Biosensors for prostate cancer detection

Prostate cancer (PC) is one of the most life-threatening diseases in men and causes numerous deaths worldwide. Early and on-time detection of PC could dramatically improve survival.Biomarkers are useful for detection and monitoring of PC due to their ease of sampling and abundancy. Biomarkers can also be used for designing reliable detection platforms.Various types of biosensors have provided simple, sensitive, specific, and cost-effective detection of PC biomarkers in patients' biological fluids, such as serum and urine.Recent advances in designing and application of biosensing platforms pave the way toward their application in clinical practice. Prostate cancer (PC) is one of the most common tumors and a leading cause of mortality among men, resulting in ~375 000 deaths annually worldwide. Various analytical methods have been designed for quantitative and rapid detection of PC biomarkers. Electrochemical (EC), optical, and magnetic biosensors have been developed to detect tumor biomarkers in clinical and point-of-care (POC) settings. Although POC biosensors have shown potential for detection of PC biomarkers, some limitations, such as the sample preparation, should be considered. To tackle such shortcomings, new technologies have been utilized for development of more practical biosensors. Here, biosensing platforms for the detection of PC biomarkers such as immunosensors, aptasensors, genosensors, paper-based devices, microfluidic systems, and multiplex high-throughput platforms, are discussed. Prostate cancer (PC) is one of the most common tumors and a leading cause of mortality among men, resulting in ~375 000 deaths annually worldwide. Various analytical methods have been designed for quantitative and rapid detection of PC biomarkers. Electrochemical (EC), optical, and magnetic biosensors have been developed to detect tumor biomarkers in clinical and point-of-care (POC) settings. Although POC biosensors have shown potential for detection of PC biomarkers, some limitations, such as the sample preparation, should be considered. To tackle such shortcomings, new technologies have been utilized for development of more practical biosensors. Here, biosensing platforms for the detection of PC biomarkers such as immunosensors, aptasensors, genosensors, paper-based devices, microfluidic systems, and multiplex high-throughput platforms, are discussed. Despite developments in diagnosis and treatment, cancer remains a leading cause of death [1.Siegel R.L. et al.Cancer statistics, 2022.CA Cancer J. Clin. 2022; 72: 7-33Crossref PubMed Scopus (4937) Google Scholar,2.Yigci D. et al.3D bioprinted glioma models.Prog. Biomed. Eng. 2022; 4042001Crossref Scopus (5) Google Scholar]. Worldwide, PC is the fifth leading cause of cancer mortality in men and was responsible for 375 000 deaths in 2020 [3.Sung H. et al.Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin. 2021; 71: 209-249Crossref PubMed Scopus (37388) Google Scholar]. Due to the inconvenience of physical examination and lack of specific symptoms, PC is often diagnosed in its advanced stages. Diagnosis of PC in the initial stages plays an undeniable role in increasing survival rate and achieving cost-effective and timely treatment. Various diagnostic approaches have been proposed for the detection of PC such as determination of serum and urine biomarkers, physical/digital rectal examination, prostate tissue biopsy and imaging methods (e.g., magnetic resonance imaging and transrectal ultrasound) [4.Soares S.C.M. et al.Digital rectal examination and its associated factors in the early detection of prostate cancer: a cross-sectional population-based study.BMC Public Health. 2019; 19: 1573Crossref PubMed Scopus (5) Google Scholar, 5.Jang J. et al.Transrectal ultrasound and photoacoustic imaging probe for diagnosis of prostate cancer.Sensors (Basel). 2021; 21: 1217Crossref PubMed Scopus (6) Google Scholar, 6.Hicks R.M. et al.Diagnostic accuracy of (68)Ga-PSMA-11 PET/MRI compared with multiparametric MRI in the detection of prostate cancer.Radiology. 2018; 289: 730-737Crossref PubMed Scopus (102) Google Scholar]. To minimize the trauma and pain during tissue biopsy and to prevent the side effects of anesthesia, the detection of serum and urine PC biomarkers (see Glossary) present a diagnostic solution. The main purpose of investigations in the field of PC diagnostics is to identify biomarkers with high specificity and sensitivity and minimal false-positive/negative results. The accurate detection of the appropriate PC biomarker can indicate the presence or severity of disease and enable physicians to determine the most effective treatment and management strategy. Here, we review serum and urine biomarkers of PC and their potential application in developing quantitative biosensing platforms for clinical and POC diagnostics. In contrast to other recently published articles, this Review discusses various biosensing platforms (e.g., paper-based, multiplexed, microfluidic, and integrated biosensors) with consideration of their biological receptors and transducers. Among the various protein biomarkers of PC, prostate-specific antigen (PSA) is a kallikrein-like seine protease glycoprotein that is encoded by KLK3, and was approved by the FDA in 1986 and 1994 as a prognostic and diagnostic serum biomarker of PC in nonsymptomatic patients [7.Rittenhouse H.G. et al.Human kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate.Crit. Rev. Clin. Lab. Sci. 1998; 35: 275-368Crossref PubMed Scopus (285) Google Scholar,8.Van Poppel H. et al.Serum PSA-based early detection of prostate cancer in Europe and globally: past, present and future.Nat. Rev. Urol. 2022; 19: 562-572Crossref PubMed Scopus (24) Google Scholar]. The serum concentration of PSA nonspecifically increases not only in PC but also in benign prostatic hyperplasia (BPH) and prostatitis [9.Yan Y. et al.On the road to accurate protein biomarkers in prostate cancer diagnosis and prognosis: current status and future advances.Int. J. Mol. Sci. 2021; 22: 13537Crossref PubMed Scopus (4) Google Scholar]. However, a diagnostic threshold of 3–10 ng/ml was determined to be sufficient in PC surveillance. Cases with PSA concentrations between 3 and 10 ng/ml should be considered as grey zone patients and referred for further diagnostic tests [10.Falagario U.G. et al.Prostate cancer biomarkers: a practical review based on different clinical scenarios.Crit. Rev. Clin. Lab. Sci. 2022; : 1-12Google Scholar]. Although PSA monitoring has aided in PC detection and treatment, there are still some limitations such as insufficient positive predictive value (PPV) and noticeable false-negative results [11.Wolf A.M. et al.American Cancer Society guideline for the early detection of prostate cancer: update 2010.CA Cancer J. Clin. 2010; 60: 70-98Crossref PubMed Scopus (741) Google Scholar]. To address such limitations, different commercial approaches such as 4Kscore, Proclarix, serum-based prostate health index (PHI), and ProMark were developed to measure several biomarkers instead of PSA alone [12.Klocker H. et al.Development and validation of a novel multivariate risk score to guide biopsy decision for the diagnosis of clinically significant prostate cancer.BJUI Compass. 2020; 1: 15-20Crossref PubMed Google Scholar,13.Parekh D.J. et al.A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer.Eur. Urol. 2015; 68: 464-470Abstract Full Text Full Text PDF PubMed Google Scholar]. Multiple isoforms have been reported for PSA. Free PSA (fPSA), an enzymatically inactive ~33-kDa fraction of PSA, was applied alone or in combination with PSA for the detection of PC [14.Jansen F.H. et al.Prostate-specific antigen (PSA) isoform p2PSA in combination with total PSA and free PSA improves diagnostic accuracy in prostate cancer detection.Eur. Urol. 2010; 57: 921-927Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar]. Another isoform of PSA, named p2PSA, has been utilized as a biomarker for PC detection. The PHI assay measures PSA, fPSA, total PSA, and p2PSA through a formula to determine the PC patients' health conditions. Human glandular kallikrein-2 (hK2) is the most structurally similar and major isoform of KLK3 and is considered as an important biomarker in the detection of PC [15.Schedlich L.J. et al.Primary structure of a human glandular kallikrein gene.DNA. 1987; 6: 429-437Crossref PubMed Google Scholar]. Compared with patients with BPH, the serum concentration of hK2 is elevated in PC patients [16.Becker C. et al.Discrimination of men with prostate cancer from those with benign disease by measurements of human glandular kallikrein 2 (hK2) in serum.J. Urol. 2000; 163: 311-316Crossref PubMed Google Scholar]. Additionally, hK2 has been recognized as a predictor of PC in gray zone patients [17.Kwiatkowski M.K. et al.In prostatism patients the ratio of human glandular kallikrein to free PSA improves the discrimination between prostate cancer and benign hyperplasia within the diagnostic "gray zone" of total PSA 4 to 10 ng/ml.Urology. 1998; 52: 360-365Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar]. The serum concentration of hK2 is 50–100-fold less than that of PSA since its concentration in the human prostate is 10–50% of the PSA concentration [18.van Gils M.P.M.Q. et al.Innovations in serum and urine markers in prostate cancer current European research in the P-Mark project.Eur. Urol. 2005; 48: 1031-1041Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Remarkably, h2K was used for development of the 4KscoreVR test (OPKO Health, Miami, FL, USA) using four main biomarkers of PC (tPSA, fPSA, PSA, and h2K) for diagnostic purposes among men with suspected PC [13.Parekh D.J. et al.A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer.Eur. Urol. 2015; 68: 464-470Abstract Full Text Full Text PDF PubMed Google Scholar,19.Vickers A.J. et al.A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Goteborg, Sweden.BMC Med. 2008; 6: 19Crossref PubMed Scopus (194) Google Scholar]. In Box 1 we discuss emerging serum biomarkers of PC.Box 1Emerging serum biomarkers of PCUnderstanding the role of neuroendocrine differentiation in PC has led to the development of new approaches for the detection and treatment of PC. Admittedly, the involvement of prostatic neuroendocrine cells in the growth and differentiation of prostate is widely recognized. These cells can be detected via immunohistochemical techniques applying antibodies against their produced biomarkers in either benign or malignant tumors of prostate [128.Hu C.D. et al.Neuroendocrine differentiation in prostate cancer: a mechanism of radioresistance and treatment failure.Front. Oncol. 2015; 5: 90Crossref PubMed Scopus (104) Google Scholar,129.Abrahamsson P.A. Neuroendocrine differentiation in prostatic carcinoma.Prostate. 1999; 39: 135-148Crossref PubMed Scopus (291) Google Scholar]. Most of the aforementioned biomarkers such as chromogranin (Cg)A and CgB, human chorionic gonadotropin, neuron-specific enolase (NSE), and somatostatin are members of calcitonin gene family and could be secreted into the peripheral blood and could be detected by immunoassays [130.Parimi V. et al.Neuroendocrine differentiation of prostate cancer: a review.Am. J. Clin. Exp. Urol. 2014; 2: 273-285PubMed Google Scholar]. Among various biomarkers, NSE and CgA were used for the detection of neuroendocrine characteristics both in tissue and blood of PC patients [131.Kamiya N. et al.Pretreatment serum level of neuron specific enolase (NSE) as a prognostic factor in metastatic prostate cancer patients treated with endocrine therapy.Eur. Urol. 2003; 44 (discussion 314): 309-314Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar,132.Ranno S. et al.The chromogranin-A (CgA) in prostate cancer.Arch. Gerontol. Geriatr. 2006; 43: 117-126Crossref PubMed Scopus (28) Google Scholar].Considering the association of obesity and overweight with PC, the impact of adipose tissue-derived hormones (adipokines), specifically omentin and leptin, as well as VEGF and hepatocyte growth factor (HGF) have been studied for the development and detection of PC. The results showed a dramatic increase in the concentrations of HGF, VEGF, omentin, and leptin in PC patients compared to those of with BPH. Additionally, the evaluation of omentin and PSA concentrations provided a useful scheme for the detection of PC compared to the PSA alone [133.Fryczkowski M. et al.Circulating levels of omentin, leptin, VEGF, and HGF and their clinical relevance with PSA marker in prostate cancer.Dis. Markers. 2018; 20183852401Crossref PubMed Scopus (23) Google Scholar]. Moreover, in another study, the serum concentrations of VEGF and pigment epithelium-derived factor (PEDF) were investigated to find an association with the severity of PC and whether these biomarkers could distinguish PC from BPH. The results revealed that the ratio of VEGF/PEDF in serum could differentiate PC patients from BPH suggesting it as a new index in personalized diagnosis and prognosis of PC [134.Rivera-Perez J. et al.Evaluation of VEGF and PEDF in prostate cancer: a preliminary study in serum and biopsies.Oncol. Lett. 2018; 15: 1072-1078PubMed Google Scholar]. Understanding the role of neuroendocrine differentiation in PC has led to the development of new approaches for the detection and treatment of PC. Admittedly, the involvement of prostatic neuroendocrine cells in the growth and differentiation of prostate is widely recognized. These cells can be detected via immunohistochemical techniques applying antibodies against their produced biomarkers in either benign or malignant tumors of prostate [128.Hu C.D. et al.Neuroendocrine differentiation in prostate cancer: a mechanism of radioresistance and treatment failure.Front. Oncol. 2015; 5: 90Crossref PubMed Scopus (104) Google Scholar,129.Abrahamsson P.A. Neuroendocrine differentiation in prostatic carcinoma.Prostate. 1999; 39: 135-148Crossref PubMed Scopus (291) Google Scholar]. Most of the aforementioned biomarkers such as chromogranin (Cg)A and CgB, human chorionic gonadotropin, neuron-specific enolase (NSE), and somatostatin are members of calcitonin gene family and could be secreted into the peripheral blood and could be detected by immunoassays [130.Parimi V. et al.Neuroendocrine differentiation of prostate cancer: a review.Am. J. Clin. Exp. Urol. 2014; 2: 273-285PubMed Google Scholar]. Among various biomarkers, NSE and CgA were used for the detection of neuroendocrine characteristics both in tissue and blood of PC patients [131.Kamiya N. et al.Pretreatment serum level of neuron specific enolase (NSE) as a prognostic factor in metastatic prostate cancer patients treated with endocrine therapy.Eur. Urol. 2003; 44 (discussion 314): 309-314Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar,132.Ranno S. et al.The chromogranin-A (CgA) in prostate cancer.Arch. Gerontol. Geriatr. 2006; 43: 117-126Crossref PubMed Scopus (28) Google Scholar]. Considering the association of obesity and overweight with PC, the impact of adipose tissue-derived hormones (adipokines), specifically omentin and leptin, as well as VEGF and hepatocyte growth factor (HGF) have been studied for the development and detection of PC. The results showed a dramatic increase in the concentrations of HGF, VEGF, omentin, and leptin in PC patients compared to those of with BPH. Additionally, the evaluation of omentin and PSA concentrations provided a useful scheme for the detection of PC compared to the PSA alone [133.Fryczkowski M. et al.Circulating levels of omentin, leptin, VEGF, and HGF and their clinical relevance with PSA marker in prostate cancer.Dis. Markers. 2018; 20183852401Crossref PubMed Scopus (23) Google Scholar]. Moreover, in another study, the serum concentrations of VEGF and pigment epithelium-derived factor (PEDF) were investigated to find an association with the severity of PC and whether these biomarkers could distinguish PC from BPH. The results revealed that the ratio of VEGF/PEDF in serum could differentiate PC patients from BPH suggesting it as a new index in personalized diagnosis and prognosis of PC [134.Rivera-Perez J. et al.Evaluation of VEGF and PEDF in prostate cancer: a preliminary study in serum and biopsies.Oncol. Lett. 2018; 15: 1072-1078PubMed Google Scholar]. The detection of PC biomarkers in urine has advantages over invasive transrectal biopsy sampling, which may result in injury/trauma to patients. Generally, urinary biomarkers are categorized into proteins, DNA-based, RNA-based, exosomes, and other molecules. The detection of PSA in the urine samples of PC patients was first reported in the 1980s. Later, studies revealed that PSA presence in the urine of PC patients after prostatectomy, might be associated with the recurrence of cancer [20.Iwakiri J. et al.An analysis of urinary prostate specific antigen before and after radical prostatectomy: evidence for secretion of prostate specific antigen by the periurethral glands.J. Urol. 1993; 149: 783-786Crossref PubMed Google Scholar]. Telomerase reverse transcriptase (TERT), another urinary biomarker of PC, plays a crucial role in protecting the telomeric ends of chromosomes. Its hyperactivity was observed in the majority of PCs since having active telomerase may cause replicative senescence [21.Botchkina G.I. et al.Noninvasive detection of prostate cancer by quantitative analysis of telomerase activity.Clin. Cancer Res. 2005; 11: 3243-3249Crossref PubMed Scopus (0) Google Scholar]. Annexin A3, a member of the calcium and phospholipid binding protein family, is responsible for cell differentiation and migration metastasis of PC. With an inverse correlation to cancer, urine annexin A3 level was found to be more specific than urinary PSA. Hence, detection of annexin A3 in urine samples could provide a new way to develop a noninvasive biomarker for specific detection of PC [22.Schostak M. et al.Annexin A3 in urine: a highly specific noninvasive marker for prostate cancer early detection.J. Urol. 2009; 181: 343-353Crossref PubMed Scopus (80) Google Scholar,23.Gerke V. et al.Annexins: linking Ca2+ signalling to membrane dynamics.Nat. Rev. Mol. Cell Biol. 2005; 6: 449-461Crossref PubMed Scopus (1163) Google Scholar]. The role of matrix metalloproteinases (MMPs) in invasiveness, growth, and metastasis of different human solid tumors, particularly in PC, has been demonstrated and high concentrations of MMPs are found in cancer patients compared with healthy people [24.Egeblad M. Werb Z. New functions for the matrix metalloproteinases in cancer progression.Nat. Rev. Cancer. 2002; 2: 161-174Crossref PubMed Google Scholar]. The detection of MMP-9 in urine could act as an independent biomarker of PC with a specificity of 82% [25.Roy R. et al.Tumor-specific urinary matrix metalloproteinase fingerprinting: identification of high molecular weight urinary matrix metalloproteinase species.Clin. Cancer Res. 2008; 14: 6610-6617Crossref PubMed Scopus (138) Google Scholar]. The simultaneous detection of MMP and vascular endothelial growth factor (VEGF) concentrations could predict the 1-year progression-free survival rate in radiotherapy-treated PC patients. Urinary VEGF concentration in PC patients was higher compared with that of the controls [26.Miyake H. et al.Urinary levels of vascular endothelial growth factor in patients with prostate cancer as a predictor of disease progression.Anticancer Res. 2005; 25: 3645-3649PubMed Google Scholar,27.Chan L.W. et al.Urinary VEGF and MMP levels as predictive markers of 1-year progression-free survival in cancer patients treated with radiation therapy: a longitudinal study of protein kinetics throughout tumor progression and therapy.J. Clin. Oncol. 2004; 22: 499-506Crossref PubMed Scopus (0) Google Scholar]. Sarcosine, a byproduct of glycine, has been found in higher concentrations in the urine of men with PC compared with the control group [28.Sreekumar A. et al.Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.Nature. 2009; 457: 910-914Crossref PubMed Scopus (1791) Google Scholar]. Since sarcosine is undetectable in BPH, urinary sarcosine in trace amounts could be an informative biomarker of PC [29.Cernei N. et al.Sarcosine as a potential prostate cancer biomarker--a review.Int. J. Mol. Sci. 2013; 14: 13893-13908Crossref PubMed Scopus (0) Google Scholar]. Among urinary biomarkers, PC gene 3 (PCA3), is an mRNA that is significantly overexpressed in PC tissues [30.Hessels D. et al.DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer.Eur. Urol. 2003; 44 (discussion 15-16): 8-15Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar]. The ratio of PSA/PCA3 mRNA is promising for detection of PC. The determination of PCA3 in combination with other biomarkers could improve the diagnostic performance of PC tests [31.Bradley L.A. et al.Comparative effectiveness review: prostate cancer antigen 3 testing for the diagnosis and management of prostate cancer.J. Urol. 2013; 190: 389-398Crossref PubMed Scopus (70) Google Scholar,32.Roobol M.J. Contemporary role of prostate cancer gene 3 in the management of prostate cancer.Curr. Opin. Urol. 2011; 21: 225-229Crossref PubMed Scopus (26) Google Scholar]. Biosensing platforms have been developed for POC diagnostic devices for accurate and reliable detection of biomarkers. Compared with conventional detection methods, such tools have demonstrated enhanced performance in diagnosis and monitoring of diseases by detection of biomolecules and drugs in body fluids such as blood, cerebrospinal fluid, urine, saliva, and tears [33.Aliakbarinodehi N. et al.Performance of carbon nano-scale allotropes in detecting midazolam and paracetamol in undiluted human serum.IEEE Sensors J. 2018; 18: 5073-5081Crossref Scopus (12) Google Scholar,34.Shafaei S. et al.Electrodeposition of cerium oxide nanoparticles on the graphenized carbon ceramic electrode (GCCE) for the sensitive determination of isoprenaline in human serum by differential pulse voltammetry (DPV).Anal. Lett. 2022; 55: 2418-2435Crossref Scopus (3) Google Scholar]. Enhanced biosensors can be developed through EC, optical, plasmonic methods for detection of PC. Metal nanoparticles such as gold, silver, and platinum, and magnetic particles have been utilized in biosensing platforms to improve sensitivity and lower limit of detection (LOD). Due to the outstanding physicochemical properties such as high stability, large active surface area, and high conductivity, carbon-based nanomaterials including graphene oxide, carbon nanotubes, and polymers, have been used in the development of biosensing platforms [35.Akbari Nakhjavani S. et al.Gold and silver bio/nano-hybrids-based electrochemical immunosensor for ultrasensitive detection of carcinoembryonic antigen.Biosens. Bioelectron. 2019; 141111439Crossref PubMed Scopus (53) Google Scholar, 36.Sarabi M.R. et al.3D printing of microneedle arrays: challenges towards clinical translation.J. 3D Print. Med. 2021; 5: 65-70Crossref Google Scholar, 37.Rezapour Sarabi M. et al.machine learning-enabled prediction of 3D-printed microneedle features.Biosensors. 2022; 12: 491Crossref PubMed Scopus (1) Google Scholar]. Recently, biosensing platforms, particularly electrochemical biosensors (EC biosensors), were extensively designed and developed for the detection of biomolecules [38.George Kerry R. et al.A comprehensive review on the applications of nano-biosensor-based approaches for non-communicable and communicable disease detection.Biomater. Sci. 2021; 9: 3576-3602Crossref PubMed Google Scholar]. While conventional methods such as rectal examination, digital rectal examination, serum PSA testing, and tissue biopsy are indispensable for the diagnosis of PC, the development of new noninvasive detection methods are highly desired. Generally, in developing a biosensor, biomolecules such as antibodies, aptamers, cells, and DNA serve as biorecognition elements [39.Thevenot D.R. et al.Electrochemical biosensors: recommended definitions and classification.Biosens. Bioelectron. 2001; 16: 121-131Crossref PubMed Scopus (0) Google Scholar,40.Akbari Nakhjavani S. et al.A highly sensitive and reliable detection of CA15-3 in patient plasma with electrochemical biosensor labeled with magnetic beads.Biosens. Bioelectron. 2018; 122: 8-15Crossref PubMed Scopus (52) Google Scholar]. The transducer system can be chemical, EC, optical, thermal, piezoelectric, magnetic, or mass-sensitive. Depending on the nature of the biorecognition elements of the sensing platform (Figure 1), the developed biosensors for detection of PC are discussed in three major categories: immunoassays, aptamer-based probes, and gene-based ligands. Furthermore, multiplexed and integrated biosensing platforms are also discussed. Table 1 summarizes the various types of biosensing platforms discussed in this Review.Table 1Biosensing platforms for detection of PC biomarkersaAbbreviations: Ag@MCM, silver hybridized mesoporous silica nanoparticles; Anti-KLK3, Kallikrein related peptidase 3; Apt, aptamer; AuNC-Cys, gold nanocluster with cysteine; AuNF, gold nanoflower; AuNRs, gold nanorods; Au-Spa, Au linked to Staphylococcal protein A; C60, fullerene; CD14, cluster of differentiation 14; CV, cyclic voltammetry; Cys, cysteamine; DETA, diethylenetriamine; DpAu, deposited gold; EN2: engrailed-2; Fc, ferrocene; FITC, fluorescein isothiocyanate; f-PSA, free PSA; FTO, fluorine-doped tin oxide; GE, gold electrode; GOD, glucose oxidase; GOLM-1, Golgi membrane protein 1; GS, graphene sheets; HRP, horseradish peroxidase; IGF-1, insulin growth factor-1; IGFBP-3, insulin-like growth factor binding protein 3; IL, ionic liquid; IL-6, interleukin-6; ITO, indium tin oxide; LF, label-free; N/A, not available; PAA-GMNP, poly acrylic acid (PAA) modified gold magnetic nanoparticles; PABA, poly para amino benzoic acid; PANI, polyaniline; PdNP, palladium nanoparticles; PF-4, platelet factor-4; PICA/FGNs, poly(indole-6-carboxylic acid)/flower-like Au nanoparticles; PMMA, poly(methyl methacrylate); rGO, reduced graphene oxide; RuBPY, Tris(bipyridine)ruthenium(II) chloride; SA, streptavidin; SiNP, silica nanoparticles; SiO2@Ag@SiO2 NPs, silica-coated silver assembled silica nanoparticles; SiO2@Au-Ag NPs, Au-Ag NP alloy assembled silica nanoparticles NPs;ssDNA, single stranded DNA; SWCNT, single walled carbon nanotube; SWV, square wave voltammetry; TA, tannic acid; TSPs, tetrahedron structural probes.BiomarkerModification/ detection strategyLODLDRDetection methodRefsEC immunosensorsPSAMWCNT, IL/ sandwich20 pg/ml0.2–1.0 and 1–40 ng/mlDPV[43.Salimi A. et al.Highly sensitive immunosensing of prostate-specific antigen based on ionic liquid-carbon nanotubes modified electrode: application as cancer biomarker for prostate biopsies.Biosens. Bioelectron. 2013; 42: 439-446Crossref PubMed Scopus (128) Google Scholar]PSACys/Fc-PAMAMs/ LF0.001 ng/ml0.01 ng–100 ng/mlDPV[44.Cevik E. et al.Construction of novel electrochemical immunosensor for detection of prostate specific antigen using ferrocene-PAMAM dendrimers.Biosens. Bioelectron. 2016; 86: 1074-1079Crossref PubMed Scopus (61) Google Scholar]PSAGO, chit/ sandwich10 fg/ml5 pg/ml0.1 pg/ml to 90 ng/ml Up to 35 ng/mlDPV,EIS[45.Kavosi B. et al.Ultrasensitive electrochemical immunosensor for PSA biomarker detection in prostate cancer cells using gold nanoparticles/PAMAM dendrimer loaded with enzyme linked aptamer as integrated triple signal amplification strategy.Biosens. Bioelectron. 2015; 74: 915-923Crossref PubMed Scopus (195) Google Scholar]PSMAPMMA sheets/ LF9.5 ng/ml10–200 ng/mlEIS[46.Rezaei Z. et al.Design and fabrication of an electrochemical-based nanofibrous immunosensor for detection of prostate cancer biomarker, PSMA.Polym. Adv. Technol. 2022; 33: 1967-1977Crossref Scopus (3) Google Scholar]PSAMWCNTs-IL-Chit-AuNPs–PAMAM/ sandwich1 pg/ml0.05-80 ng/mlDPV[47.Kavosi B. et al.A highly sensitive prostate-specific antigen immunosensor based on gold nanoparticles/PAMAM dendrimer loaded on MWCNTS/chitosan/ionic liquid nanocomposite.Biosens. Bioelectron. 2014; 52: 20-28Crossref PubMed Scopus (0) Google Scholar]PSAPdNP-PANI-C60/ sandwich1.95×10−5 ng/ml1.6×10−4 ng/ml to 38 ng/mlCV[48.Suresh L. et al.Fabrication of immunosensor based on polyaniline, fullerene-C60 and palladium nanoparticles nanocomposite: an electrochemical detection tool for prostate cancer.Electroanalysis. 2020; 32: 1439-1448Crossref Scopus (14) Google Scholar]PSAGS, Ag@MCM48/ Sandwich2 pg/ml0.01–10.0 ng/mlN/A[49.Li Y.Y. et al.Label electrochemical immunosensor for prostate-specific antigen based on graphene and silver hybridized mesoporous silica.Anal. Biochem. 2015; 469: 76-82Crossref PubMed Scopus (42) Google Scholar]PSASAM@electrode/LF100 ag/ml100 ag/ml up to 1 mg/mlEIS[50.Pihikova D. et al.Aberrant sialylation of a prostate-specific antigen: Electrochemical label-free glycoprofiling in prostate cancer serum samples.Anal. Chim. Acta. 2016; 934: 72-79Crossref PubMed Scopus (50) Google Scholar]PSMACys-AuNPs/ LF0.47 ng/ml0–5 ng/mlDPV[51.Kabay G. et al.Disposable electrochemical immunosensor for prostate cancer detection.Sensors Actuators B Chem. 2022; 360131667Crossref Scopus (4) Google Scholar]ECL immunosensorsPSAAu-rGO, novel accelerator/ sandwich0.038 pg/ml0.0001 to 10 ng-mlECL[53.Fang Q. et al.A sensitive electrochemiluminescence immunosensor for the detection of PSA based on CdWS nanocrystals and Ag+@ UIO-66-NH2 as a novel coreaction acc