Gold nanoparticles have been used in biomedical applications since their first colloidal syntheses more than three centuries ago. However, over the past two decades, their beautiful colors and unique electronic properties have also attracted tremendous attention due to their historical applications in art and ancient medicine and current applications in enhanced optoelectronics and photovoltaics. In spite of their modest alchemical beginnings, gold nanoparticles exhibit physical properties that are truly different from both small molecules and bulk materials, as well as from other nanoscale particles. Their unique combination of properties is just beginning to be fully realized in range of medical diagnostic and therapeutic applications. This critical review will provide insights into the design, synthesis, functionalization, and applications of these artificial molecules in biomedicine and discuss their tailored interactions with biological systems to achieve improved patient health. Further, we provide a survey of the rapidly expanding body of literature on this topic and argue that gold nanotechnology-enabled biomedicine is not simply an act of ‘gilding the (nanomedicinal) lily’, but that a new ‘Golden Age’ of biomedical nanotechnology is truly upon us. Moving forward, the most challenging nanoscience ahead of us will be to find new chemical and physical methods of functionalizing gold nanoparticles with compounds that can promote efficient binding, clearance, and biocompatibility and to assess their safety to other biological systems and their long-term term effects on human health and reproduction (472 references).

The golden age: gold nanoparticles for biomedicine

Nanostructures, methods of preparing nanostructures, methods of detecting targets in subjects, and methods of treating diseases in subjects, are disclosed An embodiment, among others, of the nanostructure includes a metallic gold surface- enhanced Raman scattering nanoparticle, a Raman reporter and a protection structure The protection structure may include a thiol-polyethylene glycol to which may be attached a target-specific probe

http://basicmed.med.ncku.edu.tw/admin/up_img/970425-3.pdf

In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags

The discovery of the enhancement of Raman scattering by molecules adsorbed on nanostructured metal surfaces is a landmark in the history of spectroscopic and analytical techniques. Significant experimental and theoretical effort has been directed toward understanding the surface-enhanced Raman scattering (SERS) effect and demonstrating its potential in various types of ultrasensitive sensing applications in a wide variety of fields. In the 45 years since its discovery, SERS has blossomed into a rich area of research and technology, but additional efforts are still needed before it can be routinely used analytically and in commercial products. In this Review, prominent authors from around the world joined together to summarize the state of the art in understanding and using SERS and to predict what can be expected in the near future in terms of research, applications, and technological development. This Review is dedicated to SERS pioneer and our coauthor, the late Prof. Richard Van Duyne, whom we lost during the preparation of this article.

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Present and Future of Surface-Enhanced Raman Scattering

CONTENTS 1. Introduction 1.1. Fundamental Theory of Surface-Enhanced Raman Scattering 1.2. Optical Properties of SERS Tags 2. Synthesis of SERS Tags 2.1. Noble Metal Nanosubstrates 2.1.1. Single Particle-Based SERS Substrates 2.1.2. Nanoparticle Cluster-Based Substrates 2.2. Raman Reporter Molecules 2.2.1. Selection Principles and Reporter Types 2.2.2. Self-Assembled Monolayer Coverage Strategy 2.3. Surface Coating for Protection 2.3.1. Biomolecule Coating 2.3.2. Polymer Coating 2.3.3. Liposome Coating 2.3.4. Silica Coating 2.4. Attachment of Targeting Molecules 3. Bioanalysis Applications 3.1. Ionic and Molecular Detection 3.2. Pathogen Detection 3.3. Live-Cell Imaging 3.3.1. Cancer Marker Detection 3.3.2. Intercellular Microenvironment Sensing 3.4. Tissue SERS Imaging 3.5. In Vivo SERS Imaging 4. Challenges and Perspectives 4.1. Reproducible Signal of SERS Tags 4.1.1. Precisely Controlled Hot Spots for Nanosubstrates 4.1.2. Calibration of SERS Intensities and Enhancements 4.2. Improving Multiplexing Capability 4.3. Reduced Size for Subcellular Imaging 4.4. Development of Multifunctional Nanoplatforms 4.4.1. Magnetic SERS Dots 4.4.2. Multimodal Imaging Dots 4.4.3. SERS Tag-Based Therapeutic Systems 4.5. Biocompatibility 5. Conclusions and Remarks

SERS Tags: Novel Optical Nanoprobes for Bioanalysis

Localized surface plasmon resonance: nanostructures, bioassays and biosensing--a review.

To obtain a coding system for multiplex detection, we have developed a method to synthesize a new type of nanomaterial called composite organic-inorganic nanoparticles (COINs). The method allows the incorporation of a broad range of organic compounds into COINs to produce surface enhanced Raman scattering (SERS)-like spectra that are richer in variety than fluorescence-based signatures. Preliminary data suggest that COINs can be used as Raman tags for multiplex and ultrasensitive detection of biomolecules.

Composite organic-inorganic nanoparticles (COINs) with chemically encoded optical signatures.

Composite organic-inorganic nanoparticles (COINs) are novel optical labels for detection of biomolecules. We have previously developed methods to encapsulate COINs and to functionalize them with antibodies. Here we report the first steps toward application of COINs to the detection of proteins in human tissues. Two analytes, PSA and CK18, are detected simultaneously using two different COINs in a direct binding assay, and two different COINs are shown to simultaneously label PSA in tissue samples.

Composite organic-inorganic nanoparticles as Raman labels for tissue analysis.

Raman nanoparticle probes are an emerging new class of optical labels for interrogation of physiological and pathological processes in bioassays, cells, and tissues. Although their unique emission signatures are ideal for multiplexing, the full potential of these probes has not been realized because conventional analysis methods are inadequate. We report a novel spectral fitting method that exploits the entire spectral signature to quantitatively extract individual probe signals from multiplex spectra. We evaluate the method in a series of multiplex assays using unconjugated and antibody-conjugated composite organic−inorganic nanoparticles (COINs). Results show sensitive multiplex detection of small signals (<2% of total signal) and similar detection limits in corresponding 4-plex and singlet plate binding assays. In a triplex assay on formalin-fixed human prostate tissue, two antibody-conjugated COINs and a conventional fluorophore are used to image expression of prostate-specific antigen, cytokeratin-18...

Spectral Analysis of Multiplex Raman Probe Signatures

Surface-enhanced Raman scattering (SERS) nanoparticles are emerging as a new approach for optical detection of biomolecules. In a model assay in formalin-fixed paraffin-embedded (FFPE) prostate tissue sections, we detect prostate-specific antigen (PSA) using antibody (Ab) conjugated to composite organic-inorganic nanoparticles (COINs), and we use identical staining protocols to compare COIN-Ab and Alexa-Ab conjugates in adjacent tissue sections. Spectral analysis illustrates the fundamental difference between fluorescence and Raman signatures and accurately extracts COIN probe signals from background autofluorescence. Probe signals are used to generate images of PSA expression on the tissue, and quality measures are presented to characterize the performance of the COIN assay in comparison to Alexa. Staining accuracy (ability to correctly identify PSA expression in epithelial cells) is somewhat less for COIN than Alexa, which is attributed to an elevated false negative rate of the COIN. However, COIN provided signal intensities comparable to Alexa, and good intra-, inter-, and lot-to-lot consistencies. Overall, COIN and Alexa detection reagents possess similar performance with FFPE tissues, supporting the further development of Raman probes for this application. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

Raman Nanoparticle Probes for Antibody-based Protein Detection in Tissues

Composite organic-inorganic nanoclusters (COINs) are provided that produce surface-enhanced Raman signals (SERS) when excited by a laser. The nanoclusters include metal particles and a Raman-active organic compound. The metal required for achieving a suitable SERS signal is inherent in the nanocluster and a wide variety of Raman-active organic compounds and combinations thereof can be incorporated into the nanocluster. In addition, polymeric microspheres containing the nanoclusters and methods of making them are also provided. The nanoclusters and microspheres can be used, for example, in assays for multiplex detection of biological molecules.

Lei Sun

Papers

Composite organic-inorganic nanoparticles (COINs) with chemically encoded optical signatures.

Composite organic-inorganic nanoparticles as Raman labels for tissue analysis.

Spectral Analysis of Multiplex Raman Probe Signatures

Raman Nanoparticle Probes for Antibody-based Protein Detection in Tissues

Composite organic-inorganic nanoclusters