Highly Specific Plasmonic Biosensors for Ultrasensitive MicroRNA Detection in Plasma from Pancreatic Cancer Patients

MicroRNAs (miRs) are small noncoding RNAs that regulate mRNA stability and/or translation. Because of their release into the circulation and their remarkable stability, miR levels in plasma and other biological fluids can serve as diagnostic and prognostic disease biomarkers. However, quantifying miRs in the circulation is challenging due to issues with sensitivity and specificity. This Letter describes for the first time the design and characterization of a regenerative, solid-state localized surface plasmon resonance (LSPR) sensor based on highly sensitive nanostructures (gold nanoprisms) that obviates the need for labels or amplification of the miRs. Our direct hybridization approach has enabled the detection of subfemtomolar concentration of miR-X (X = 21 and 10b) in human plasma in pancreatic cancer patients. Our LSPR-based measurements showed that the miR levels measured directly in patient plasma were at least 2-fold higher than following RNA extraction and quantification by reverse transcriptase-polymerase chain reaction. Through LSPR-based measurements we have shown nearly 4-fold higher concentrations of miR-10b than miR-21 in plasma of pancreatic cancer patients. We propose that our highly sensitive and selective detection approach for assaying miRs in plasma can be applied to many cancer types and disease states and should allow a rational approach for testing the utility of miRs as markers for early disease diagnosis and prognosis, which could allow for the design of effective individualized therapeutic approaches.

[1]  A. Mulchandani,et al.  Electronic detection of microRNA at attomolar level with high specificity. , 2013, Analytical chemistry.

[2]  H. Taubert,et al.  Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival , 2010, International journal of cancer.

[3]  W. P. Hall,et al.  A Localized Surface Plasmon Resonance Biosensor: First Steps toward an Assay for Alzheimer's Disease , 2004 .

[4]  K. Hagino-Yamagishi,et al.  [Oncogene]. , 2019, Gan to kagaku ryoho. Cancer & chemotherapy.

[5]  Yong Wang,et al.  Nanopore-based detection of circulating microRNAs in lung cancer patients , 2011, Nature nanotechnology.

[6]  Hai-Qing Lin,et al.  Shape-Dependent Refractive Index Sensitivities of Gold Nanocrystals with the Same Plasmon Resonance Wavelength , 2009 .

[7]  Younan Xia,et al.  Shape-Controlled Synthesis of Gold and Silver Nanoparticles , 2002, Science.

[8]  Shiping Fang,et al.  Attomole microarray detection of microRNAs by nanoparticle-amplified SPR imaging measurements of surface polyadenylation reactions. , 2006, Journal of the American Chemical Society.

[9]  Milan Mrksich,et al.  A conformation- and ion-sensitive plasmonic biosensor. , 2011, Nano letters.

[10]  N J Halas,et al.  Surface-enhanced Raman scattering on tunable plasmonic nanoparticle substrates , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Alaaldin M. Alkilany,et al.  Gold nanoparticles in biology: beyond toxicity to cellular imaging. , 2008, Accounts of chemical research.

[12]  M. Korc,et al.  MicroRNA-10b Expression Correlates with Response to Neoadjuvant Therapy and Survival in Pancreatic Ductal Adenocarcinoma , 2011, Clinical Cancer Research.

[13]  G. Schatz,et al.  Electromagnetic fields around silver nanoparticles and dimers. , 2004, The Journal of chemical physics.

[14]  Laura M Lechuga,et al.  Identification of the optimal spectral region for plasmonic and nanoplasmonic sensing. , 2010, ACS nano.

[15]  R. Gregory,et al.  Many roads to maturity: microRNA biogenesis pathways and their regulation , 2009, Nature Cell Biology.

[16]  C. Mirkin,et al.  Localized surface plasmon resonance spectroscopy of single silver triangular nanoprisms. , 2006, Nano letters.

[17]  R. Sardar,et al.  Ultrasensitive photoreversible molecular sensors of azobenzene-functionalized plasmonic nanoantennas. , 2014, Nano letters.

[18]  M. Korc,et al.  Analysis of microRNAs in pancreatic fine-needle aspirates can classify benign and malignant tissues. , 2008, Clinical chemistry.

[19]  Sarah M. Stranahan,et al.  Super-resolution optical imaging of single-molecule SERS hot spots. , 2010, Nano letters.

[20]  K. Livak,et al.  Real-time quantification of microRNAs by stem–loop RT–PCR , 2005, Nucleic acids research.

[21]  P. Nordlander,et al.  Plasmons in strongly coupled metallic nanostructures. , 2011, Chemical reviews.

[22]  George C Schatz,et al.  Localized surface plasmon resonance spectroscopy near molecular resonances. , 2006, Journal of the American Chemical Society.

[23]  A. Jemal,et al.  Cancer statistics, 2014 , 2014, CA: a cancer journal for clinicians.

[24]  F. Zamborini,et al.  Selective attachment of antibodies to the edges of gold nanostructures for enhanced localized surface plasmon resonance biosensing. , 2009, Journal of the American Chemical Society.

[25]  John A Rogers,et al.  Nanostructured plasmonic sensors. , 2008, Chemical reviews.

[26]  S. Lowe,et al.  A microRNA polycistron as a potential human oncogene , 2005, Nature.

[27]  J. Hafner,et al.  Localized surface plasmon resonance sensors. , 2011, Chemical reviews.

[28]  M. Korc,et al.  Fluorescence-Based Codetection with Protein Markers Reveals Distinct Cellular Compartments for Altered MicroRNA Expression in Solid Tumors , 2010, Clinical Cancer Research.

[29]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[30]  J. Storhoff,et al.  Selective colorimetric detection of polynucleotides based on the distance-dependent optical properties of gold nanoparticles. , 1997, Science.

[31]  Yunqi Yan,et al.  Photoswitchable oligonucleotide-modified gold nanoparticles: controlling hybridization stringency with photon dose. , 2012, Nano letters.

[32]  Jeffrey N. Anker,et al.  Biosensing with plasmonic nanosensors. , 2008, Nature materials.

[33]  C. Mirkin,et al.  Photoinduced Conversion of Silver Nanospheres to Nanoprisms , 2001, Science.

[34]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[35]  Suresh Shrestha,et al.  Bioluminescence-based detection of microRNA, miR21 in breast cancer cells. , 2008, Analytical chemistry.

[36]  Adam Wax,et al.  Rational Selection of Gold Nanorod Geometry for Label-Free Plasmonic Biosensors , 2009, ACS nano.

[37]  R. Sardar,et al.  Improved localized surface plasmon resonance biosensing sensitivity based on chemically-synthesized gold nanoprisms as plasmonic transducers , 2012 .

[38]  A. Kumbhar,et al.  Designing Efficient Localized Surface Plasmon Resonance-Based Sensing Platforms: Optimization of Sensor Response by Controlling the Edge Length of Gold Nanoprisms , 2012 .

[39]  Naomi J. Halas,et al.  Controlling the surface enhanced Raman effect via the nanoshell geometry , 2003 .

[40]  Mikael Käll,et al.  Plasmon-enhanced colorimetric ELISA with single molecule sensitivity. , 2011, Nano letters.

[41]  Adam D. McFarland,et al.  Single Silver Nanoparticles as Real-Time Optical Sensors with Zeptomole Sensitivity , 2003 .

[42]  Abraham J. Qavi,et al.  Multiplexed detection and label-free quantitation of microRNAs using arrays of silicon photonic microring resonators. , 2010, Angewandte Chemie.

[43]  Paul Mulvaney,et al.  Direct observation of chemical reactions on single gold nanocrystals using surface plasmon spectroscopy. , 2008, Nature nanotechnology.

[44]  Xiaohua Huang,et al.  Noble metals on the nanoscale: optical and photothermal properties and some applications in imaging, sensing, biology, and medicine. , 2008, Accounts of chemical research.

[45]  Raj Mutharasan,et al.  Sample preparation-free, real-time detection of microRNA in human serum using piezoelectric cantilever biosensors at attomole level. , 2012, Analytical chemistry.

[46]  Dag L. Aksnes,et al.  Mesopelagic fish biomass and trophic efficiency of the open ocean , 2014 .

[47]  G. Whitesides,et al.  Formation of Monolayers by the Coadsorption of Thiols on Gold: Variation in the Length of the Alkyl Chain , 1989 .

[48]  R. V. Van Duyne,et al.  Localized surface plasmon resonance spectroscopy and sensing. , 2007, Annual review of physical chemistry.

[49]  Jianzhong Xi,et al.  Real-time polymerase chain reaction microRNA detection based on enzymatic stem-loop probes ligation. , 2009, Analytical chemistry.

[50]  Jingmin Jin,et al.  Rapid electronic detection of probe-specific microRNAs using thin nanopore sensors. , 2010, Nature nanotechnology.

[51]  N. Shah,et al.  Surface-enhanced Raman spectroscopy. , 2008, Annual review of analytical chemistry.

[52]  Selim Elhadj,et al.  Optical properties of an immobilized DNA monolayer from 255 to 700 nm. , 2004, Langmuir : the ACS journal of surfaces and colloids.

[53]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[54]  Keiko Munechika,et al.  Dependence of fluorescence intensity on the spectral overlap between fluorophores and plasmon resonant single silver nanoparticles. , 2007, Nano letters.

[55]  M. Moskovits Surface‐enhanced Raman spectroscopy: a brief retrospective , 2005 .

[56]  P. Weiss Functional molecules and assemblies in controlled environments: formation and measurements. , 2008, Accounts of chemical research.

[57]  Sarit S. Agasti,et al.  Gold nanoparticles in chemical and biological sensing. , 2012, Chemical reviews.

[58]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[59]  K. Lance Kelly,et al.  Chain Length Dependence and Sensing Capabilities of the Localized Surface Plasmon Resonance of Silver Nanoparticles Chemically Modified with Alkanethiol Self-Assembled Monolayers , 2001 .

[60]  Anant Kumar Singh,et al.  Development of a long-range surface-enhanced Raman spectroscopy ruler. , 2012, Journal of the American Chemical Society.

[61]  G. Calin,et al.  microRNA-10b: A New Marker or the Marker of Pancreatic Ductal Adenocarcinoma? , 2011, Clinical Cancer Research.