Clinica Chimica Acta 527 (2022) 79–88

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Clinica Chimica Acta

journal homepage: www.elsevier.com/locate/cca

Surface plasmon resonance: A promising approach for label-free early

cancer diagnosis
Anushree Gade a, 1, Ankita Sharma a, 1, Nidhi Srivastava a, S.J.S. Flora b, *
a
Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Bijnor-Sisendi Road, Post Office Mati, Lucknow 226002, India
b
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research-Raebareli, Bijnor-Sisendi Road, Post Office Mati, Lucknow
226002, India

A R T I C L E I N F O A B S T R A C T

Keywords: Cancer is the second leading cause of death worldwide after cardiovascular disease. The major cause of high
Cancer mortality is delayed detection. Therefore, detection at an early stage followed by early treatment can mitigate
Biomarkers morbidity as well as mortality. The utilization of biomarker-based detection tools helps in early-stage recogni­
Biosensors
tion. Fortunately, biomarkers indicating disease status are released in to the circulation. These include traditional
Plasmonic nanomaterials
marker proteins as well as exosomes, micro-RNA (miRNA) and circulating tumor DNA (ct-DNA). Biosensors are
biological and chemical reaction devices that generate signals based on analyte concentration. Due to analyte
binding, these devices demonstrate high sensitivity and specificity. This review examines the use of surface
plasmon resonance (SPR)-based sensors in the diagnosis of various cancer including those of the breast, prostate,
lung, ovary, cervix and pancreas. SPR is a label-free, real-time and non-invasive optical biosensing technology
representing a novel diagnostic tool in cancer detection.

1. Introduction Early diagnosis requires: 1) responding to the signs and symptoms of

Cancer is one of the leading causes of death worldwide representing
almost 20 million new cases and almost 10 million deaths in 2020 [1]. It
is approximated that 30–50% of these malignancies can now be miti­
gated by avoiding risk factors like smoking, alcohol intake, poor nutri­
tion, sparse physical activities, sedentary lifestyle, air pollution, and
using evidence-based preventive methods. Early diagnosis of cancer, as
well as adequate treatment and care can also minimize disease burden.
various cancers, as well as obtaining medical help when needed; 2)
clinical assessment and availability of diagnostic services; and 3) prompt
referral for treatment. Cancer programs should be developed to decrease
delay and obstacles in detection, treatment and care [2] (see Fig. 1).
Currently, cancer detection involves:
1) Laboratory examination of blood, urine and other body fluids for
tumor markers.

Abbreviations: ALDH1, Aldehyde Dehydrogenase; BRCA1/BRCA2, Breast cancer gene 1/ Breast cancer gene 2; BSA, Bovine serum albumin; CA, Cancer antigen;
CD, Cluster of differentiation; CDK, Cyclin dependent kinases; CEA, Cancer embryogenic antigen; CSF, Cerebrospinal fluid; ct-DNA, Circulating tumor DNA; cVCAM,
Circulating Vascular Cell Adhesion Molecule; CYFRA, Cytokeratin 19 fragment; DNA, Deoxyribonucleic acid; EGDMA, Ethylene glycol dimethacrylate; EGFR,
Epidermal Growth Factor Receptor; ELISA, Enzyme immunosorbent assay; EM wave, Electromagnetic waves; ER/PR, Estrogen/ Progesteron; FISH, Fluorescence in
situ hybridization; FOLR1, Folate receptor alpha; FPIA, Fluorescence polarization immuno-assay; GCE, Glassy carbon electrode; G-CSF, Granulocyte-colony stimu­
lating factor; GPC1, Glypican 1; GSTM1, GSTT1, GSTP1, Glutathione S-Transferase; HE4, Human Epididymis protein; HER2, Human epidermal growth factor re­
ceptor 2; HMV, High molecular weight; HPV, Human papillomavirus type; HRP, Horseradish peroxidase; IHC, Immunohistochemical test; IL-2R, Interlukin-2
receptor; IL-6, Interlukin-6; IRMA, Immuno-radiometric assay; ITO, Indium tin oxide; KLK6, Kallikrein; LNA, Locked nucleic acid; LOX, Lipo-oxygenase; LSPR,
Localised surface plasmon resonance; MAA, Methacrylic acid; MIF, Macrophage migration inhibitory factor; miR, micro RNA; mi-RNA, Micro RNA; MNP, Metallic
nanoparticles; MNP-CNT, Metallic nanoparticles-enhanced carbon nanotubes; MUC1, Mucin type 1 glycoprotein; NCI, National Cancer Institute; nPLEX, Nano-
plasmonic exosome; NSE, Neuron-specific enolase; PDC, Pancreatic ductal adenocarcinoma; PNA, Protein nucleic acid; P-NMs, Plasmonic nanomaterials; proGRP,
Pro-gastrin-releasing peptide; PRSS8, Human prostasin; PSA, Prostate specific antigen; RNA, Ribonucleic acid; SPR, Surface plasmon resonance; SPRi, nonfluidic
surface plasmon resonance imaging; TMV, Tumor vascular marker; VEGF, Vascular endothelial growth factor; WHO, World Health Organization.
* Corresponding author.
E-mail address: sjsflora@hotmail.com (S.J.S. Flora).
1
Both the authors have contributed equally.

https://doi.org/10.1016/j.cca.2022.01.023
Received 11 January 2022; Received in revised form 12 January 2022; Accepted 28 January 2022
Available online 2 February 2022
0009-8981/© 2022 Elsevier B.V. All rights reserved.
A. Gade et al.
2) Imaging modalities like CT, MRI, nuclear scan, bone scan, PET, ul­
trasound and X-ray.
3) Biopsy-based like immunohistochemistry (IHC), fluorescence in situ
hybridization (FISH).
4) Endoscopic methods like colonoscopy and bronchoscopy [3,4].
Drawbacks of endoscopic screening include hemorrhage, adverse
reactions, infections, over-diagnosis, and false-positive findings. Alter­
native methods include real-time PCR, enzyme-linked immunosorbent
assay (ELISA), immuno-radiometric assay (IRMA), and fluorescence
polarization immunoassay (FPIA) to eliminate the disadvantages
mentioned [5].
Several molecules, ie, biomarkers, exhibit significant change in their
expression in cancer and accordingly have potential clinical significance
in diagnosis, therapy and follow-up [6]. Diagnostic tests and analytical
procedures are in high demand and biosensors are at the frontline of
analytical approaches. Biosensors are diagnostic tools that comprise a
biosensing component and a transducer. The sensing substance, ie, the
biorecognition element, can comprise of enzymes, antibodies, bacteria,
tissues, organelles, DNA and RNA. These components create digital
electrical signals in response to biomolecular interaction enabling
labeled as well as “label-free” analyte detection. Biosensors are catego­
rized according to the biorecognition element and transducer type
(Fig. 2) [7,8] (see Fig. 3).
Affordability, convenience, rapid response, good sensitivity as well
as specificity, and combinatorial capacity are all the advantages of
biosensors over larger traditional instrument-dependent technologies.
Also, these devices are environmental and consumer-friendly, as well as
portable, durable, and resistant to a broad variety of other circumstances
like temperature, electromagnetic radiation, moisture, and so on [5,9].
Early detection and assessment of cancer employing biosensor plat­
forms may drastically enhance prediction and life expectancy, reducing
mortality followed by contributing to social development and thereby
opening up access to worldwide healthcare.
Fig. 1. Global distribution of different types of cancers This distribution of types of cancer cases is estimated by GLOBOCAN International agency for Research
on cancer.
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2. Surface plasmon resonance (SPR): A propitious technique in
biosensor development
Surface plasmon resonance (SPR) refers to an optical phenomenon
that can be used in quantifying molecular bonding in real-time and in a
label-free manner [10]. The cumulative vibration of electrons in the
conduction band (i.e surface plasmons) at the boundary between a
conducting material and a dielectric material when a plane-polarized
light interacts with them is called as surface plasmon resonance (SPR).
This produces a wave referred to as surface plasmon wave which extends
over the contact area between the conductor and dielectric material but
is restricted to the plane perpendicular within a range of 100–200 nm.
The main function of SPR devices is to assess the affinity and binding
kinetics of the interplay taking place at the surface [9,10]. (Fig. 4)
In 1956, David Pines coined the term “plasmon.” He attributed the
quick decrease in the potential of electrons traveling across metals to
aggregate vibrations of delocalized electrons on the metal’s surface,
which he named plasmons. The likeness of electron oscillations to par­
ticle oscillations in plasma led to this name. Rufus Ritchie gave the first
report of a surface plasmon in 1957, where he proposed that plasmons
may be found near metal surfaces. A notable development in the realm
of surface plasmons happened later when techniques for optical acti­
vation of surface plasmons on thin metal layers were revealed. Re­
searchers were able to conduct surface plasmon tests more easily as a
result of this improvement [5].
SPR was first demonstrated as an optical biosensor by Liedberg and
Nylander in 1982. Fundamental bio-monitory studies, research in
medical sciences, drug development, clinical diagnostics, even envi­
ronmental and agricultural monitoring all have benefited from the usage
of SPR biosensors [9,11].
Plasmonic nanomaterials (P-NMs) are the basis of nano-plasmonic
biosensors. Metallic nano-particles like gold, silver, platinum, and car­
bon nanotubes have been developed. Hybrid plasmonic nanomaterials,
such as bimetal nanoparticles, core–shell MNP, and MNP-enhanced
carbon nanotubes (MNP-CNT) have been designed to obtain an
improved plasmonic effect. The overall specificity of localized detection
and point-of-care diagnosis platforms has increased because of P-NMs
[12,13].
A. Gade et al.
Fig. 2. Classification of Biosensors, Biosensors are broadly classified based upon the biorecognition element and the type of transducer used to design it. A wide
range of biosensors have been developed till date.
The highest absorption of light takes place only when the electro­
magnetic (EM) wave frequency of the incoming light coincides with the
frequency of surface plasmon wave when the surface is irradiated with a
directed ray of monochromic and plane-polarized light from an angle
adequate to produce a total internal reflection. This causes a decrease in
the luminance of reflected light as well as in the SPR band, which is
generally shown as a factor of incidence angle on the X-axis and
reflection intensity on the Y-axis [10]. The index of refraction and sur­
face plasmon wave frequency will vary if biomolecular adsorption oc­
curs at the contact. As a result, the number of attached atoms may be
determined by either monitoring the variation in mirrored luminance at
a particular angle of incidence or via retaining the reflectance while
recording the change in the angle of incidence, also known as the
angular shift [14]. SPR biosensing is premised on the concept that
almost any alterations on the dielectric surface will generate a change in
the angle of reflectance, which will then be tracked by a detector to fulfil
the resonance requirement [15].
SPR sensing may be used in conjunction with a variety of transducer
designs, including the prism-associated configuration, fiber-optic sen­
sors, and phase sensors as well [16–18].The most widely and tradi­
tionally used configuration is the Prism-associated configuration. In
Prism-associated configuration, the laser light travels via a glass prism
prior to undergoing total internal reflection in the prism-linked
arrangement. The Otto and Kretschmann configurations are the two
most common variations of this layout [10]. Two primary formats may
be used to detect biomolecular substances. A thin layer of gold, which is
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Clinica Chimica Acta 527 (2022) 79–88
commonly used as a plasmon producing surface, is derivatized with
particular biosensing components like complement nucleic acid strands,
antibodies, etc., and passivated by a polymeric coating in the first
technique. When a sample solution is delivered for analysis, this strategy
optimizes the quantity of target molecules deposited on the interface
while minimizing the non-specific deposition of all the other molecules.
The quantity of bound target is immediately revealed by the angular
displacement upon the SPR spectra, which is monitored over time dur­
ing measurement [19]. But in the case of small biomolecules (<10–25
nm), the angular shift that will occur may also be less, leading to errors.
Another technique has been developed to overcome this problem.
Linking pre-treated gold nanoparticles with an additional biosensing
element with the objects that have already been trapped on the metallic
surface, leading to the formation of a sandwich panel, adds another
signal amplification step. As a result, there is an effective rise in
refractive index, resulting in larger changes in the SPR response [20,21].
SPR biosensors can analyze a number of biological fluids, including
saliva, blood, urine, plasma, demonstrating their flexibility in compli­
cated matrices and capturing the majority of possible clinical samples
[22]. The fact that light does not enter the sample gives SPR a significant
advantage over conventional optical detection methods.
Biosensors are often employed with one of three SPR approaches-
Fluidic Surface Plasmon Resonance (Fluidic SPR), non-fluidic Surface
Plasmon Resonance imaging (SPRi), or Localised surface plasmon
resonance (LSPR). The fluidic form of SPR is the most widely utilized
SPR method in cancer diagnosis followed by LSPR and SPRi [23]. (Fig. 5)
A. Gade et al. Clinica Chimica Acta 527 (2022) 79–88

Fig. 3. Schematic representation of Biosensors. The figure represents the basic principle and working of biosensor. When the sample with biomarkers is to be
analysed, it is allowed to flow through the biorecognition element. The surface of the biorecognition element is modified with the complementary material to that of
the nature of biomarker so that interaction takes place in between the biomarker and the recognition element. This interaction is detected by the detector and
accordingly processed.

Fig. 4. Surface Plasmon Resonance. This figure represents the phenomenon of surface plasmon resonance.

The fluidic SPR is designed such that the biosensors measure the
biomarkers when it is in contact with the circulation solution (sample).
During the monitoring, a sensor is developed in situ through sequen­
tially incorporating a receptor and a sample solution holding the specific
biomarker, which is driven by a flowing buffer. A chip is often pri­
marily coated with a linker after it has been treated with roughly 50 nm
of gold. Carboxylated dextran is commonly employed as a linker. As a
receptor, an appropriate antibody chemically bound with the linker is
often employed. Following that, an analyte-containing solution is
channelled towards the biosensor. The analyte is captured by the
antibody, causing variations with in the SPR signal and the formation of
a signal. Lastly, the chip sensor is cleansed so that it may be employed
for the next measurement. Nonfluidic SPR is often carried out at a fixed
configuration with an array of discrete measurement sites. The sensor is
created ex situ by sequentially immobilising a linker, a receptor, and
lastly the sample solution. The primary difference between fluidic
SPR and SPRi estimations is that SPR is done after gradually removing
the solution from the surface of the sensor. The light emitted back is sent
to a CCD (charge-coupled device) camera, which creates an image. The
next stage of optical, label-free biosensors would be composed of

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Fig. 5. Detection of cancer biomarkers with the help of SPRi (SPR imaging), Fluidic SPR and LSPR.
metal nanoparticles that support localized surface plasmon resonances
(LSPR). Gold or silver nanoparticles mounted on a piece of glass or fibre
optic cable are used to quantify localized SPR. In LSPR, the diagnostic
evidence is the red shift of the maximum absorbance [23,24].
3. Cancer biomarkers
3.1. Exosomes as tumour progressors
Extracellular vesicles known as exosomes with sizes ranging from 30
to 150 nm are produced by eukaryotic cells [25]. These exosomes are
detected in a variety of biological fluids, including saliva, urine, blood,
and cerebrospinal fluid (CSF). Exosomes include a variety of nucleotide
and protein-rich contents including biomolecular data arising from
tumor cells replicating the chromosomal or signaling changes of the
primary tumors, presenting a huge opportunity for non-invasive cancer
diagnostics [26]. Exosomes are extensively secreted from cancer cells
(≥109 vesicles mL− 1) in the circulation [27]. Existing exosome separa­
tion and quantification approaches such as Western blotting, ultracen­
trifugation, and ELISA are inconvenient, less specific, and also require
large amounts of samples [28]. New techniques must be coupled with
microfluidic systems to identify biomarkers at very low concentrations
for the early detection in asymptomatic individuals with illnesses such
as cancer. Magnetic nanoparticles for signal amplification and analyte
capture are one such approach, which opens up the prospect of multi­
plex biomarker detection [29,30]. Im et al. (2014) published ground-
breaking work on the nano-plasmonic exosome (nPLEX) technique. It
uses transmission SPR via sequential nanohole arrays for uninterrupted
and synchronous exosome separation, identification, and high
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throughput measurement. The device design used a parallel fluidic
channel layout that allowed for the collection and detection of up to 12
distinct exosome subpopulations. The device may be adjusted for real-
time analysis of molecular bonding measurements, using just 0.3 µL of
sample volume each test, exhibiting 97% accurate diagnosis and vastly
increasing lower-limit detection [31].
3.2. micro-RNAs (mi-RNA) as gene expression regulators
Apoptotic cell death, proliferative growth, division, incursion, and
migration are all influenced by micro-RNA (miRNA), which is a single-
stranded, non-coding RNA compound with a small length (around
18–25 nucleotides) [22,32]. When released into circulation, miRNA is
extremely stable, making it a convenient biomarker candidate. Cancer
has been linked to abnormal miRNA expression. The over-expression or
suppression of miRNA or miRNA expression profiles are used to establish
a link between miRNA and a certain kind of cancer [33]. As miRNA is
tiny (6–8 nm), its identification utilizing SPR-based sensors generally
requires intensification of signal, since miRNA uptake without any
intensification will lead to negligible SPR displacement [34]. Post-
modification methods may be used, and miRNA could be easily tagged
with macromolecules or nanostructures for signal intensification, lead­
ing to the efficient production of nano-sandwiches and a substantial
increase in the SPR signal [35]. Three steps involved in the identification
and detection of miRNA are- 1) Target miRNAs are bound with ss-locked
nucleic acid (LNA) probes, 2) polyadenylated tails are added by the
polyadenylation polymerase reaction, and 3) the polyadenylated tails
are hybridized with T30-DNA plated gold nanoparticles for signal
amplification prior to the identification of the signal [36].
A. Gade et al. Clinica Chimica Acta 527 (2022) 79–88

3.3. Circulating tumor DNA (ct-DNA) with multiple genetic changes Table 1
List of biomarkers for cancer detection.
Circulating tumor DNA (ctDNA) is a tiny molecule with a length Cancer Biomarker Full name Type Reference
around 100–200 nucleotide bp (30–60 nm). Identification of CTCs and
Breast HER2 Human Gene {Zhu, 2013 #
ctDNA is much more difficult due to its extremely low quantity and more cancer epidermal 90}
background quantities of circulatory wild-type DNA. Certain sequences growth factor
(cancer-associated genes) indicate specific forms of cancer and may receptor 2
be identified using highly specific hybridization reactions using an ER/PR Estrogen/ Receptor {Yang, 2014
Progesteron #47}
extremely particular surface anchored probe with a corresponding receptor
sequence towards the target sequence [37]. To obtain improved sensi­ CA 15–3 Cancer antigen Protein {Yang, 2014
tivities in detecting nucleic acids, several methods have been utilized, #47}
like plasmonic signal intensification using metallic nanostructures for BRCA1/ Breast cancer Gene {Benvidi,
BRCA2 gene 1/Breast 2015 #49}
ultrasensitive DNA detection [38]. In general, the presence of mutations
cancer gene 2
in ctDNA is the basis for cancer detection. Peptide/protein-nucleic acid p53 Gene/ {Yang, 2014
(PNA) probes are also crucial in creating ultrasensitive biosensors that Protein #47}
can detect single-base mutations in target nucleic acids at ultralow Prostate PSA Prostate specific Protein {Damborský,
concentrations. PNA probe is a useful as well as a beneficial alternative cancer antigen 2015 #50}
VEGF Vascular Protein {Crulhas,
to the DNA probe because it has a neutral peptide framework that has no endothelial 2021 #51}
electrostatic interaction with the negatively charged phosphate frame­ growth factor
work of target DNA, and therefore the functionalization procedure is MUC1 Mucin type 1 Glycoprotein {Crulhas,
unaffected by salinity levels [39]. 2021 #51}
IL-6 Interlukin-6 Protein {Aydın, 2020
#52}
3.4. Proteins as signature molecules in cancer detection Lung CEA Cancer Protein {Niho, 2001
cancer embryogenic #53}
Proteins are huge, complex biomacromolecules that range in size antigen
from 10 to 100 nm. In general, a particular antibody reaction can be SCC Squamous cell Protein {Niho, 2001
carcinoma #53}
used to identify proteins. The elevated levels (due to overexpression) of antigen
proteins as tumor markers are generally used to identify the type of NSE Neuro-specific Enzyme {Scott, 2008
cancer [40]. Protocols for the design of protein assays and concentration enolase #55}
measurements are also well known, making it easier to adapt for the CYFRA Cytokeratin 19 Protein {Niho, 2001
fragment #58}
screening of tumor diagnostic proteins. The detection surface is deriv­
proGRP Pro-gastrin- Protein {Niho, 2001
atized using antibodies or oligonucleotides which acts as the bioreceptor releasing peptide #58}
for a particular protein of interest in a conventional SPR-based moni­ EGFR Epidermal Protein {Teotia, 2018
toring approach. However, because cancer diagnostic proteins are growth factor #54}
generally found in the blood at ultralow concentrations, an additional receptor
CDK Cyclin-dependent Enzyme {Banerjee,
effort is frequently required to enhance the output [10]. In the work kinases 2017 #56}
done by Eletxigerra et al., gold nanoparticles were used for enhancing CK-17 Cytokeratin-17 Protein {Loyez, 2019
SPR performances in blood samples and raw cell lysates to identify #57}
ErbB2 protein which is a cancer marker [41]. Ovarian CA-125 Cancer antigen- Protein {Muinao,
cancer 125 2019 #60}
The biomarkers for respective cancers are summarised in Table 1.
HE4 Human Protein {Sarojini,
epididymis 4 2012 #59}
4. Cancer detection employing SPR-based biosensors KLK6 Kallikrein Enzyme {Muinao,
2019 #60}
4.1. Breast cancer PRSS8 Protease serine 8 Enzyme {Sarojini,
2012 #59}
GSTM1, Glutathione S- Enzyme {Sarojini,
As per National Cancer Institute (NCI), breast cancer is the most GSTT1, transferase 2012 #59}
frequent form of cancer on the list posing the need for the development GSTP1
of a specific and precise sensor for its detection. Various biomarkers for FRα Folate receptor Protein {Sarojini,
alpha 2012 #59}
breast cancer detection are known which mainly include HER2, ER/PR
ALDH1 Aldehyde Enzyme {Sarojini,
(Estrogen receptor or Progesterone receptor), CA 15–3 protein, BRCA1/ dehydrogenase 2012 #59}
BRCA2 genes, p53 protein, etc [42]. Cervical VEGF Vascular Protein {Liu, 2012
In roughly 20–30% of breast cancer tumors, the expression level of cancer endothelial #61}
HER2 protein rises. People with breast cancer who test positive for growth factor
Pancreatic CA 19–9 Cancer antigen Protein {Nan-Fu, 2019
protein HER2 have higher HER2 levels in their blood than healthy cancer 19–9 #62}
people. Shim and colleagues created a sandwich-like electrochemical GPC1 Glypican 1 Protein {Hasan, 2019
biosensor to detect breast tumor cells that are causing overexpression of #63}
HER2 [43]. Exosomes and micro-vesicles are significant in cancer
development, eliciting a wide range of biological responses in their
tyrosine-protein kinase (ERBB2) or cluster of differentiation 340 (CD
target cells [44]. In a method developed by Abu Ali Ibn Sina et al.,
340), is a protein with both endogenous and exogenous zones. Matrix
sensing of exosomes extravasated by BT474 breast cancer cells from
metalloproteases can degrade the extracellular zone of HER2, allowing it
complex biological samples using SPR was demonstrated. This method
to enter the breast cancer patients’ serum. The concentration of the
had a great sensitivity along with a detection limit of 8280 exosomes/µL
HER2 extracellular zone in the blood of a patient with blood cancer is
[45]. In the work done by Raghu et al., they combined nanofabrication
generally greater than 15 ng mL− 1. Eletxigerra et al., created a sensor for
and microfabrication techniques to create nano-sensing panels for a
HER2 measurement utilizing the fluidic SPR method [41]. The enzyme
specific exosome detection. Exosomes produced by MCF7 breast cancer
arachidonate 5-lipoxygenase (5-LOX) is made up of 673 amino acids
cells were used to validate the method [46]. HER2, called as receptor

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(around 78 k Da). It is an indicator of breast cancer. Kumar et al., created
a 5-LOX which was utilized in conjunction with the fluidic SPR method.
Antibody against 5-LOX was mounted upon the CM5 substrate. For the
first time, the serum concentration of 5-LOX in people with breast cancer
was identified in this study [47]. Collagen IV has also been recognized as
a possible biomarker for breast tumor. The protein is an important part
of the basal layer, which protects the tumor cells. As a result, it might be
used as a tracer of angiogenesis, which is greatly increased in cancer.
Sankiewicz et al., created a biosensor that can detect collagen IV. The
non-fluidic SPRi method was utilized with the biosensor. A monoclonal
anti-collagen IV antibody of mouse mounted on the metallic surface
(gold) of an array chip using a cysteamine linker serves as the bio­
sensor’s sensing component. In conjunction with ELISA testing, a set of
blood plasma samples of people having breast cancer and healthy donors
had been employed to validate the biosensor [48]. Estrogen and Pro­
gesterone are endocrine receptors that serve a critical role in the for­
mation and evolution of mammary glands as well as in the genesis and
progression of breast tumors. The competitive inhibition immuno test,
which used an antibody against estradiol as a high molecular weight
(HMW) interactant, was used by Kumbhat et al., to demonstrate a SPR-
based biosensor for extremely sensitive and specific detection of 17-
estradiol. Covalent amide coupling via a self-formed layer was used to
immobilize the estradiol-BSA conjugate on the nano-thin layer of gold.
The suggested biosensor has the potential to gain importance in cancer
detection [49]. All women have BRCA1 and BRCA2 genes. Any muta­
tions in these genes cause cells to proliferate and change more quickly
which in turn leads to the development of breast cancer. A. Benvide
et al., created an electrochemical sensor to identify the BRCA1 5382 insC
mutation employing a glassy carbon electrode (GCE) enhanced by Au
nanoparticles and graphene oxide. ssDNA was employed as a probe in
the biosensor. The electrical as well as chemical reactivity of the probe
for synthesis and DNA hybridization was evaluated using cyclic vol­
tammetry and electrochemical impedance spectroscopy methods [50].
4.2. Prostate cancer
Prostate cancer is the second leading form of tumor all over the
world. PSA (prostate-specific antigen) is among the major biomarkers
that are used to diagnose prostate cancer. It is a 34-kDa glycoprotein
that’s a serine protease. PSA is found in blood serum in two forms: free
and in a combination with − 1-antichymotrypsin, a PSA inhibitor [51].
Vascular endothelial growth factor (VEGF) and the transmembrane
glycoprotein mucin-type 1 (MUC1) are also the biomarkers in prostate
cancer detection [52].
Turcot et al., carried out the SPR and fluorescence measurements in a
multichannel fluidic using a PSA sensing method that included a sand­
wich assay. SPR sensing offered real-time monitoring of sequential steps
in the binding of a biomolecule, whereas the plasmonic substrate in the
form of micro-hole arrays provided sensitive PSA detection with the
help of a secondary antibody. The enhanced SPR-fluorescence setup was
used to enable fluorescent detection by inserting an HRP-modified sec­
ondary antibody into the experiment. The sensitivity of this test was
found to be higher than that of SPR [53]. For sensitive, real-time PSA
detection, a microcontact PSA-imprinted SPR sensor chip was designed.
The embossed chip was made with the monomer methacrylic acid
(MAA) and the cross-linker ethylene glycol dimethacrylate (EGDMA).
The designed method was put to the test by analyzing 10 clinical serum
samples which gave quite good results [54]. Interleukin 6 (IL-6) is also a
prostate cancer marker that has recently been detected by Aydin et al.,
using an impedimetric biosensor constructed on a coupled polypyrrole
polymer along with a carbon nanotube. As a biorecognition molecule,
the IL-6 receptor was effectively mounted upon the modified Indium tin
oxide (ITO) electrode through covalent bonding. Suggested immuno­
sensor proved successful in quantifying the IL-6, a marker in the serum
sample of the suspect, and also demonstrated a phenomenal response in
real-time analysis of serum specimens [55].
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4.3. Lung cancer
Biomarkers for lung cancer include CEA (Carcinoembryonic anti­
gen), SCC (Squamous cell carcinoma antigen), NSE (Neuron-specific
enolase), CYFRA (cytokeratin 19 fragment), and proGRP (pro-gastrin-
releasing peptide). Adenocarcinoma is responsive to CEA, squamous cell
carcinoma to SCC and CYFRA, and SCC to NSE and proGRP. According
to S. Niho et al., high blood CEA levels, histopathology of adenocarci­
noma, and massive tumor size are all major determinants of the pa­
thology of N2 disease (ipsilateral mediastinal lymph node metastasis)
for patients with non-small cell lung cancer. CEA had a novel function in
predicting mediastinal lymph node metastases [56]. In one more work
reported by Teotia et al., the diagnosis of lung cancer markers utilizing
the Vroman-effect has been described using a grating-based SPR wave­
guide sensor. The suggested grating-based multi-layered biosensor is
designed to detect epidermal growth factor receptor (EGFR) (a lung
tumor biomarker) as well as CEA with high accuracy [57]. NSE is also
one of the well-known markers for lung tumor. This has been used to
track the treatment’s efficacy. Ever since a patient experiences clinical
manifestations or any alterations in several other analysis or evalua­
tions, NSE can aid in determining if cancer has spread and if the illness
has returned [58]. Cyclin-dependent kinases (CDK) are important reg­
ulators of tumor genesis and progression. From the study performed by
Banerjee et al., it may be concluded that older lung cancer patients had
elevated CDK4 levels in their serum, and has the capability to become a
marker in clinical evidence-based research. SPR was used to evaluate the
binding characteristics of CDK4 protein present in serum, with an anti-
CDK4 antibody [59]. This is followed by the detection of cytokeratin 19
which is also the biomarker of lung cancer. Graphene oxide-based SPR
chip modified with carboxyl group was used in the work done by Chiu
et al., for the rapid detection of cytokeratin 19. It is also proposed that
the responsiveness of the SPR biosensor can be improved with the use of
an Au layer with carboxyl-functionalized graphene oxide to increase the
energy propagation intensity [60]. Cytokeratin 17, a lung cancer marker
that is a type I cytokeratin and is acidic in nature. Loyez et al., developed
a catheter-based sensor for the screening of cytokeratin 17 within lung
tissues. The cytokeratin 17 antibody was bound on a gold-coated in­
clined fibre Bragg grating. The biosensor was tested on lung cancer
tissue using immunohistochemistry to detect cytokeratin 17 [61].
4.4. Ovarian cancer
Ovarian cancer mostly strikes women above the age of 50 those who
have gone through menopause, although it could also hit younger
people. Ovarian cancer that is localized to ovaries (in stage I) can mostly
be treated in nearly 90% of the women combining currently existing
surgery and chemotherapy [62]. The most common markers that are
employed to identify ovarian cancer mainly include Cancer antigen-125
(CA-125), Human epididymis protein 4 (HE4), Kallikrein (KLK6),
Human prostasin (PRSS8), Glutathione S-Transferase (GSTM1, GSTT1,
and GSTP1), Folate receptor alpha (FOLR1), Aldehyde Dehydrogenase
(ALDH1) [63,64]. It is also noted that, CA-125 in combination with
Cancer antigen 19–9 (CA 19–9), Epidermal Growth Factor Receptor
(EGFR), Granulocyte-colony stimulating factor (G-CSF), Eotaxin,
Interleukin-2 receptor (IL-2R), (Circulating vascular cell adhesion
molecule (cVCAM), and Macrophage migration inhibitory factor (MIF)
enhanced the responsiveness and explicitness of initial developmental
stage ovarian cancer diagnosis by 98.2% and 98.7%, respectively [64].
Szymanska et al., designed a new detector to determine the HE4
levels in blood plasma. It is made up of a rabbit polyclonal anti-HE4
antibody that is covalently bonded to a gold chip through a cyste­
amine linker. The biosensor is utilized in conjunction with the SPRi non-
fluidic array technology. The analytical signal response of the biosensor
was linear, with adequate precision and recovery and it can detect HE4
in healthy people as well as in people with ovarian cancer [65].
Cathepsin L hypersecretion was detected within the patients’ serum with
A. Gade et al.
epithelial ovarian cancer (EOC), which could be owing to over­
expression of this enzyme in tumor cells in a hypoxic surrounding, as
evidenced by increased cathepsin L mRNA concentrations in tumors. It
was eventually discovered to be crucial in the invasion and spread of
cancer [66]. Using the SPRi technology, another new method for
determining the cathepsin L biosensor was developed by Tokarzewicz
et al. The utilization of the devised approach was proven via determining
the concentration of cathepsin L in the blood of some healthy people and
the blood of patients. It was concluded that the correlation between this
method and ELISA was found to be quite strong, implying that the
created method could be utilized as a competitor to ELISA [67].
4.5. Cervical cancer
Cervical cancer has now become the third leading malignancy in
women, and it is caused by the human papillomavirus type (HPV). HPV
is amongst the most often sexually spread viruses in the world [68]. HPV
types 16 and 18 are associated with gynaecologic malignancy and cer­
vical carcinoma (CC) in women all over the world [69].
In the study done on 150 patients suffering from cervical cancer by
Liu et al., the SPR approach was utilized to detect 24 kinds of HPV using
an HPV typing kit. It was concluded that SPR may be useful in the
detection of HPV infection [70]. SPR sensor that is able to measure
proteomic biomarkers released through the cells was used to detect the
release of vascular endothelial growth factor (VEGF) from live SKOV-3
ovarian cancer cells. A unique design is presented that combines a
tiny cell culture module and the SPR system. Live cells are grown upon
the surface of a modified SPR flow cell chamber, followed by monitoring
of the biomarker released from the cells employing an immunological
SPR sensing device, in contrast to the typical design of SPR systems for
identification of biomarker. This biosensor may potentially expand and
offer new frontiers for the identification and evaluation of biomarkers
from alive cells and tissues for various illnesses by utilizing surface
modification in the SPR assay [71].
4.6. Pancreatic cancer
Barely 8% of pancreatic cancer patients live more than 5 years fol­
lowed by diagnostic testing, owing to the disease’s late discovery [72].
Symptoms do not appear until late in the course of the disease. The
emergence of a non-invasive screening method would indeed be
immensely valuable in improving survival rates.
Carbohydrate antigen 19–9 (CA 19–9), is perhaps the most widely
used and well-validated screening tumor marker in the case of pancre­
atic cancer, with significant sensitivity and accuracy. miR-21, miR-155,
and miR-196 are among the miRNAs that have been shown to be
increased in PDC (Pancreatic ductal adenocarcinoma) which is one of
the most prevalent kinds of pancreatic carcinoma and can also distin­
guish pre-cancerous lesions. The levels of MIC-1 (Macrophage inhibitory
cytokine 1, an autocrine regulatory molecule) in the blood can get uti­
lized as a new potential biomarker for pancreatic tumor detection.
Overexpression of Glypican 1 (GPC1), a membrane anchoring protein, is
already discovered in a wide range of malignancies. GPC1 is substan­
tially expressed in pancreatic cancer tissue when compared to normal
tissue [73].
In the study by Chiu et al., they used the Carbohydrate antigen (CA)
19–9 (CA19-9) biomarker to develop a super-sensitive graphene oxide
that is functionalized with a carboxyl group (GO-COOH)-based SPR
sensor to diagnose pancreatic cancer. The optic and sensory features of
carboxyl-GO sheets increased biomarker detection sensitivity and af­
finity. The results revealed that using carboxyl-treated graphene oxide
as the substrate can detect the lowest antigen detection limit of 10 units/
ml [74].
86
Clinica Chimica Acta 527 (2022) 79–88
5. Conclusions and future perspectives
A wide variety of studies have utilized the SPR technique for the
identification of possible and potential biomarkers for various kinds of
malignancies, and many technological developments have however
been proposed to enhance and optimize the efficiency and productivity
of SPR-mediated detection techniques. SPR-based sensing platforms are
quickly evolving, with the advent of distinct surface topography, avant
accoutrements, and improved substrate conformations, and the ambits
for this arising platform have expanded dramatically over the last
several years. Surface plasmon resonance combined with Mass spec­
trometry (SPR-MS), electrochemical SPR, and Surface plasmon fluores­
cence spectroscopy (SPFS) with multi-faceted applicability are examples
of highly efficient combined techniques established by combining SPR
with multiple technological approaches. The fundamental challenge for
bioanalytical implementations of SPR sensors is attaining maximum
sensitivity in complicated biological specimens within an actual physi­
ological environment. To reduce the binding of non-specific molecules
which modify the localized refractive index and hence the SPR signal,
consistent and well-established surface chemistry for the formation of a
specific sensory surface is critical for the progression of efficient SPR
biosensors.
The early-stage cancer detection has become easy with the help of
SPR-based biosensors. One of the prevailing constraints in tumor diag­
nosis is the detection of recurrent cancer. Many a times, recurrence of
cancer is diagnosed lately, reducing the survival time of the patient. So,
there is a need to design and develop the biosensors which can identify
the relapse of cancer.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
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