Hierarchical zwitterionic modification of a SERS substrate enables real-time drug monitoring in blood plasma.

Fang Sun,Shaoyi Jiang,Andrew Sinclair,Daniel David Galvan,Peng Zhang,Qiuming Yu,Hsiang-Chieh Hung,Tao Bai,Bowen Li,Priyesh Jain

doi:10.1038/ncomms13437

Abstract

Surface-enhanced Raman spectroscopy (SERS) is an ultrasensitive analytical technique with molecular specificity, making it an ideal candidate for therapeutic drug monitoring (TDM). However, in critical diagnostic media including blood, nonspecific protein adsorption coupled with weak surface affinities and small Raman activities of many analytes hinder the TDM application of SERS. Here we report a hierarchical surface modification strategy, first by coating a gold surface with a self-assembled monolayer (SAM) designed to attract or probe for analytes and then by grafting a non-fouling zwitterionic polymer brush layer to effectively repel protein fouling. We demonstrate how this modification can enable TDM applications by quantitatively and dynamically measuring the concentrations of several analytes—including an anticancer drug (doxorubicin), several TDM-requiring antidepressant and anti-seizure drugs, fructose and blood pH—in undiluted plasma. This hierarchical surface chemistry is widely applicable to many analytes and provides a generalized platform for SERS-based biosensing in complex real-world media.

Highlights

Surface-enhanced Raman spectroscopy (SERS) is an ultrasensitive analytical technique with molecular specificity, making it an ideal candidate for therapeutic drug monitoring (TDM)
The SERS spectrum of plasma is complex and displayed several characteristic peaks similar to those found in previous reports[15,22]; detailed assignments are summarized in Supplementary Table 1
Diminished pH sensitivity has been previously reported for SERS sensors modified solely with 4-mercaptobenzoic acid (4MBA), even in simple protein solutions40—the non-fouling poly(carboxybetaine acrylamide) (pCBAA) hierarchical modification we demonstrate here comparatively achieves robust and reliable pH detection in undiluted plasma with the same Raman reporter

Summary

Introduction

Surface-enhanced Raman spectroscopy (SERS) is an ultrasensitive analytical technique with molecular specificity, making it an ideal candidate for therapeutic drug monitoring (TDM). This modification contains two layers: a self-assembled monolayer (SAM) of ‘attracting’ or ‘probing’ functional thiols closest to the SERS-active substrate to physically attract analytes with weak surface affinity or chemically amplify the signals of analytes with small Raman activity and a second layer of non-fouling zwitterionic poly(carboxybetaine acrylamide) (pCBAA) grafted via surface-initiated atom transfer radical polymerization (SI-ATRP) to protect the ‘hotspots’ from the barrage of proteins in whole blood plasma that would typically limit detection sensitivity (Fig. 1b) We used this system to quantify the dynamic concentration of anticancer drug doxorubicin (DOX) in undiluted human blood plasma and demonstrated continuous real-time monitoring of the free DOX concentration with high sensitivity and accuracy alongside a rapid response time. As this surface chemistry is widely applicable to many analytes, this strategy provides a generalized platform for real-world SERS-based biosensing directly and continuously in complex media

Methods

Results

Conclusion