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Nanotechnology: Multifunctional Smart Nanoparticles Measure Previously Invisible Diagnostic Analytes

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Air date: Thursday, February 6, 2014, 10:00:00 AM
Time displayed is Eastern Time, Washington DC Local
Views: Total views: 181, (15 Live, 166 On-demand)
Category: Proteomics
Runtime: 00:55:36
Description: Proteomics Interest Group

A critical need within the biomedical research sector is the identification and reliable clinical measurement of novel low abundance biomarkers that are predictive of early stage diseases such as cancer, or that correlate with therapeutic outcome or toxicity. Unresolved challenges in the biomarker discovery and measurement field are 1) Early disease biomarkers exist in body fluids at a concentration below the detection limit of biomarker discovery and measurement platforms, 2) Proteins and peptides are masked by billion fold excess quantities of resident proteins such as immunoglobulin and albumin, and 3) Degradation and perishability of candidate biomarkers ex vivo following clinical sample collection, particularly for point of care collection, shipping and storage of biospecimens, and routine testing. We have developed a new class of versatile multifunctional nanotechnology that addresses all of these challenges in one step. The technology is novel porous, buoyant, core-shell hydrogel nanoparticles containing novel high affinity reactive chemical baits that harvests biomarkers in body fluids. Upon contact with the sample, the suspended nanoparticles immediately affinity-sequester target biomarkers inside the particles, exclude albumin, fully protect the biomarkers from degradation (even at elevated temperatures), and massively concentrate the sequestered biomarkers into a small volume. The technology can dramatically (demonstrated up to 10,000 fold) improve the lower limits of detection and the precision of: a) mass spectrometry (MS) biomarker discovery, b) quantitation by multiple reaction monitoring (MRM), or c) quantification by any clinical grade immunoassay. The technology has been applied to biomarker discovery and high precision measurement of clinical analytes in a variety of body fluids including, serum, plasma, saliva, urine, eye vitreous, and sweat. The technology can be pre loaded into the body fluid collection vessel such as a vacutainer or the collection pad of a lateral flow immunoassay. In one example embodiment the nanoparticles are bound within a simple point of care non invasive diagnostic skin patch that harvests, and protects from degradation, biomarkers elaborated from dermatologic lesions, or biomarkers present in skin exudate or transudate. We scaled up the technology to conduct blind validation of its performance precision, accuracy, improved detection sensitivity, and preservation capacity, in large well-controlled clinical plasma sample sets, under our CAP accredited Clinical Proteomics Laboratory. In addition, we extended the technology to urine and we magnetized the nanoparticles using a novel magnetic label tag for immediate reduction of sample volume with full preservation of analytes, obviating the need for freezing. The technology maintains or improves linearity (R2=0.964 and 0.959 with and without the particles, respectively) and reproducibility (between run precision was 5.8 % (%CV) and 4.4 % (%CV) without and with the nanoparticles, respectively) in serum, while increasing sensitivity 100 fold (depending on the sample volume). Five low abundance (0.05-1 ng/mL) endogenous peptides were monitored before releasing the nanoparticle batch for use, and qualified the technology for a one year shelf life. A unique dataset of plasma from 40 non-small cell lung cancer (NSCLC) patients and 40 matched controls obtained from Harvard’s physician health study (PHS) cohort was analyzed. Plasma samples were collected while subjects were healthy (6 months before (NSCLC) lung cancer diagnosis) and matched to healthy control. High values (0.88, 0.92)area under the curve (AUC) of the receiver operating characteristic (ROC) analysis were obtained for linear combination of 8-10 protein biomarkers for each class (smoker, former smoker, never smoker) and validated in an independent set. Considerable overlap was observed in the selected protein biomarkers in smoker and past smoker categories whereas candidate biomarkers for the never smoker category belonged to markedly different functional classes compared to smokers. This might reflect the fact that molecular mechanisms of carcinogenesis are believed to be different in smokers and never smokers. The candidate biomarkers discovered constitute a new class of biomarkers that can potentially correlate with future risk for lung cancer. Our nanotechnology was originated under NIH NCI IMAT, and NIAMS program awards, is covered by a series of issued patents, and is commercialized.
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NLM Title: Nanotechnology : multifunctional smart nanoparticles measure previously invisible diagnostic analytes / Lance Liotta.
Author: Liotta, L A.
National Institutes of Health (U.S.). Proteomics Interest Group,
Publisher:
Abstract: (CIT): Proteomics Interest Group A critical need within the biomedical research sector is the identification and reliable clinical measurement of novel low abundance biomarkers that are predictive of early stage diseases such as cancer, or that correlate with therapeutic outcome or toxicity. Unresolved challenges in the biomarker discovery and measurement field are 1) Early disease biomarkers exist in body fluids at a concentration below the detection limit of biomarker discovery and measurement platforms, 2) Proteins and peptides are masked by billion fold excess quantities of resident proteins such as immunoglobulin and albumin, and 3) Degradation and perishability of candidate biomarkers ex vivo following clinical sample collection, particularly for point of care collection, shipping and storage of biospecimens, and routine testing. We have developed a new class of versatile multifunctional nanotechnology that addresses all of these challenges in one step. The technology is novel porous, buoyant, core-shell hydrogel nanoparticles containing novel high affinity reactive chemical baits that harvests biomarkers in body fluids. Upon contact with the sample, the suspended nanoparticles immediately affinity-sequester target biomarkers inside the particles, exclude albumin, fully protect the biomarkers from degradation (even at elevated temperatures), and massively concentrate the sequestered biomarkers into a small volume. The technology can dramatically (demonstrated up to 10,000 fold) improve the lower limits of detection and the precision of: a) mass spectrometry (MS) biomarker discovery, b) quantitation by multiple reaction monitoring (MRM), or c) quantification by any clinical grade immunoassay. The technology has been applied to biomarker discovery and high precision measurement of clinical analytes in a variety of body fluids including, serum, plasma, saliva, urine, eye vitreous, and sweat. The technology can be pre loaded into the body fluid collection vessel such as a vacutainer or the collection pad of a lateral flow immunoassay. In one example embodiment the nanoparticles are bound within a simple point of care non invasive diagnostic skin patch that harvests, and protects from degradation, biomarkers elaborated from dermatologic lesions, or biomarkers present in skin exudate or transudate. We scaled up the technology to conduct blind validation of its performance precision, accuracy, improved detection sensitivity, and preservation capacity, in large well-controlled clinical plasma sample sets, under our CAP accredited Clinical Proteomics Laboratory. In addition, we extended the technology to urine and we magnetized the nanoparticles using a novel magnetic label tag for immediate reduction of sample volume with full preservation of analytes, obviating the need for freezing. The technology maintains or improves linearity (R2=0.964 and 0.959 with and without the particles, respectively) and reproducibility (between run precision was 5.8 % (%CV) and 4.4 % (%CV) without and with the nanoparticles, respectively) in serum, while increasing sensitivity 100 fold (depending on the sample volume). Five low abundance (0.05-1 ng/mL) endogenous peptides were monitored before releasing the nanoparticle batch for use, and qualified the technology for a one year shelf life. A unique dataset of plasma from 40 non-small cell lung cancer (NSCLC) patients and 40 matched controls obtained from Harvard"s physician health study (PHS) cohort was analyzed. Plasma samples were collected while subjects were healthy (6 months before (NSCLC) lung cancer diagnosis) and matched to healthy control. High values (0.88, 0.92)area under the curve (AUC) of the receiver operating characteristic (ROC) analysis were obtained for linear combination of 8-10 protein biomarkers for each class (smoker, former smoker, never smoker) and validated in an independent set. Considerable overlap was observed in the selected protein biomarkers in smoker and past smoker categories whereas candidate biomarkers for the never smoker category belonged to markedly different functional classes compared to smokers. This might reflect the fact that molecular mechanisms of carcinogenesis are believed to be different in smokers and never smokers. The candidate biomarkers discovered constitute a new class of biomarkers that can potentially correlate with future risk for lung cancer. Our nanotechnology was originated under NIH NCI IMAT, and NIAMS program awards, is covered by a series of issued patents, and is commercialized.
Subjects: Biomarkers--analysis
Nanoparticles
Nanotechnology--methods
Publication Types: Lectures
Webcasts
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NLM Classification: QT 36.5
NLM ID: 101628100
CIT Live ID: 13680
Permanent link: https://videocast.nih.gov/launch.asp?18271