicine transport.

Precisely Regulated Luminescent Gold Nanoparticles for Identification of Cancer Metastases.

The nanoprobes for identification of cancer metastases in the mononuclear phagocyte system (MPS) organs are of significant importance but are limited due to the long-standing challenge of low tumor-targeting specificity with inadequate targeting efficiency and high nonspecific accumulation. Here, we report a surface regulation strategy that integrates the tumor-acidity-activated charge-reversal behavior and precise control in both hydrodynamic diameter (HD) and surface charge on ultrasmall luminescent gold nanoparticles (AuNPs) to achieve significantly high tumor-targeting specificity. The precise regulation of AuNPs to a rational HD and surface charge could rapidly and selectively recognize small metastatic tumors (∼1 mm) in liver and lung with high signal-to-noise ratios of 4.6 and 4.5, respectively. These results help further understand the in vivo transport of nanoprobes and provide guidance for design of translatable nanosized nanomedicines in cancer metastasis theranostics.

Strict DNA Valence Control in Ultrasmall Thiolate-Protected Near-Infrared-Emitting Gold Nanoparticles.

Realizing robust DNA functionalization with strict valence control in the sub-2-nm thiolate-protected luminescent gold nanoparticles (AuNPs) is highly demanded but remains unsolved due to their unique Au(0) core and Au(I)-S shell structures. Herein, we report a facile strategy using phosphorothioates (ps)-modified DNA (psDNA) as a template for in situ growth of near-infrared (NIR)-emitting AuNPs with precisely controlled DNA valence. In addition, the particle size could be finely tuned in ultrasmall ranges from 1.3 to 2.6 nm with regulation of the ps length of psDNA. The ultrasmall NIR-emitting AuNPs bearing strict DNA valence are also demonstrated to be as powerful building block for well-organized one-dimensional assembly and optical probe for targeted cellular imaging. Such a facile strategy in decoration of luminescent AuNPs with strict DNA valence provides a new pathway for development of surface-functionalizable ultrasmall metal nanoplatforms toward various downstream applications.

Green and transparent cellulose nanofiber substrate-supported luminescent gold nanoparticles: A stable and sensitive solid-state sensing membrane for Hg(II) detection

Mercury(II) pollution is a growing threat to the environment and humanity. But most of the solution-based Au nanomaterial sensors suffer from low stability seriously. Here, inspired by high-affinity metallophilic Hg2+–Au(I) interaction mechanism, we introduced a transparent cellulose nanofiber matrix-supported luminescent gold nanoparticle (AuNPs) stable sensing membrane. In this solid-state membrane, the AuNPs with strong red fluorescence emission were synthesized as the sensor unit. Cellulose nanofibrilatted (CNF) matrix was fabricated as the supporting substrate. With a large specific surface area, the nanostructured CNF matrix offers abundant immobilizing spots to the sensor unit of AuNPs. More importantly, the excited fluorescence can escape directly without apparent scattering loss due to the high transparency of the CNF substrate. With strong emission of the AuNPs, coupled with abundant AuNP immobilizing spots and high transparency of the CNF substrate, the fluorescence signaling path was manipulated sequentially from signal generation, transmission until to quenching, resulting in the membrane demonstrates high sensitivity, selectivity, and stability. The detection limit of 1.0 nM is markedly lower than the threshold level of 10.0 nM permitted by US EPA. Aided with the high-performance membrane, the detection of Hg(II) becomes simple, fast, easy handing, and green. We envision the membrane will be an attractive material for Hg(II) monitor.

Renal Clearable Gold Nanoparticle-Functionalized Silk Film for in vivo Fluorescent Temperature Mapping.

Implantable optical sensing devices that can continuously monitor physiological temperature changes hold great potential toward applications in healthcare and medical field. Here, we present a conceptual foundation for the design of biocompatible temperature sensing device by integrating renal clearable luminescent gold nanoparticles (AuNPs) with silk film (AuNPs-SF). We found that the AuNPs display strong temperature dependence in both near-IR fluorescence intensity and lifetime over a large temperature range (10–60°C), with a fluorescence intensity sensitivity of 1.72%/°C and lifetime sensitivity of 0.09 μs/°C. When integrated, the AuNPs with biocompatible silk film are implanted in the dorsal region of mice. The fluorescence imaging of the AuNPs-SF in the body shows a linear relationship between the average fluorescence intensity and temperature. More importantly, <3.68% ID gold are left in the body, and no adverse effect is observed for 8 weeks. This AuNPs-SF can be potentially used as a flexible, biocompatible, and implantable sensing device for in vivo temperature mapping.