Shining Gold Nanostars: From Cancer Diagnostics to Photothermal Treatment and Immunotherapy.

Cancer has been a significant threat to human health with more than eight million deaths each year in the world. There is an urgent need to develop novel methods to improve cancer management. Biocompatible gold nanostars (GNS) with tip-enhanced electromagnetic and optical properties have been developed and applied for multifunctional cancer diagnostics and therapy (theranostics). The GNS platform can be used for multiple sensing, imaging and treatment modalities, such as surface-enhanced Raman scattering, two-photon photoluminescence, magnetic resonance imaging and computed tomography as well as photothermal therapy and immunotherapy. GNS-mediated photothermal therapy combined with checkpoint immunotherapy has been found to reverse tumor-mediated immunosuppression, leading to the treatment of not only primary tumors but also cancer metastasis as well as inducing effective long-lasting immunity, i.e. an anticancer 'vaccine' effect.

Multifunctional gold nanostars for molecular imaging and cancer therapy.

Plasmonics-active gold nanoparticles offer excellent potential in molecular imaging and cancer therapy. Among them, gold nanostars (AuNS) exhibit cross-platform flexibility as multimodal contrast agents for macroscopic X-ray computer tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), as well as nanoprobes for photoacoustic tomography (PAT), two-photon photoluminescence (TPL), and surface-enhanced Raman spectroscopy (SERS). Their surfactant-free surface enables versatile functionalization to enhance cancer targeting, and allow triggered drug release. AuNS can also be used as an efficient platform for drug carrying, photothermal therapy, and photodynamic therapy (PDT). This review paper presents the latest progress regarding AuNS as a promising nanoplatform for cancer nanotheranostics. Future research directions with AuNS for biomedical applications will also be discussed.

In vivo detection of SERS-encoded plasmonic nanostars in human skin grafts and live animal models.

Surface-enhanced Raman scattering (SERS)-active plasmonic nanomaterials have become a promising agent for molecular imaging and multiplex detection. Among the wide variety of plasmonics-active nanoparticles, gold nanostars offer unique plasmon properties that efficiently induce strong SERS signals. Furthermore, nanostars, with their small core size and multiple long thin branches, exhibit high absorption cross sections that are tunable in the near-infrared region of the tissue optical window, rendering them efficient for in vivo spectroscopic detection. This study investigated the use of SERS-encoded gold nanostars for in vivo detection. Ex vivo measurements were performed using human skin grafts to investigate the detection of SERS-encoded nanostars through tissue. We also integrated gold nanostars into a biocompatible scaffold to aid in performing in vivo spectroscopic analyses. In this study, for the first time, we demonstrate in vivo SERS detection of gold nanostars using small animal (rat) as well as large animal (pig) models. The results of this study establish the usefulness and potential of SERS-encoded gold nanostars for future use in long-term in vivo analyte sensing.

A Plasmonic Gold Nanostar Theranostic Probe for In Vivo Tumor Imaging and Photothermal Therapy.

Nanomedicine has attracted increasing attention in recent years, because it offers great promise to provide personalized diagnostics and therapy with improved treatment efficacy and specificity. In this study, we developed a gold nanostar (GNS) probe for multi-modality theranostics including surface-enhanced Raman scattering (SERS) detection, x-ray computed tomography (CT), two-photon luminescence (TPL) imaging, and photothermal therapy (PTT). We performed radiolabeling, as well as CT and optical imaging, to investigate the GNS probe's biodistribution and intratumoral uptake at both macroscopic and microscopic scales. We also characterized the performance of the GNS nanoprobe for in vitro photothermal heating and in vivo photothermal ablation of primary sarcomas in mice. The results showed that 30-nm GNS have higher tumor uptake, as well as deeper penetration into tumor interstitial space compared to 60-nm GNS. In addition, we found that a higher injection dose of GNS can increase the percentage of tumor uptake. We also demonstrated the GNS probe's superior photothermal conversion efficiency with a highly concentrated heating effect due to a tip-enhanced plasmonic effect. In vivo photothermal therapy with a near-infrared (NIR) laser under the maximum permissible exposure (MPE) led to ablation of aggressive tumors containing GNS, but had no effect in the absence of GNS. This multifunctional GNS probe has the potential to be used for in vivo biosensing, preoperative CT imaging, intraoperative detection with optical methods (SERS and TPL), as well as image-guided photothermal therapy.

Plasmonic gold nanostars for multi-modality sensing and diagnostics.

Gold nanostars (AuNSs) are unique systems that can provide a novel multifunctional nanoplatform for molecular sensing and diagnostics. The plasmonic absorption band of AuNSs can be tuned to the near infrared spectral range, often referred to as the "tissue optical window", where light exhibits minimal absorption and deep penetration in tissue. AuNSs have been applied for detecting disease biomarkers and for biomedical imaging using multi-modality methods including surface-enhanced Raman scattering (SERS), two-photon photoluminescence (TPL), magnetic resonance imaging (MRI), positron emission tomography (PET), and X-ray computer tomography (CT) imaging. In this paper, we provide an overview of the recent development of plasmonic AuNSs in our laboratory for biomedical applications and highlight their potential for future translational medicine as a multifunctional nanoplatform.

SERS nanosensors and nanoreporters: golden opportunities in biomedical applications.

This article provides an overview of recent developments and applications of surface-enhanced Raman scattering (SERS) nanosensors and nanoreporters in our laboratory for use in biochemical monitoring, medical diagnostics, and therapy. The design and fabrication of different types of plasmonics-active nanostructures are discussed. The SERS nanosensors can be used in various applications including pH sensing, protein detection, and gene diagnostics. For DNA detection the 'Molecular Sentinel' nanoprobe can be used as a homogenous bioassay in solution or on a chip platform. Gold nanostars provide an excellent multi-modality theranostic platform, combining Raman and SERS with two-photon luminescence (TPL) imaging as well as photodynamic therapy (PDT), and photothermal therapy (PTT). Plasmonics-enhanced and optically modulated delivery of nanostars into brain tumor in live animals was demonstrated; photothermal treatment of tumor vasculature may induce inflammasome activation, thus increasing the permeability of the blood brain-tumor barrier. The imaging method using TPL of gold nanostars provides an unprecedented spatial selectivity for enhanced targeted nanostar delivery to cortical tumor tissue. A quintuple-modality nanoreporter based on gold nanostars for SERS, TPL, magnetic resonance imaging (MRI), computed tomography (CT), and PTT has recently been developed. The possibility of combining spectral selectivity and high sensitivity of the SERS process with the inherent molecular specificity of bioreceptor-based nanoprobes provides a unique multiplex and selective diagnostic modality. Several examples of optical detection using SERS in combination with other detection and treatment modalities are discussed to illustrate the usefulness and potential of SERS nanosensors and nanoreporters for medical applications.

Plasmonic nanoprobes: from chemical sensing to medical diagnostics and therapy.

This article provides an overview of the development and applications of plasmonics-active nanoprobes in our laboratory for chemical sensing, medical diagnostics and therapy. Molecular Sentinel nanoprobes provide a unique tool for DNA/RNA biomarker detection both in a homogeneous solution or on a chip platform for medical diagnostics. The possibility of combining spectral selectivity and high sensitivity of the surface-enhanced Raman scattering (SERS) process with the inherent molecular specificity of nanoprobes provides an important multiplex diagnostic modality. Gold nanostars can provide an excellent multi-modality platform, combining two-photon luminescence with photothermal therapy as well as Raman imaging with photodynamic therapy. Several examples of optical detection using SERS and photonics-based treatments are presented to illustrate the usefulness and potential of the plasmonic nanoprobes for theranostics, which seamlessly combines diagnostics and therapy.

Plasmonic nanoprobes for intracellular sensing and imaging.

Recent advances in integrating nanotechnology and optical microscopy offer great potential in intracellular applications with improved molecular information and higher resolution. Continuous efforts in designing nanoparticles with strong and tunable plasmon resonance have led to new developments in biosensing and bioimaging, using surface-enhanced Raman scattering and two-photon photoluminescence. We provide an overview of the nanoprobe design updates, such as controlling the nanoparticle shape for optimal plasmon peak position; optical sensing and imaging strategies for intracellular nanoparticle detection; and addressing practical challenges in cellular applications of nanoprobes, including the use of targeting agents and control of nanoparticle aggregation.

Physical and structural basis for the strong interactions of the -ImPy- central pairing motif in the polyamide f-ImPyIm.

The polyamide f-ImPyIm has a higher affinity for its cognate DNA than either the parent analogue, distamycin A (10-fold), or the structural isomer, f-PyImIm (250-fold), has for its respective cognate DNA sequence. These findings have led to the formulation of a two-letter polyamide "language" in which the -ImPy- central pairings associate more strongly with Watson-Crick DNA than -PyPy-, -PyIm-, and -ImIm-. Herein, we further characterize f-ImPyIm and f-PyImIm, and we report thermodynamic and structural differences between -ImPy- (f-ImPyIm) and -PyIm- (f-PyImIm) central pairings. DNase I footprinting studies confirmed that f-ImPyIm is a stronger binder than distamycin A and f-PyImIm and that f-ImPyIm preferentially binds CGCG over multiple competing sequences. The difference in the binding of f-ImPyIm and f-PyImIm to their cognate sequences was supported by the Na(+)-dependent nature of DNA melting studies, in which significantly higher Na(+) concentrations were needed to match the ability of f-ImPyIm to stabilize CGCG with that of f-PyImIm stabilizing CCGG. The selectivity of f-ImPyIm beyond the four-base CGCG recognition site was tested by circular dichroism and isothermal titration microcalorimetry, which shows that f-ImPyIm has marginal selectivity for (A.T)CGCG(A.T) over (G.C)CGCG(G.C). In addition, changes adjacent to this 6 bp binding site do not affect f-ImPyIm affinity. Calorimetric studies revealed that binding of f-ImPyIm, f-PyImIm, and distamycin A to their respective hairpin cognate sequences is exothermic; however, changes in enthalpy, entropy, and heat capacity (DeltaC(p)) contribute differently to formation of the 2:1 complexes for each triamide. Experimental and theoretical determinations of DeltaC(p) for binding of f-ImPyIm to CGCG were in good agreement (-142 and -177 cal mol(-)(1) K(-)(1), respectively). (1)H NMR of f-ImPyIm and f-PyImIm complexed with their respective cognate DNAs confirmed positively cooperative formation of distinct 2:1 complexes. The NMR results also showed that these triamides bind in the DNA minor groove and that the oligonucleotide retains the B-form conformation. Using minimal distance restraints from the NMR experiments, molecular modeling and dynamics were used to illustrate the structural complementarity between f-ImPyIm and CGCG. Collectively, the NMR and ITC experiments show that formation of the 2:1 f-ImPyIm-CGCG complex achieves a structure more ordered and more thermodynamically favored than the structure of the 2:1 f-PyImIm-CCGG complex.