biosensors Review

Potential of Surface Enhanced Raman Spectroscopy (SERS) in Therapeutic Drug Monitoring (TDM). A Critical Review Aleksandra Jaworska, Stefano Fornasaro, Valter Sergo and Alois Bonifacio * Department of Engineering and Architecture, University of Trieste, Via Valerio 6a, 34127 Trieste, Italy; [email protected] (A.J.); [email protected] (S.F.); [email protected] (V.S.) * Correspondence: [email protected]; Tel.: +39-040-558-3768 Academic Editor: Torsten Frosch Received: 4 July 2016; Accepted: 9 September 2016; Published: 19 September 2016

Abstract: Surface-Enhanced Raman Spectroscopy (SERS) is a label-free technique that enables quick monitoring of substances at low concentrations in biological matrices. These advantages make it an attractive tool for the development of point-of-care tests suitable for Therapeutic Drug Monitoring (TDM) of drugs with a narrow therapeutic window, such as chemotherapeutic drugs, immunosuppressants, and various anticonvulsants. In this article, the current applications of SERS in the field of TDM for cancer therapy are discussed in detail and illustrated according to the different strategies and substrates. In particular, future perspectives are provided and special concerns regarding the standardization of self-assembly methods and nanofabrication procedures, quality assurance, and technology readiness are critically evaluated. Keywords: SERS; TDM; drug monitoring; Individualized cancer chemotherapy

1. Introduction 1.1. Therapeutic Drug Monitoring (TDM) Therapeutic drug monitoring (TDM) has been used in clinical practice since the beginning of the 1970s, and it is now routinely required for a small fraction of drugs (~30) used in pharmacotherapy [1]. For these drugs (e.g., antiepileptics, immunosuppressants, anti-HIV agents, anticonvulsants, some antibiotics, and some cytotoxic drugs), such monitoring is essential to provide patients with effective treatment, while minimizing drug toxicity and minimizing the risk of adverse drug reactions. More recently, cancer therapy has become a burgeoning field for the development of novel analytical procedures for less frequently monitored drugs [2]. Personalized medicine has been increasingly advocated to improve the standard of care for oral/new molecularly targeted therapeutics, where side effects can be substantial and life threatening. However, TDM is seldom performed in clinical oncology due to cost/time considerations, analytical issues, and the lack of point-of-care instrumentation available [3–6]. TDM, in practice, involves assessing drug concentration in a biological matrix (most commonly plasma or serum) at a known time related to administration, and interpreting these concentrations in terms of relevant clinical parameters (target range, pharmacokinetics of the drug) [7]. Only a small fraction of prescription drugs requires TDM because, for the majority of drugs, there is a wider difference between the minimum effective concentration and the toxic concentration (therapeutic index). Thus the dose is easily adjusted by empirically assessed pharmacodynamic parameters (titration to clinical effect) [8,9]. TDM is required for drugs with a narrow therapeutic index when: (i) it is hard to correlate therapeutic or low toxicity levels with clinical effects alone; (ii) the relationship between the drug dose and serum concentration is highly variable and/or not predictable; (iii) there is Biosensors 2016, 6, 47; doi:10.3390/bios6030047

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a clear correlation between serum concentration of the drug and its therapeutic response or toxicity; (iv) serious consequences for under- or overdosing may be avoided by TDM [8,10]. Most of the analytical platforms commonly used for TDM in clinical practice rely on many different immunoassays, or on separation techniques coupled with mass spectrometry (MS). The fundamentals and application of these platforms will not be discussed in this review but have been extensively reported elsewhere [11,12]. A brief summary is reported in Table 1. In general, immunoassays are routine methods due to the ease of operation and speed, but they carry many limitations, such as interferences from components of matrices, drug metabolites, structurally similar drugs, as well as endogenous compounds. In addition, they are not available for all drugs currently monitored. On the other hand, reference methods such as liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) are in some cases still the gold standard for TDM in clinical laboratories, because they are analytically more robust and relatively free from interferences. However, the analysis is time-consuming and labor-intensive, due to the extensive sample preparation and significant volume of samples needed for processing the biofluids. Since the infrastructure required for TDM on chromatographic, mass spectrometric, and immunoassay techniques is expensive and not necessarily available in small hospitals, methods such as surface plasmon resonance (SPR) [13], localized SPR [14], electrochemical sensors [15], and quartz crystal microbalance (QCM) [16], have recently been proposed as potential TDM platforms able to provide a rapid response with limited infrastructure and sample preparation. However, the listed methods feature biofouling problems while performing the measurements, preventing their use for routine, large-scale testing. In fact, nonspecific binding of unwanted proteins and other molecules onto the sensing interface of devices can easily foul the active surface of the biosensors, thus generating overwhelming background signal and preventing the detection of target drugs [17,18]. In spite of the amount of research recently dedicated to the protection against fouling agents, this issue is still not fully resolved to date [19]. Therefore, new techniques, that are cheaper and faster than the current reference methods, are still sought which could be regularly and easily used in hospitals. Table 1. Pros and cons of analytical techniques currently used in TDM, compared with SERS. Technique Chromatographybased methods

GC-MS/MS LC-MS/MS

Description Chromatography separates individual compounds by their physical or chemical interaction with an immobile material. Once separated, combined selective MS techniques provide mass-based identification of the compounds

Gold standard; Robust methods with superior sensitivity and sensibility; Relatively free from interferences; Multiplexing capabilities; Reduced drug class/metabolites cross reactivity

Analyte is detected by its binding with a specific binding molecule, which in most cases is an analyte-specific antibody

Small amount of sample (

Potential of Surface Enhanced Raman Spectroscopy (SERS) in Therapeutic Drug Monitoring (TDM). A Critical Review.

Surface-Enhanced Raman Spectroscopy (SERS) is a label-free technique that enables quick monitoring of substances at low concentrations in biological m...
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