List of current HER2‐directed targeted drugs that are approved for the management of HER2‐positive breast cancer.
\r\n\t
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Tiefenbacher",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10765.jpg",keywords:"Managing Urbanization, Managing Development, Managing Resource Use, Drought Management, Flood Management, Water Quality Monitoring, Air Quality Monitoring, Ecological Monitoring, Modeling Extreme Natural Events, Ecological Restoration, Restoring Environmental Flows, Environmental Management Perspectives",numberOfDownloads:22,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 12th 2021",dateEndSecondStepPublish:"February 9th 2021",dateEndThirdStepPublish:"April 10th 2021",dateEndFourthStepPublish:"June 29th 2021",dateEndFifthStepPublish:"August 28th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A geospatial scholar working at the interface of natural and human systems, collaborating internationally on innovative studies about hazards and environmental challenges. Dr. Tiefenbacher has published more than 200 papers on a diverse array of topics that examine perception and behaviors with regards to the application of pesticides, releases of toxic chemicals, environments of the U.S.-Mexico borderlands, wildlife hazards, and the geography of wine.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"73876",title:"Dr.",name:"John P.",middleName:null,surname:"Tiefenbacher",slug:"john-p.-tiefenbacher",fullName:"John P. Tiefenbacher",profilePictureURL:"https://mts.intechopen.com/storage/users/73876/images/system/73876.jfif",biography:"Dr. John P. Tiefenbacher (Ph.D., Rutgers, 1992) is a professor of Geography at Texas State University. His research has focused on various aspects of hazards and environmental management. Dr. Tiefenbacher has published on a diverse array of topics that examine perception and behaviors with regards to the application of pesticides, releases of toxic chemicals, environments of the U.S.-Mexico borderlands, wildlife hazards, and the geography of wine. More recently his work pertains to spatial adaptation to climate change, spatial responses in wine growing regions to climate change, the geographies of viticulture and wine, artificial intelligence and machine learning to predict patterns of natural processes and hazards, historical ethnic enclaves in American cities and regions, and environmental adaptations of 19th century European immigrants to North America's landscapes.",institutionString:"Texas State University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"Texas State University",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"12",title:"Environmental Sciences",slug:"environmental-sciences"}],chapters:[{id:"76073",title:"Integrating Ecological Site Descriptions with Soil Morphology to Optimize Forest Management: Three Missouri Case Studies",slug:"integrating-ecological-site-descriptions-with-soil-morphology-to-optimize-forest-management-three-mi",totalDownloads:22,totalCrossrefCites:0,authors:[{id:"185895",title:"Dr.",name:"Michael",surname:"Aide",slug:"michael-aide",fullName:"Michael Aide"},{id:"269286",title:"Dr.",name:"Christine",surname:"Aide",slug:"christine-aide",fullName:"Christine Aide"},{id:"269287",title:"Dr.",name:"Indi",surname:"Braden",slug:"indi-braden",fullName:"Indi Braden"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"194667",firstName:"Marijana",lastName:"Francetic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/194667/images/4752_n.jpg",email:"marijana@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"600",title:"Approaches to Managing Disaster",subtitle:"Assessing Hazards, Emergencies and Disaster Impacts",isOpenForSubmission:!1,hash:"e97caba8487382025a1e70eb85e4e390",slug:"approaches-to-managing-disaster-assessing-hazards-emergencies-and-disaster-impacts",bookSignature:"John Tiefenbacher",coverURL:"https://cdn.intechopen.com/books/images_new/600.jpg",editedByType:"Edited by",editors:[{id:"73876",title:"Dr.",name:"John P.",surname:"Tiefenbacher",slug:"john-p.-tiefenbacher",fullName:"John P. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"53942",title:"Cardiac Toxicity of HER2-Directed Therapy in Women with Breast Cancer: Epidemiology, Etiology, Risk Factors, and Management",doi:"10.5772/66437",slug:"cardiac-toxicity-of-her2-directed-therapy-in-women-with-breast-cancer-epidemiology-etiology-risk-fac",body:'\nBreast cancer is one of the most common cancers in women worldwide [1]. In 2012, nearly 1.7 million women were diagnosed with breast cancer. This represents about 12% of all new cancer cases and 25% of all cancers in women [2]. Approximately 20–25% of all breast cancers overexpressed the human epidermal growth factor receptor‐2 (HER2). This protein is a member of the HER family of transmembrane receptor tyrosine kinases and is located at the cell surface. HER2 is involved in cellular growth and differentiation, and its overexpression has been associated with adverse prognosis. Prior to the development of HER2‐targeted therapy, women with HER2‐positive breast cancer had poor outcomes. However, access to HER2‐directed therapy including monoclonal antibodies, small molecule inhibitors, and antibody‐drug conjugates in the management of early and advanced breast cancer has transformed the natural history of HER2‐positive breast cancer [3, 4]. HER2‐targeted therapy alone or in combination with chemotherapy has been associated with improvements in response rate, disease control rates, and overall survival in HER2‐positive metastatic breast cancer [3–5]. Combination of HER2‐targeted agents including dual HER2 blockade and selected delivery of potent chemotherapeutic agent along with HER2 inhibition are new therapeutic approaches that in many women have transformed metastatic HER2‐positive breast cancer into a chronic disease. More importantly, HER2 blockade in early‐stage breast cancer has resulted in lower recurrence and mortality [3, 6].
\nAs the outcomes of women with HER2‐positive breast cancer have improved, increasingly attention has been directed toward minimizing both acute and chronic treatment‐related toxicities. Cardiac toxicity is a known adverse effect of trastuzumab and other HER2‐directed therapy [7, 8]. In most cases, it manifests as mild and reversible left ventricle dysfunction. Nevertheless, overt heart failure is not unusual. Serial monitoring of cardiac function is recommended for women treated with HER2‐directed therapy. In women with treatment‐related cardiac dysfunction, trastuzumab and other HER2‐directed therapy interruptions and treatment of cardiac dysfunction are recommended. This chapter provides a summary of efficacy of HER2‐directed therapy in breast cancer and reviews the incidence, pathophysiology, risk factors, monitoring, and management and prevention of HER2‐targeted treatment‐related cardiac dysfunction.
\nThe current HER2‐directed treatments for women with HER2‐positive breast cancer include monoclonal antibodies, small molecule inhibitors, and antibody‐drug conjugates (\nTable 1\n). Trastuzumab is the prototype humanized monoclonal antibody directed against the extracellular domain of human epidermal growth factor receptor‐2 [9]. It was first evaluated in women with HER2‐positive metastatic breast cancer. The combination of trastuzumab and chemotherapy resulted in improvement in progression‐free and overall survival compared with chemotherapy alone, in women with HER2‐positive metastatic breast cancer [5]. A Cochrane review assessed efficacy and safety of trastuzumab in seven trials, involving 1497 women with advanced breast cancer [10]. The combined hazard ratios (HRs) for overall survival and progression‐free survival favored the trastuzumab‐containing regimens (HR 0.82, 95% confidence interval (CI) 0.71–0.94,
Class | \nComments | \n
---|---|
\n | \n|
Trastuzumab | \nA humanized monoclonal antibody directed against the extracellular domain of the HER2 receptor that prevents ligand‐independent HER2 signaling. It has demonstrated efficacy in both early and advanced stage breast cancer | \n
Pertuzumab | \nA humanized monoclonal antibody that binds to the extracellular domain II of HER2 and inhibits ligand‐dependent HER2‐HER3 dimerization. It has been evaluated in combination with trastuzumab in preoperative setting and advanced breast cancer | \n
\n | \n|
Ado‐trastuzumab emtansine | \nAn antibody‐drug conjugate consisting of the cytotoxic agent DM1 linked to trastuzumab. It has demonstrated efficacy in advanced breast cancer | \n
\n | \n|
Lapatinib | \nAn oral dual EGFR/ErbB2 reversible tyrosine kinase inhibitor blocking both HER1 and HER2 that suppresses the downstream pathways. It has been evaluated in both early and advanced breast cancer. | \n
Afatinib, Neratinib | \nIrreversible tyrosine kinase inhibitor of EGFR/HER2/HER4 | \n
List of current HER2‐directed targeted drugs that are approved for the management of HER2‐positive breast cancer.
Later trastuzumab was evaluated in women with early‐stage breast cancer, in both adjuvant and neoadjuvant settings, and demonstrated improvement in disease‐free and overall survival. A Cochrane review evaluated efficacy and toxicity of trastuzumab in eight studies involving 11,991 women with early‐stage breast cancer [11]. The combined HRs for overall survival and disease‐free survival significantly favored the trastuzumab‐containing regimens (HR 0.66; 95% CI 0.57–0.77,
Lapatinib is a dual EGFR/HER2 reversible tyrosine kinase inhibitor that suppresses the downstream signaling involving MAPK/Erk1/2 and PI3K/Akt pathways by blocking both HER1 and HER2 [15]. Lapatinib has demonstrated efficacy in HER2‐positive advanced breast cancer [16]. In addition, it has been assessed in both adjuvant and neoadjuvant settings in women with early‐stage breast cancer. However, overall the data suggest that lapatinib in early‐stage breast cancer is inferior compared with trastuzumab [3, 17].
\nPertuzumab is a humanized monoclonal antibody that binds to the extracellular domain II of HER2. It inhibits ligand‐dependent HER2‐HER3 dimerization and reduces signaling via intracellular pathways such as PI3K/Akt [18]. Pertuzumab has limited antitumor clinical activity alone, but it is a very good synergistic drug when combined with trastuzumab and has demonstrated benefit in combination with trastuzumab in the treatment of both early (neoadjuvant setting) and advanced HER2‐positive breast cancer [3, 19, 20]. In the neoadjuvant setting, the pooled pathological complete response rate in the dual anti‐HER2 therapy group was 54.8% compared with 36% in the monotherapy group when used in combination with chemotherapy (relative risk [RR], 1.56; 95% CI 1.23–1.97;
Ado‐trastuzumab emtansine (T‐DM1) is an antibody‐drug conjugate consisting of an antimicrotubule cytotoxic agent DM1 linked to trastuzumab [22]. In women with HER2‐positive advanced breast cancer, who were previously treated with trastuzumab and a taxane, it has shown significant improvement in progression‐free and overall survival compared with lapatinib plus capecitabine [23].
\nNeratinib is an irreversible binder of HER1, HER2, and HER3 receptors [22, 24] It has demonstrated efficacy in HER2‐positive breast cancer that progress on trastuzumab [3]. In addition, 1 year of neratinib following adjuvant chemotherapy and trastuzumab in women with HER2‐positive breast cancer has been associated with modest improvement in disease‐free survival [25].
\nIn summary, over the past 15 years, HER2‐directed therapy has revolutionized the management of HER2‐positive breast cancer. In women with early‐stage cancer, neoadjuvant and adjuvant HER2‐directed therapies have substantially improved the disease‐free and overall survival. Likewise, for many women, HER2‐targeted therapy has transformed HER2‐positive advanced breast cancer into a chronic disease. For example, median overall survival of women with HER2‐positive advanced cancer has improved from 20.3 months reported by Slamon et al. in the first randomized trial using trastuzumab with chemotherapy to 48 months with the use of triple combination of pertuzumab, trastuzumab, and docetaxel [5, 26].
\nTrastuzumab‐related cardiac dysfunction incidence varies according to the underlying treated population and the definition of cardiac toxicity used in the clinical trials. In the pivotal clinical trial that evaluated trastuzumab in combination with chemotherapy (anthracycline or taxane) in women with HER2‐positive metastatic breast cancer, a high rate of cardiac dysfunction was noted, especially when trastuzumab was given in combination with an anthracycline‐based chemotherapy [5]. In this trial, cardiac dysfunction was observed in 27% of the women who received an anthracycline, cyclophosphamide, and trastuzumab; 8% of the women who received an anthracycline and cyclophosphamide alone; 13% of the women who received paclitaxel and trastuzumab; and only 1% of the women who received paclitaxel alone. Among these women, the incidence of cardiac dysfunction of New York Heart Association class III or IV was 16% among women who were treated with an anthracycline, cyclophosphamide, and trastuzumab; 3% among women who received an anthracycline and cyclophosphamide alone; 2% among women who received paclitaxel and trastuzumab; and 1% among those who were treated with paclitaxel alone (\nTable 2\n). Given a high risk of symptomatic heart failure with the concomitant use of trastuzumab with anthracycline, in all adjuvant breast cancer trials, trastuzumab was only used after anthracyclines or with anthracycline‐free chemotherapy. A Cochrane review assessed efficacy and safety of trastuzumab in seven trials, involving 1497 women with advanced breast cancer [10]. Trastuzumab increased the risk of congestive heart failure (CHF) (RR 3.49, 90% CI 1.88–6.47,
Class | \nNew York association functional classification | \nCanadian Cardiovascular Society functional classification | \n
---|---|---|
I | \nPatients with cardiac disease but without resulting limitations of physical activity | \nOrdinary physical activity, such as walking and climbing stairs, does not cause angina | \n
II | \nPatients with cardiac disease resulting in slight limitation of physical activity | \nSlight limitation of ordinary activity | \n
III | \nPatients with cardiac disease resulting in marked limitation of physical activity | \nMarked limitation of ordinary physical activity | \n
IV | \nPatients with cardiac disease resulting in inability to carry on any physical activity without discomfort | \nInability to carry on any physical activity without discomfort | \n
New York association and Canadian Cardiovascular Society functional classifications.
In the major adjuvant trastuzumab clinical trials, the rates of symptomatic CHF varied from 0.6 to 4.1%, whereas the rates of symptomatic or minimally symptomatic reduction in LVEF ranged from 4 to 34% (\nTable 3\n). The Herceptin Adjuvant (HERA) trial compared 1 or 2 years of trastuzumab given once every 3 weeks with observation in women with HER2‐positive breast cancer. The incidence of trastuzumab discontinuation due to cardiac disorders was 4.3% [8]. The incidence of cardiac end points was higher in the trastuzumab group compared with observation: severe CHF, 0.60% compared with 0.06%; symptomatic CHF, 2.15% compared with 0.12%; and confirmed significant LVEF drops, 3.04% compared with 0.53%. Most women with cardiac dysfunction recovered in fewer than 6 months.
\nTrial | \nN | \nDesign | \nDefinition of severe cardiotoxicity | \nFrequency of monitoring | \nAsymptomatic drop in LVEF (≥10% points to <55%) | \nSevere CHF/cardiac events (NYHA class III/IV CHF or death) | \nDiscontinued for cardiac reasons | \n
---|---|---|---|---|---|---|---|
FinHer12, 29\n | \n232 | \nV or T + H versus V or Ta ≥FEC × 3 | \nMyocardial infarction; HF; or LVEF decrease >15 points | \nEcho or MUGA before chemotherapy, after FEC, and 12 and 36 months after chemotherapy | \n3.5 versus 8.6% | \n0.9 versus 1.7% | \nn/a | \n
NSABP B‐3127, 14\n | \n2030 | \nAC + TH + H versus AC + T | \nGrade III/IV HF or cardiac death; or LVEF decrease >15 pointsb | \nMUGA 3 weeks, 6, and 9 months after end of initial AC, and 3 months after last trastuzumab dose | \n34 versus 17% | \n4.1 versus 0.8% | \n19%c\n | \n
BCIRG 0066\n | \n3222 | \nAC + T versus AC + TH + H versus TCaHd\n | \nGrade III/IV HF; cardiac death; grade 3–4 arrhythmias; grade 3–4 ischemia/infarction; or LVEF decrease >10 pointsb\n | \nAfter AC, after second dose of docetaxel, at end of chemotherapy, and 3, 12, and 36 months after randomization | \n11 versus 19% versus 9% | \n0.7 versus 2.0% versus 0.4% | \nn/a | \n
NCCTG N983128, 14\n | \n3505 | \nAC + TH + H versus AC + T + H versus AC + T | \nGrade III/IV HF or cardiac death; or LVEF decrease >15 pointsb\n | \nMUGA or echo at entry, after AC, and 6, 9, 18, and 21 months after entry | \n5.8–10.4 versus 4.0–7.8% versus 4.0–5.1% | \n3.3 versus 2.8% versus 0.3% | \nn/ab\n | \n
HERA8, 13\n | \n5090 | \nAdj chemoce ≥H versus Adj chemo alone | \nSevere HF; symptomatic HF; or LVEF decrease >10 points | \nLVEF (echo or MUGA) at baseline, 3, 6, 12, 18, 24, 30, 36, and 60 months | \n7.1 versus 2.2% | \n0.6 versus 0.06% | \n4.3% | \n
Rates of asymptomatic and symptomatic cardiac dysfunction in various adjuvant trastuzumab phase 3 clinical trials.
A: anthracycline; C: cyclophosphamide; T: taxane; H: trastuzumab; Ca: carboplatin; V: vinorelbine; F: 5‐flourouracil; E: epirubicin; n/a: information not available; HF: heart failure; LV0EF: left ventricular heart failure; MUGA: multi‐gated acquisition scan.
a No prior anthracycline before H exposure; H exposure limited to 9 weeks.
b Measured from baseline.
c 6.7% did not receive H after A due to unacceptable drops in LVEF.
d Included a nonanthracycline arm.
e 96% of chemotherapy was A containing.
The National Surgical Adjuvant Breast and Bowel Project trial B‐31 compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel plus 52 weeks of trastuzumab beginning concurrently with paclitaxel in women with node‐positive, HER2‐positive breast cancer [27]. Among women with normal post‐AC LVEF who began post‐AC treatment, 5 of 814 (0.006%) women in the control group developed a cardiac event compared with 31 of 850 (0.036%) women treated with trastuzumab. The difference in cumulative incidence at 3 years was 3.3% (4.1% for trastuzumab‐treated women minus 0.8% for control patients; 95% CI 1.7–4.9%). Twenty‐seven of the 31 patients in the trastuzumab arm have been followed for ≥6 months after diagnosis of a CE; 26 were asymptomatic at last assessment; and 18 remained on cardiac medication. Fourteen percent of patients discontinued trastuzumab because of asymptomatic decreases in LVEF; 4% discontinued trastuzumab because of symptomatic cardiotoxicity.
\nIn the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial, women with HER2‐positive operable breast cancer were randomly assigned to AC followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C) [28]. There were 1944 women with satisfactory or no LVEF evaluation who proceeded to post‐AC therapy. Cardiac events (CHF or cardiac death) were as followed: arm A, n = 3; arm B, n = 19; and arm C, n = 19 with 3‐year cumulative incidences of 0.3, 2.8, and 3.3%, respectively. Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8–10%; LVEF recovered and trastuzumab were restarted in approximately 50%.
\nThe Breast Cancer International Research Group randomly assigned 3222 women with HER2‐positive early‐stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC‐T), the same regimen plus 52 weeks of trastuzumab (AC‐T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH) [6]. The incidence of congestive heart failure in the two trastuzumab‐containing regimens was higher in the group receiving AC‐T plus trastuzumab (2.0%) than in the AC‐T group (0.7%) or the TCH group (0.4%); the incidence with AC‐T plus trastuzumab as compared with TCH was increased by a factor of five. In addition, a significant difference in sustained, subclinical loss of mean LVEF (defined as >10% relative loss), was observed in the group receiving AC‐T plus trastuzumab, as compared with the TCH group (18.6 versus 9.4%,
The FinHer investigators randomly assigned 1010 women to receive three cycles of docetaxel or vinorelbine, followed by three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). The 232 women with HER2‐positive cancer were further assigned to receive or not to receive nine weekly trastuzumab infusions [12]. The incidence of symptomatic heart failure among the HER2‐positive women was 0.9% (one patient) with trastuzumab and 1.7% (two patients) without trastuzumab. The incidence of absolute declines in LVEF >20% points from baseline was 6.8% with trastuzumab and 10.5% without trastuzumab [12, 29].
\nThe Cochrane review evaluated toxicity of trastuzumab in eight studies involving 11,991 women with early‐stage breast cancer [11]. Trastuzumab significantly increased the risk of CHF (RR 5.11; 90% CI 3.00–8.72,
In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (ALTTO), 8381 women with HER2‐positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with trastuzumab, lapatinib, their sequence (T → L), or their combination (L + T). Overall, incidence of primary or secondary cardiac end points was low in all treatment arms; primary cardiac end points occurred in 0.25–0.97% of women. Three fatal cardiac events occurred in the T → L arm and one in each of the other treatment arms [17].
\nA comprehensive analysis of 49 clinical trials involving 3689 women treated with lapatinib reported a low rated of cardiac events [30]. For example, asymptomatic cardiac events were reported in 53 women (1.4%), and symptomatic grade III and IV systolic dysfunction was observed only in 7 women (0.2%) treated with lapatinib. Cardiac safety of lapatinib in combination with trastuzumab is reviewed in the section of dual HER2‐directed therapy.
\nCardiotoxicity of pertuzumab was usually reported with the trastuzumab combination, and no additive cardiotoxicity was reported with addition of pertuzumab to trastuzumab. In phase I–III trials of pertuzumab, cardiac dysfunction was seen in 4.5–14.5% of women with pertuzumab treatment and cardiac dysfunction was usually grade I and II [30]. Cardiac safety of pertuzumab is reviewed in more detail in the section of dual HER2‐directed therapy.
\nT‐DM1 had a better safety profile compared to trastuzumab, and no significant cardiotoxicity was observed with T‐DM1 in heavily pre‐treated women. In the EMILIA study, only in 1.7% of women in the T‐DM1 group experienced reduction in LVEF and grade III LVEF reduction developed only in one woman (0.2%) in the T‐DM1 group compared to the lapatinib plus capacitabine group [23]. In phase I‐II trials with neratinib, no cardiotoxicity was reported, whereas cardiotoxicity was seen between 0 and 5.3% with afatinib treatment [30].
\nSeveral trials have evaluated dual HER2‐directed therapy using trastuzumab in combination with lapatinib or pertuzumab in the neoadjuvant setting and metastatic breast cancer. These trials reported the risk of heart failure with dual HER2‐directed therapy [20, 26, 31–34]. A meta‐analysis of randomized clinical trials compared the risk of cardiac adverse events with dual HER2‐directed therapy to HER2 monotherapy and reported a comparable cardiac toxicity between combination and mono‐HER2‐directed therapies [35]. Overall incidence results for CHF in dual HER2‐directed and monotherapy were 0.88% (95% CI 0.47–1.64%) and 1.49% (95% CI 0.98–2.23%). The incidence of LVEF decline was 3.1% (95% CI 2.2–4.4%) and 2.9% (95% CI 2.1–4.1%), respectively. When stratified by each treatment combination, the incidence of CHF was 0.96% (95% CI 0.40–2.31%) for the trastuzumab plus lapatinib combination and 0.80% (95% CI 0.33–1.93%) for the trastuzumab plus pertuzumab combination, while the LVEF decline was 3.2% (95% CI 1.8–5.7%) and 3.1% (95% CI 1.9–4.8%), respectively. The odd ratio of CHF between dual and monotherapy was 0.58 (95% CI 0.26–1.27,
Overall, cardiac toxicity is more often noted with the regimens employing sequential anthracycline and taxanes. Nonetheless, the majority of women who received the therapy displayed neither acute nor delayed cardiac toxicity [29]. The rates of cardiac dysfunction with the novel HER2‐targeted therapies are significantly lower than the trastuzumab. Furthermore, the combination of anti‐HER2 treatment does not increase the cardiac toxicity compared to trastuzumab alone. Longer‐term follow‐up is required to determine the full effect of adverse cardiac events.
\nCardiac dysfunction is a potential short‐ or long‐term complication of several anticancer therapies. Although the underlying pathophysiology of trastuzumab and other novel HER2‐directed therapy‐induced cardiac toxicity is not fully understood, it is different from that of anthracycline‐related or type I cardiac dysfunction and has been classified as type II cardiac dysfunction [36]. Whereas anthracycline‐associated or type I cardiac dysfunction is dose dependent, cumulative, and potentially irreversible and has been associated with structural myocardial abnormalities, such as vacuolization, myofibrillar disarray and drop‐out, and myocyte necrosis, trastuzumab‐related or type II cardiac dysfunction is not dose related, does not appear to occur in all individuals, is expressed in a broad range of severity, is not related to identifiable structural changes, and, more importantly, appears to be reversible (\nTable 4\n) [36, 37].
\n\n | Type I cardiac dysfunction (myocardial damage) | \nType II cardiac dysfunction (myocardial dysfunction) | \n
---|---|---|
Prototype drug | \n\n
| \n\n
| \n
Natural history | \n\n
| \n\n
| \n
Dose relationship | \n\n
| \n\n
| \n
Pathophysiology | \n\n
| \n\n
| \n
Electron microscopic findings | \n\n
| \n\n
| \n
Noninvasive cardiac testing Findings | \n\n
| \n\n
| \n
Effect of rechallenge | \n\n
| \n\n
| \n
Effect of late sequential stress | \n\n
| \n\n
| \n
Cancer treatment‐related cardiac dysfunction.
Trastuzumab‐induced cardiac dysfunction is considered to be the result of attenuated HER2‐mediated signaling in the heart, culminating in decreased functionality of cardiac myocytes. HER signaling plays an important role in modulating myocardial response to chemotherapy‐induced injury and inhibition of the HER‐2/erbB2 receptor worsens anthracycline‐associated cardiotoxicity [38]. HER or ErbB receptors are family of transmembrane tyrosine kinase receptors that bind extracellular ligands and regulate cell growth, differentiation, and survival [39]. HER2 appears to function as a compensatory mechanism acting against cardiac stress, such as anthracycline‐induced cardiotoxicity. Subsequent administration of trastuzumab may then lead to an inhibition of this compensation, resulting in heart failure [40]. Trastuzumab induces down‐regulation of HER2 receptors which leads to apoptosis by disrupting downstream cytoprotective signaling pathways and by decreasing expression of Bcl‐2 anti‐apoptotic protein [41]. Discontinuation or trastuzumab withdrawal allows recovery of signaling pathway and reversal of LVEF decline, in contrast to the permanent myocyte dysfunction and damage caused by anthracyclines.
\nTrastuzumab‐induced cardiotoxicity is demonstrated by inhibiting ErbB2 signaling in rat cardiac myocytes with a suitable antibody. This process promotes intrinsic (mitochondrial) apoptotic pathway that involves an increase in Bcl‐XS/Bcl‐XL ratio [42, 43]. Some studies showed that trastuzumab down‐regulates neuregulin‐1 (NRG‐1), which is released in endocardium and activates MAPK and the PI3K/AKT cell survival pathways as well as focal adhesion kinases (FAK) in cardiomyocytes which are all important for the function and structure of cardiomyocytes [44].
\nIn general, women who develop cardiotoxicity while receiving trastuzumab therapy improve upon withdrawal of the drug. Evidence suggests that reintroducing trastuzumab may be appropriate for some individuals who previously have experienced trastuzumab‐related cardiac dysfunction.
\nThe following are the risk factors for trastuzumab‐associated cardiotoxicity identified in the adjuvant clinical trials: prior treatment with anthracycline‐based chemotherapy; a borderline low normal left ventricle ejection fraction; prior treatment with antihypertensive medication; older age; and a body mass index >25 kg/m2 [7, 29]. In the HERA trial, the women who had a cardiac end point received a significantly higher dose of epirubicin and doxorubicin than the women without [8]. Furthermore, women with a screening LVEF of <60% had a significantly higher incidence of cardiac end points than women with a higher screening LVEF ≥60% (6.90% versus 2.72%; 95% CI 1.33–7.02%). Women with a risk factor of hypertension, current smoker, diabetes, hypothyroidism, or age ≥60 showed a trend to a higher incidence of cardiac end points that was not significant.
\nIn NSABP B‐31 trial, CHFs were more frequent in older women and women with marginal post‐AC LVEF [27]. LVEF, assessed either at baseline or after AC, was strongly associated with subsequent CHF (
The NSABP B31 data about risk factors for a cardiac event are supported by NCCTG N9831 trial [28, 29]. For example, women ≥60 years had a risk of 6.6%, women aged 50–59 years had a 2.8% risk, and women <50 years had a 2.1% risk (
Women treated with adjuvant trastuzumab and other HER2‐directed treatment require appropriate monitoring of LV function. LVEF measurement, obtained by echocardiogram or radionuclide ventriculography (multiple‐gated acquisition [MUGA] scans), is currently the generally accepted diagnostic tool to detect cardiotoxicity of antineoplastic agents. It is important to note that the LVEF reflects the functional status of the left ventricle, and until functional impairment occurs, myocardial injury will not be detected by LVEF measurement [40].
\nWith about a decade of follow‐up involving women treated in the adjuvant setting with trastuzumab‐containing regimens, the optimal surveillance for trastuzumab‐related cardiotoxicity is not known. The available evidence does not definitively support a specific schedule of screening or demonstrates improved outcomes for the screened patients [45]. In the adjuvant setting, a baseline evaluation for cardiac function is performed with a repeat testing at 3, 6, 9, and 12 months [46]. In metastatic disease, HER2‐directed therapy is continued until disease progression. LVEF is typically monitored at baseline, during the first 3–12 months of therapy and then as clinically indicated such as the presence of symptoms suggestive of cardiac dysfunction.
\nThe optimal cardiac monitoring of women who are receiving novel HER2‐directed therapy is not known. The United States Food and Drug Administration (US FDA) prescribing information recommends that all women who are treated with pertuzumab or lapatinib or TDM1 have LVEF assessed at the treatment initiation and subsequently at regular intervals (i.e., every 3 months in the metastatic setting and every 6 weeks in the neoadjuvant setting) [47–49]. Given that cardiac dysfunction rates of novel HER2‐targeted therapies are not high and the combination of anti‐HER2 treatment does not increase the cardiac toxicity compared with trastuzumab, periodic monitoring of cardiac function in otherwise asymptomatic women with metastatic breast cancer may not be cost effective.
\nThe early detection of injured myocardial cells is required more sensitive diagnostic tools than the use of conventional methods for LVEF measurement. For example, several small studies have evaluated tissue Doppler and strain rate imaging to detect early subclinical changes in cardiac function during and after cancer treatment that preceded a decrease in LVEF [50, 51]. Contrast ECG and real‐time 3D ECG are under investigation that may allow improvement in the accuracy of calculating LVEF. In addition, early identification of women at high risk of cardiotoxicity by cardiac biomarkers, in particular, troponin can be more effective for targeted preventive strategies [50].
\nA multidisciplinary approach for the management of treatment‐related cardiotoxicity is important for optimal outcomes. Cardio‐oncology is a new interdisciplinary field of growing interest focusing on management and prevention of therapy‐related cardiac dysfunction in cancer patients [52].
\nManagement of trastuzumab and other HER2‐directed treatment‐related cardiac dysfunction has two key components: withdrawal of trastuzumab and other HER2‐directed therapy and treatment of underlying cardiac dysfunction. Although in the adjuvant clinical trials, various “stopping and restarting” criteria were used for asymptomatic declined in LVEF, the optimal withdrawal and continuation schedule for asymptomatic decline in LVEF in general population are not known.
\nThe NSABP B‐31 and the NCCTG N9831 trials used the following dosing guidelines.\n
If there is 16% or greater decline in LVEF from the baseline value or 10–15% declined in ejection fraction to below the lower limit of normal of LVEF, trastuzumab is withheld for 4 weeks and reassessment of LVEF at week four. Discontinue trastuzumab if at 4 weeks LVEF remains below that levels.
Discontinue trastuzumab if a person develop symptomatic heart failure during treatment with trastuzumb, it is discontinued.
Symptomatic heart failure is defined as the presence of:\n
dyspnea, pedal edema, and orthopnea;
the presence of sinus tachycardia, raised jugular venous pressure, tachypnea, crackles, and S3 heart sound;
radiographic evidence of pulmonary congestion or edema.
One of the algorithms for monitoring of cardiac function for women on adjuvant trastuzumab is described in \nFigure 1\n.
\nAlgorithm for stop and restarting trastuzumab based on LVEF assessments.
Unlike early‐stage breast cancer, the dosing criteria for women with metastatic breast cancer are not well defined. In clinical practice, left ventricle function monitoring is infrequently performed in otherwise asymptomatic women with metastatic breast cancer.
\nAngiotensin‐converting enzyme (ACE) inhibitors and beta‐blockers have been proven to delay or reverse LV dilation and improve ejection fraction [53–55]. All women with symptomatic heart failure should be treated with an ACE inhibitor in combination with a beta‐blocker unless a specific contraindication exists. HER2‐directed therapy should be permanently discontinued in such women. ACE inhibitors in combination with a beta‐blocker should be used in all asymptomatic women with LV dysfunction and an ejection fraction below 40% unless a specific contraindication exists. Women with LVEF >40% may also get benefit from pharmacological intervention [56, 57]. The optimal duration of therapy is not known and is determined by several factors such as the degree of lv dysfunction, recovery of LV function, patient symptoms, and preference.
\nThe US FDA prescribing information recommends discontinuation of lapatinib for a decline in the LVEF to <50%, for those whose LVEF drops below the institution\'s lower limit of normal and for any women who develop symptomatic heart failure during therapy [49]. Dose reduction is recommended if the LVEF recovers to normal after a minimum of 2 weeks in otherwise asymptomatic patients.
\nThe US FDA prescribing information recommends to withhold both pertuzumab and trastuzumab if LVEF is <45% or is 45–49% with a ≥10% absolute decrease below the baseline value and suggests discontinuing both pertuzumab and trastuzumab if the LVEF has not improved or has declined further on repeat assessment in 3 weeks [47].
\nFor women who are treated with T‐DM1, at least temporary discontinuation of therapy is recommended if the LVEF falls to <40% or is 40–45% with a ≥10% absolute decrease below the pretreatment value [48].
\nThe presence of underlying cardiovascular risk factors can increase the risk of treatment‐related cardiac dysfunction. Cardiovascular risk reduction with appropriate control of blood pressure, cholesterol, and blood glucose, as well as positive health‐promoting behavior, including healthy diet, smoking cessation, regular exercise, and weight control, is recommended for women with breast cancer to reduce the risk of treatment‐related cardiotoxicity [50, 58, 59]. Several strategies have been developed to mitigate the risk of both symptomatic and asymptomatic cardiac dysfunction related to HER2‐directed therapy. These interventions include periodic cardiac function monitoring, use of a non‐anthracycline‐based chemotherapy, stopping and restarting HER2‐directed therapy, and early detection of cadiotoxicity by biomarkers, followed by prophylactic intervention in selected high‐risk patients.
\nHER2‐directed therapy should be avoided in women with a significant cardiovascular history such as recent myocardial infarction, CHF, unstable angina, significant arrhythmias, uncontrolled hypertension, LV hypertrophy, or significant valvular heart disease. The cardiac toxicity data from the adjuvant trastuzmab trials suggest three approaches which have been associated with a reduced risk of cardiac toxicity. The first approach employed by the HERA investigators, which is the sequential use of trastuzumab after completion of adjuvant chemotherapy. This approach resulted in very low rates of cardiac toxic effects, despite the fact that 94% of women received an anthracycline‐based regimen [29]. However, the direct comparison of concurrent versus sequential administration of trastuzumab in the N9831 trial suggests that even though the sequential approach is effective, concurrent administration provides greater benefit with minimal increased risk for cardiac toxicity [3, 29].
\nA second approach was employed in FinHer trial which used 9‐week duration of adjuvant trastuzumab and showed a very low rate of cardiac dysfunction [29]. However, the non‐inferiority of shorter duration of trastuzumab is not confirmed in a randomized clinical trial. In the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial, 3380 women were randomly assigned 6 versus 12 months of trastuzumab [60]. The overall incidences of CHF were 0.65 and 0.53% in the 12 and 6 months arms, respectively (p > 0.05). Cardiac dysfunction occurred in 5.9 and 3.4% of women in the 12 and 6 months arms, respectively (p = 0.001) [61]. However, with a median follow‐up of 42.5 months, treatment for 6 months resulted in a shorter 2‐year DFS rate compared with 12 months of therapy (91 versus 94%, respectively; HR 1.28, 95% CI 1.05–1.56). In addition, treatment for 6 months resulted inferior overall survival (93 versus 66 events; HR 1.46, 95% CI 1.06–2.01) and more frequent distant recurrences (HR 1.33, 95% CI 1.04–1.71). Hence, the approach of 6 months or shorter duration of adjuvant trastuzumab is not recommended.
\nThe third approach is the use of a non‐anthracycline‐based chemotherapy regimen such as docetaxel and carboplatin plus 1 year of trastuzumab (TCH → H) that was employed in the BCIRG 006 trial. The rate of symptomatic congestive heart failure was only 0.4% with TCH → H compared with a rate of 2.0% with AC → TH → H [6]. A non‐anthracycline‐based regimen also eliminates the risk of cardiac dysfunction from anthracycline that may preclude the use of adjuvant trastuzumab. The risk for cardiotoxicity with an anthracycline‐based regimen can be reduced by identifying women who are at increased risk for cardiac dysfunction and avoiding such regimen in these women.
\nThe primary prevention using a beta‐blocker or an ACE inhibitor has been employed as an approach to reduce cancer therapy‐related cardiac toxicity [62–64]. The results of the PRADA (prevention of cardiac dysfunction during adjuvant breast cancer therapy) trial have shown that candesartan—but not metoprolol—concomitantly administrated with adjuvant chemotherapy including epirubicin, with or without trastuzumab, can protect against early decline in LVEF, assessed with cardiac magnetic resonance [62]. MANTICORE 101‐Breast (Multidisciplinary Approach to Novel Therapies in Cardiology‐Oncology Research) is a randomized trial that evaluated if conventional heart failure pharmacotherapy can prevent trastuzumab‐mediated left ventricular remodeling, measured with cardiac MRI. The study randomized 99 women with HER2‐positve breast cancer in a 1:1:1 ratio to an ACE inhibitor (perindopril), beta‐blocker (bisoprolol), or placebo [63, 64]. The study failed to achieve its primary end point and neither a beta‐blocker nor an ACE inhibitor, used as prophylaxis against trastuzumab\'s adverse cardiac effects, and successfully prevented left ventricle remodeling. The post‐treatment LVEF for placebo patients was significantly but not clinically worse than in either of the experimental arms—56% versus 59% for perindopril and 61% for bisoprolol (down from 61, 62 and 62%, respectively). Although prophylactic beta‐blocker or ACE inhibitor is currently not recommended in women with normal baseline LVEF, it may consider in woman at high risk of cardiac dysfunction.
\nThe HER2‐directed therapy including monoclonal antibodies such as trastuzumab, small molecule inhibitors, and antibody‐drug conjugates has revolutionized the management of women with early and advanced HER2‐positive breast cancer. Left ventricle dysfunction is a known adverse effect of trastuzumab and other HER‐2 directed therapy. In most cases, it is mild and reversible; however, symptomatic heart failure is not a rare complication. The optimal approach to reduce treatment‐related LV dysfunction, the best method for its early detection, and the optimal regimen to prevent it remain unknown. Appropriate patient selection for HER2‐directed therapy and cardiac monitoring is essential to prevent and manage potential cardiac adverse events. A monitoring schedule that assesses baseline and on‐treatment cardiac function but potentially reduces the overall number of assessments is suggested for women on HER2‐directed therapy. Intervention strategies with cardiovascular medication such as treatment with ACE inhibitor and beta‐blockers and cardiovascular risk reduction to improve cardiac status before, during and after treatment, are important to reduce incidence of heart failure. Simplified rules for starting, interrupting and discontinuing trastuzumab are important for the management of LVEF reduction in women on HER2‐directed therapy. We recommend a multidisciplinary approach for the management and prevention of treatment‐related cardiac dysfunction for the optimal outcomes.
\nOver the last two decades, nanotechnology and nanoscience have generated great scientific interest focusing mainly on the development of nanomaterials with specific and tunable properties and their applications in various areas [1]. Nanotechnology offers the ability to design, synthesize, and control length scales ranging from <1 to >100 nm. In the literature, reports of discoveries based on novel properties arising from these small size features have been increasing and nano-sized noble metal particles have occupied a central place [2]. Also, nanotechnology has grown in significance in the study of fibrous materials, namely nanofibers and silicate nanocomposites wherein the synthesis and characterization along with the unique properties have been studied [3]. An emerging area of great interest is that of nanowire research which will interface with living cells for precise delivery of small molecules, proteins, and deoxyribonucleic acid (DNA) [4]. From the viewpoint of the relationship between nanostructures and properties, remarkable advances have been made in the commercial use of thin films that find wide-ranging applications in almost all the industrial fields such as optics, electronics, mechanics, and even biotechnology [5]. There is a surge of interest seen in the scientific community when it comes to NPG due to its intriguing material properties arising from its high specific surface area, high electrical conductivity, reduced stiffness, and the prospect of easy surface modification. NPG has controllable pore morphology and ligament size that opens up a wide range of studies of its mechanical and surface properties [6]. Compared to regular gold thin films which are dense inside, NPG films have interconnected ligaments with nanometers-sized gaps throughout the bulk of the film. The pore size can be modulated depending on the type of synthesis protocol followed ranging from typically 20–50 nm in size but to as small as 5 nm [7]. Additionally, the porous structure of the NPG electrode tremendously increases the number of adsorption sites for various molecules of biological interest making it an attractive candidate in the field of biosensors [8]. Gold electrodes with nanoporous structures possess a higher roughness factor (the ratio between the real surface area and the geometrical area of the electrode) and better electron transport in comparison with their counterparts with smooth surfaces [9]. Metal nanoporous films have been prepared by various methods of high productivity and controllability of which chemical and electrochemical dealloying laid the foundation for other methods [10]. Moreover, dealloying is a potent approach for the fabrication of both monoporous (i.e., nanoporous or microporous) and hierarchical (i.e., possessing both microporosity and nanoporosity) porous metal structures with novel properties [11]. Multimodal pore size distribution on the nanometer and micrometer scale is highly desirable. The presence of larger size pores enables fast transport of the reactants, while the nanopores are responsible for providing high surface area thereby increasing the rate of electrochemical reactions. High surface area gold could be prepared by the electrodeposition technique, illustrated in Figure 1. Porous metals prepared via dealloying often contain some amount of residual less noble metal and therefore other fabrication techniques were explored [12].
A representation of the electrochemical deposition set up.
The electrochemical deposition of NPG on a solid substrate has been extensively researched in recent years. This facile technique enhances the electrochemical activity of the nanoporous film by offering fine control over the growth and nucleation mechanism which in turn determines the morphology of the deposited film [13]. The three-dimensional (3-D) nanoporous films, membranes or powders of large surface area have received great attention and it has been seen that the templating strategy is the most popular method for their preparation using polycarbonate membranes, colloidal crystals, lyotropic liquid crystalline phases of surfactants, and echinoid skeletal structures as the templates and will be discussed in this chapter [14, 15]. Electroplated gold continues to play an integral role in modern electronics technology, and it is hard to find an equivalent substitute due to the unique combination of properties of the metal. It is speculated that as information technologies continue to expand, the quantity of gold used will continue to increase [16]. Experimental parameters have been seen to influence the morphology of gold and therefore, this chapter will give insights into the various methods used for fabricating NPG thin films with special emphasis on electrodeposition strategies. Along with the synthetic approaches, applications and the characterization of the NPG film will be discussed.
There are various methods for fabricating porous gold films, and these are categorically described below.
De-alloying is an effective corrosion method for the fabrication of NPG films wherein the presence of less noble metals in the gold alloy has been exploited in a way that they are chemically or electrochemically dissolved to produce monolithic metal bodies with nanoscale pore structure. Au-Ag alloys are considered ideal due to their similar atomic volumes and continuous solid solubility allowing for coherent transformation from the master alloy to the nanoporous structure, see Table 1 [17, 18]. Chemical dealloying has been studied employing Metropolis Monte Carlo simulations wherein the simulation of the dealloying process in the first stage describes the equilibrated systems followed by the second stage of dealloying with the exclusion of interaction parameters [19]. A simple method to dealloy the precursor alloy is to immerse it in nitric acid leading to selective etching of silver forming a 3-D pattern resulting in the formation of an open, bicontinuous highly porous network of gold with tunable ligament and channel width by varying the alloy composition, electrochemical potential, or by thermal annealing after dealloying [20]. Figure 2 depicts the outcome of NPG structures upon a change in the experimental parameters.
Fabrication techniques | Advantages | Application |
---|---|---|
This approach enables the fabrication of NPG thin films, either free-standing or supported on a conductive substrate | Enhanced electrocatalytic activity towards methanol oxidation, potential in the field of catalysis, optics, and sensor technology | |
Thin films formed exhibit enhanced thermal stability and capability of electron transfer. This method can be applied to various conductive surfaces without harmful pretreatment | Energy storage, photovoltaics, sensing, and electrochemical usage | |
Simple green method, reproducible and generates low-price final product | Electrochemical biosensing, used as supercapacitors, in microelectronics and photovoltaics | |
One-step fabrication of thin films directly on a substrate, control of particle morphology, size, and density is relatively easy. Uniform deposition is seen along with good stability | Electroanalytical and catalytic field |
Summary of the fabrication techniques used to synthesize NPG thin films.
SEM images of NPG structures. (a) NPG membrane made by dealloying 1 μm thick gold leaf in nitric acid for 1 h. (b) Coarsened NPG structure generated via annealing of (a) at 400°C for 8 h. (c) Hierarchical porous membrane structure produced by performing second dealloying (of sample b) in nitric acid for 5 min and annealing at 400°C for 4 h. (d) Cross-section micrograph of sample (c). Reproduced with permission from reference [
Variables such as acid concentration, etching time, and solution temperature are known to influence the size of pores and ligaments. NPG films with ultrafine pores have been produced by a pulse electrochemical dealloying carried out at a potential of 0.6 V with 50 ms on-time and 10 ms off-time in 8 M HNO3 at 23°C [21]. It has been seen that with the use of strong acid or alkali corrosion, the rearrangement is very rapid leaving little scope for porosity adjustment in such nanoporous products. Therefore, instead of the traditional corrosive acid etching, a two-step dealloying method has been reported which utilized FeCl3 to synthesize NPG wherein the pore size was easily tunable by using a surfactant like polyvinyl pyrrolidone (PVP) or replacing corrosion reaction solvent with ethylene glycol (EG) [22]. Dealloying can be further classified into three categories namely, (i) chemical dealloying, (ii) electrochemical or potentiostatic dealloying, and (iii) liquid metal dealloying. The driving force towards the selective dissolution of the active component is varied in the above-mentioned categories. It is a corrosive solution such as an acid in the case of chemical dealloying, the constant potential for electrochemical dealloying and the nature of liquid metal medium and temperature are the crucial deciding factors in the emerging field of liquid metal dealloying [11]. Extensive investigations have demonstrated that nanoporous metals with 3-D bicontinuous structures fabricated by the dealloying method, has many active sites for the excitation of localized surface plasmons and can, therefore, serve as a potential substrate for practical surface-enhanced Raman scattering (SERS) application [23]. Unlike single-sized porous materials, a hierarchical (bimodal) porous structure can impart novel properties to the material wherein large pores can favor increased mass transport and small pores can impart high specific surface area [24].
Self-assembly is one of the most versatile, simple, and inexpensive methods aiding the formation of porous polymer films with finely controlled topography [25]. The self-assembly strategy is a powerful approach to create functional nanomaterials due to the high selection capability of the precursor materials and inclusion of functional groups, and nanoarchitectonics. The process is usually carried out under ambient and mild conditions, making the process suitable for biological materials, see Table 1 [26]. The self-assembled nanostructured film is a rapidly emerging field of great fundamental and practical interest due to the prospective applications in the field of microelectronics, non-linear optics, catalysis, and sensor science. Controlled covalent attachment of nanoparticles to functionalized surfaces is a versatile approach for producing thin-film structures. It has been seen that self-assembly of gold nanoparticles (AuNPs) on thiol modified surfaces exhibited non-metallic optical and electronic properties [27]. The self-assembly process of the AuNPs via aggregation and coalescence leads to the porous structure directly without relying on external assistance. Zhang and coworkers successfully fabricated porous gold films from a colloidal gold solution by evaporation induced self-assembly method (EISA) [28]. A facile synthetic approach for the self-assembly of AuNPs on sulfide functionalized polydopamine surface in high-density has been reported. AuNPs were seen to self-assemble strongly on the modified surface due to the strong interaction between gold and sulfur atoms [29]. Nanostructural control is very critical in material chemistry to bring out unique physical and chemical properties. So far, many mesoporous materials with varying compositions have been reported via self-assembly of amphiphilic organic molecules and have attracted keen interest due to their wide range of potential applications in energy storage, separation, catalysis, ion exchange, sensing, and drug delivery [30]. Another useful technique to immobilize gold thin films on micro- and nanopatterns is via the use of directed self-assembly on templates that are prepared by phase- separated mixed Langmuir Blodgett (LB) films. Atomic force microscopy (AFM), Auger electron spectroscopy, and scanning Auger electron mapping of the gold thin films revealed that the immobilized layer was following the patterns of the original mixed LB films [31]. Systematic analysis of the thermodynamics and kinetics of self-assembly in thin films of supramolecular nanocomposite has been studied in detail to extract information about the interfacial area defects, chain mobility, and activation energy needed for the diffusion of materials. Co-assemblies of nanoparticles and organic moieties are promising, and the resultant material will combine the properties of both the families of building blocks. Hierarchically structured nanocomposite thin films over macroscopic distances have been created by a fast ordering process with minimal usage of solvent via a deep understanding of the kinetic pathways [32].
Sputter deposition is an industry-relevant, high-rate, large-scale, and well-controllable deposition technique used to prepare gold films and other device fabrication processes. It is a large-scale deposition method, allowing high-rate vacuum coating with nanoscale precision, see Figure 3. Sputter deposition is an ideal method for preparing nanometer-thick films along with precise control over the deposition rate, highly adhesive films, large area uniformity, uniform temperature, and the ability to coat a variety of substrates including the non-heat resistant [33].
Schematic illustration of the
Sputtering is a pollution-free (“green”) technique that offers the advantage of reproducibility and low price of the final product. Nanostructured gold film adhesion and electrical contact properties are strongly influenced by interface structure, see Table 1 [34]. Thin gold films prepared by this strategy are found to be continuous and relatively homogeneous, with distinct grain surfaces without showing the formation of islands. Films of thickness ranging between 5 and 52 nm have been prepared for the study of third-order non-linear properties where the third-order susceptibility was found to be of the order of 10−9 esu. This non-linear optical interaction enhancement has helped to construct nanodevices to be used in metrology, sensing, imaging, and telecommunications [35]. It has been shown that pure sputtered gold films can match the hardness of gold electrodeposits. The hardness of sputtered films and the grain size of the deposit is controlled by maintaining the temperature of the substrate during deposition [36]. It has been reported that ultrathin semi-transparent gold films have been deposited using radio frequency (RF) magnetron sputtering at room temperature over a small area (23 mm2) of the porous silicon layer. Various film thicknesses were obtained by changing the sputtering time from 5 to 20 s at constant chamber pressure and argon gas flow rate [37]. Thin films have been deposited by varying the experimental conditions concerning the substrate tilt angle and background pressure. Growth regimes of thin gold films deposited via magnetron sputtering at oblique angles and low temperatures have been studied from both theoretical and experimental points of view [38]. The growth and morphology of a room temperature sputter-coated thin gold film on a soft polymeric substrate from nucleation to thin film formation has been investigated using AFM. It was observed that an initial 3-D island-type growth starts with the deposition and with increasing time the morphology evolved from hemispherical islands to partially coalesced worm-like island structures, to percolation, and finally to a rough and continuous film [39]. In a study, it was seen that after the stage of nucleation, the growth of gold clusters proceeds mainly in the lateral direction. As the discontinuous islands change into a continuous thin film, a rapid decline in the resistance of the gold layer has been observed [40]. A unique method for synthesizing porous gold films by co-deposition of Au-Cu alloy has been done via co-sputtering Au and Cu using a multi-target sputtering system at room temperature. Selective removal of Cu was done via corrosive dealloying leading to the formation of the porous gold film via the physical–chemical combination method [41]. Sputter deposited thin porous gold films find applications in the field of electrochemical biosensing for enhancing redox signals by modulating the nanopore size and film thickness. Higher detection resolution is exhibited to that obtained by conventional bulk gold electrodes [42]. The atom sputtering deposition technique has allowed scientists to study the optical and electrical properties, density, and crystalline structure of gold nanostructures sputtered on glass [40].
Electrodeposition is a simple, controllable, and cost-effective method that can control the growth process by varying deposition current density. Kinetic control over the growth process can give insights into the mechanisms in the synthesis of deposits with various sizes and shapes. The mass of gold on the electrode is controlled by the electric charge passed during the electrodeposition process, based on Faraday’s laws of electrolysis [43]. Deng and co-workers gave a mechanistic viewpoint to the facile method of electrodeposition in the electrochemical cell, where a process of electrodissolution-disproportion-deposition is involved. Upon the potential step, the gold substrate undergoes active electrodissolution in HCl providing the diffusion control, forming AuCl2− and AuCl4−. With the progress of the reaction, HCl depletes and AuCl2− starts accumulating near the gold surface immediately giving off Au atoms and AuCl4− wherein the newly formed Au atoms aggregate and deposit on the substrate to form NPG film [44, 45]. NPG morphology evolution has a direct relationship with the topography of the underlying substrate. A study has very well demonstrated that micropattern widths that are within the magnitude of film thickness produce tunable pores with less cracking [46]. Porous nanomaterials particularly NPG has drawn tremendous research interests mainly in the development of electrochemical sensors due to the high surface area and the trait of being electrocatalytically active. Electrosynthesis can impart precise control over the bicontinuous network of interconnected nanometric gold grains and multiple sized pores [47].
Conductive substrates coated with AuNPs can be exploited as biochemical sensors and electrodes owing to their excellent electrocatalytic activity. A simple, powerful, and cost-effective way for attachment of AuNPs onto a substrate has been electrodeposition with pulsating current resulting in smoother, brighter, finer, and less porous Au grains concerning the direct current [48]. A simple template-less, surfactant-less and effective electrochemical method for the preparation of AuNP arrays with an average diameter of ~14 nm onto indium tin oxide (ITO) glass has been reported. The system exhibits excellent catalytic properties due to the presence of large active sites on the surface [49]. The deposition of thin metallic films onto non-conductive surfaces by the wet processing technique of electrodeposition is another route for fabricating various unique electronic devices and systems. Amine terminated self-assembled monolayer (SAM) modified insulator surface has been employed for the lateral growth of electrodeposited gold. Controlled morphology and thickness of laterally grown metal films has paved a way to create nanogap electrodes [50].
Electrochemical deposition methods have been classified into two groups namely, templated electrodeposition and self-templated electrodeposition. Template technology offers advantages for designing new types of electrode materials aided by “hard” or “soft” templates that give rise to functional materials with diverse structures and morphologies, such as, one-dimensional nanostructures, two-dimensional films, and 3-D porous frameworks. In templated electrodeposition, porous gold is deposited on a template by reducing gold near the electrode surface via fixed potential application followed by the removal of the template. The self-templated approach initializes with the generation of H2 bubbles in the solution containing a supporting electrolyte by applying a potential of at least −2 V vs. saturated calomel electrode (SCE), allowing a gold reduction in the interstitial space [51, 52]. The monolithic NPG film has been synthesized using a bottom-up synthesis from a bicontinuous microemulsion (BME) acting as a dynamic soft template, depicted in Figure 4. The aqueous phase of BME acted as a medium for gold electrodeposition and the intertwined structure came from the aqueous and oil phases of BME compartmentalized by surfactant and cosurfactant. The resultant film nanostructure has been controlled by adjusting the initial BME composition and by varying kinetic parameters such as deposition potential and time [53].
Schematic representation of the dynamic soft templating of a nanoporous thin gold film from BME by electrodeposition. Reproduced with permission from reference [
The role of electrodeposition potential on the growth morphologies has been seen in a study where gold deposition from sulfite electrolyte exhibits a range of geometries from vertically oriented nanowires to lenticular grains and dendrites at more negative potentials [54].
In recent years, studies have been performed to produce 3D porous materials that have the advantage of increasing the mass transport for electrolytes but also allow rapid electrochemical reactions due to considerable active surface area. A new way of producing such materials is via concurrent generation of hydrogen bubbles with simultaneous metal deposition at high cathodic current densities. The reduction of H+ giving rise to hydrogen bubbles acts as a dynamic template for metal electrodeposition [15]. The electrodeposition parameters such as time and potential are the deciding factors for the pore size and film density. The dynamic hydrogen bubble template (DHBT) method results in a gold nanoporous structure with outstanding properties, like high specific surface area, large pore volume, uniform nanostructure, good conductivity, and enhanced electrochemical activity [55]. A simple method has been proposed for the one-step electrodeposition of NPG-islands films on the surface of the glassy carbon (GC) electrode via the hydrogen bubble template approach. The 3-D structure generated via the DHBT method is more attractive as it is clean and porous in an efficient way in the absence of inorganic and organic templates and exhibited improved electrocatalytic activity for oxygen reduction and hydrogen evolution reactions (HER) [56]. Recently, self-supported 3D metal foams of copper, tin, and silver have been reported. 3D porous noble metals such as gold have higher equilibrium potential and lower overpotential for HER and therefore, a two-step rout was taken involving the deposition of the less noble element followed by its galvanic displacement. Chung and coworkers have therefore shown a fast one-step preparation of high surface area NPG with a multimodal pore-size distribution utilizing a DHBT [12].
Another study produced porous gold incorporating nanocorrals on gold screen-printed electrodes (SPEs) utilizing hydrogen bubbles as a dynamic template. The structure produced using this one-step electrodeposition using high overpotential had a high roughness factor [57]. Moreover, distinct pore morphology can be obtained by taking advantage of electrical conductivity and morphological plasticity of NPG. Pore morphology can be tuned using the novel and versatile technique of electro-annealing on NPG thin films at low temperatures [58]. The microstructure of electrodeposited gold films and their deposition characteristics are affected by base metal ions. It has been seen that gold deposits obtained from Co and Ni-containing electrolytes are generally hard, while Pb and Tl-containing electrolytes tend to give soft gold deposits [59]. The crystallographic structure of gold films is also dependent on the current density at which electrodeposition has been carried out. It has been seen that Au electrodeposited at a current density less than 0.25 mA cm−2 from dicyanoaurate baths with or without Cu2+ or Tl+, gave rise to the formation of hexagonal structure [60].
The electrochemical potential and the concentration of HAuCl4 have been modified to create a variety of morphologies in the final structure. Nanopyramidal, nano rod-like, and spherical gold nanostructures were fabricated on polycrystalline gold substrates via one-step, non-templated electrochemical overpotential deposition (OPD) [61]. Moreover, the chemical nature of the organic ions present in the organic electrolytes has a huge role to play on the morphology of the deposits produced. The organic species adsorb onto the electrodeposits due to high surface energy and finally influence the shape of the growing grains and the roughness of gold electrodeposits [62]. Recently, a study described the electrodeposition of gold nanostructures at the interface of a Pickering emulsion. The controlled electrodeposition of AuNPs on the surface of an emulsion droplet gave rise to intricate structures with fine control over the locus or duration of nanoparticle growth. Decamethylferrocene present in the emulsion droplet acted as a heterogeneous electron transfer agent for the reduction of aqueous phase Au (III) resulting in its deposition as nanoparticles [63]. In one of the studies, it was found that SERS of the electrodeposited gold was correlated to the roughness and the size of surface nanostructures where these two parameters were largely controlled by the applied potential during deposition [64]. Over the last decade, researchers have focused on improving methods for fabricating reproducible substrates for surface-enhanced resonance Raman scattering (SERRS). Amongst these, deposited gold films have been the most heavily researched, and therefore, Bartlett and his group fabricated ordered-spherical-cavity gold films using colloidal templated electrodeposition method for the first time. The net enhancements are found to be ~109 for SERRS over normal Raman [65]. Nanostructured gold films for use in localized surface plasmon resonance (LSPR) spectroscopy have been prepared from flat gold film substrate made by stripping off epoxy coated glass slides off the gold-sputtered silicon wafers and then subsequent two-step chronoamperometry to electrodeposit gold from potassium dicyanoaurate solution [66].
Solid thin film deposition on the soft ionic liquid (IL) substrate was used for L-arginine detection. A gold monolayer was deposited on the surface of the IL substrate using the conventional electro-co-deposition (CECD) technique using an electrochemical workstation with three electrodes system in 0.5 M NaCl and 3 mM KAuCl4 electrolyte solutions [67]. A new study described the bottom-up approach of lithographically patterned nanowire electrodeposition (LPNE) for synthesizing noble metal nanowires on glass or oxidized silicon surfaces. The process of LPNE starts with the preparation of a nickel nanoband electrode which acts as the surface for electrodeposition [68].
LPNE has been combined with colloidal lithography to create a novel low-cost method for the lithographically patterned electrodeposition of metallic nanoring close-packed arrays over large areas. By altering the width and radius of the nanoring during the fabrication, near-infrared (NIR) plasmonic resonances could be tuned from 3500 to 8000 cm−1 with potential applications in the fabrication of plasmonic antennae, plasmonic semiconductors, and negative-index metamaterials [69]. Direct electrodeposition of porous gold nanowire arrays has been developed utilizing a one-step electrodeposition methodology utilizing nanochannel alumina templates. Current density during deposition is the deciding factor for the microstructure of gold nanowires and the resulting structure has shown excellent electrochemical biosensing ability towards the detection of glucose [70].
It has been known that the surface roughness and the structure of gold deposits can be influenced by periodically reversed or pulsed current and in some electronic applications pulse plated gold deposits are considered superior to DC plated deposits. Electrodeposition of gold using pulse plating produces a dense fine-grained structure with half the resistivity of normal DC plated films [71]. The pulse potentiostatic method (PPSM) offers numerous advantages in terms of controllability, particle size, stronger adhesion, and uniform film morphology. PPSM has been used to deposit gold nanoflowers (AuNFs) onto a polymer film. Through this simple and rapid method, a new organic–inorganic hybrid film has been fabricated with superior electroactivity, electrochemical, and interfacial characteristics suggesting the suitability of such electrodes for sensors, electrocatalysis, and diode applications [72]. Epitaxial, ultrathin, semitransparent, and catalytic gold films were electrodeposited on n-type silicon (n-Si) to protect the substrate from photo-passivation, see Figure 5. In addition to being a good redox catalyst, the ultrathin gold layers serve to induce band bending in n-Si thereby making it a diode of an ideal quality factor due to minimal electron–hole recombination [73].
Illustration showing the formation of an ultrathin epitaxial gold layer electrodeposited on n-Si (111) to form a Schottky junction in a regenerative photoelectrochemical cell. Reproduced with permission from reference [
Fabrication methods have been used in combination in the past to generate a promising eco-friendly biosensor platform with advantages coming from both the techniques. One such study has been done to fabricate a glucose biosensor wherein AuNPs and glucose oxidase multilayer films were generated via electrodeposition and self-assembly respectively [74]. As an eco-friendly alternative, deep eutectic solvents (DESs) are a new class of green and sustainable solvents extensively used for electrodepositions due to their intrinsic properties of good solubility, non-flammability, low toxicities, and suitable electrochemical windows. Recently, an electrochemical method has been developed to fabricate NPG electrodes by alloying and dealloying the precursor alloy in ZnCl2-urea deep eutectic solvent [75]. The wide acceptance of DES in metal/alloy electrodeposition processes has been seen in recent times due to their ability to act as stabilizers and reducing agents in metal nanoparticle synthesis. Moreover, the nucleation rates are enhanced leading to a decrease in the particle size in the presence of DES as it has relatively low surface tension [76]. Remarkable optical behavior has been observed when the bulk material is transformed into nanostructured surfaces. A simple two-step electrochemical process has been developed wherein electrodeposition and anodization is used in conjunction to generate black gold surfaces that can absorb more than 93% of the incident light over the entire visible spectrum due to the canopy of dendritic nanostructures within a nanoscale roughness with potential applications in photovoltaic solar cells [77]. Figure 6 summarizes the general methods used for electrodeposition to form thin nanoporous films.
A general overview of the techniques used for electrodeposition to form thin nanoporous films.
The physical and morphological properties of nanoporous thin films are strongly linked with material’s porosity (defined as the ratio of void volume to the total volume of the film). Hence, many efforts have been devoted to developing a reliable self-consistent quantitative characterization of their porosity [78]. The physical characteristics of thin films have been characterized by a combination of X-ray photoelectron spectroscopy (XPS), grazing-incidence small-angle X-ray scattering (GISAXS) along with adsorption isotherm surface area measurements. Porosity and internal feature sizes range from a few to tens of nanometers [79]. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) experiments have the potential to find the electrochemically active surface area of the NPG film. Studies have shown that using CV and EIS it was shown that NPG films have 4–8.5 times more accessible surface area than thermally evaporated gold (EG) films [80]. Potential step (PS) chronoamperometry has also been combined with surface plasmon resonance (SPR) for probing electrochemical deposition, conformational changes linked with redox-initiated film reorganization, and the quantification of electrodeposited thin film thickness [81]. A well-recognized approach to determine the specific surface area of nanoporous materials is the Brunauer, Emmett, and Teller (BET) method which is based on physical adsorption of gas molecules to determine the specific surface area [82]. Many groups have extensively used scanning electron microscopy (SEM) for rapidly exploring pore size and ligament size due to their ease of use and applicability to varying types of samples. Elastic modulus is an important mechanical property to calculate residual stress in free-standing beams. This in turn determines film stiffness and therefore, sensor performance [83]. SEM and AFM techniques have been used by many researchers to characterize the surface morphology, size, and shape of the pores as well as the surface roughness of the porous gold films [84]. Maaroof and coworkers have measured the optical properties of porous gold film using the techniques of spectrophotometry and ellipsometry. The spectral response was delivered using a homogeneous Lorentz-Drude (L-D) model and showed that the optical properties of NPG films are dependent on void occupancies [44]. Nanoporous metals have significant geometric complexity in the form of random bicontinuous structures possessing bubbles within ligaments, regions of very high negative, positive, and saddlepoint curvature, and multiple facets. Erlebacher introduced methods to geometrically quantify the structure of nanoporous metals using large-scale kinetic Monte Carlo simulations using mesh-smoothing algorithms [85]. Atom probe tomography (APT) analysis of NPG material, produced by dealloying can give huge information regarding the compositional variation within the structure of nanoscale ligaments. 3-D analysis of materials at the sub-nanometer scale is possible by careful preparation of samples through a reproducible process for complete pore filling through electrodeposition of copper into finely sized pores. Compositional profiling and mapping of ligaments are now possible by APT analysis [86]. Electrodeposition of gold nanostructures having sharper features yield higher refractive index sensitivity and therefore, can be used as transducers in LSPR spectroscopy for probing many types of biomolecular interactions [66].
Nanoporous materials such as carbon nanotubes, nanoporous anodic alumina, nanotubular titania, porous silicon, and NPG have significant potential in the field of biomedicine involving high drug loading capacity and its controlled release. It was seen that a sub-micron-thick sputter-coated NPG thin films have a loading capacity of 1.12 μg/cm2 and molecular release half-lives between 3.6 hours to 12.8 hours [87]. NPG is a promising material for drug delivery applications and for studying the influence of surface modification on the drug release kinetics due to its high effective surface area, well-known surface gold-thiol chemistry, and tunable pore morphology and is depicted in Figure 7 [88].
Depiction of surface engineering of NPG film via immobilizing alkanethiols with varying functional groups and chain lengths to enhance the drug delivery performance monitored via fluorescein release signal. Reproduced with permission from reference [
Rough and activated noble metals exhibit some unexpected properties in comparison with their smooth counterparts. The electrocatalytic activities of the porous films depend on the roughness factor and the existence of special binding sites on the surface. NPG films possess higher roughness and better electron transport leading to its distinguished performance in the field of catalysis [89]. Studies have shown that NPG is active towards catalyzing low-temperature CO oxidation which is attributed to the peculiar structure of NPG and the prevalence of step and kink sites on the surface of the material [90]. Nanoporous metals have recently attracted considerable attention fueled by their potential use in the filed od catalysis, sensor, and actuator applications by increasing the activity drastically via thick oxide film deposition to stabilize the nanoscale morphology [91]. The potential of nanostructured metallic surfaces has also been seen in optical applications and has been demonstrated for biosensing applications, SERS, guiding and manipulating light, and trapping of micro-sized particles [92]. The electrodeposition approach has been used for depositing a thin layer of AuNPs from 10 mM HAuCl4 for 20 s at −0.2 V (vs. Ag/AgCl) yielding oblate particles of 200 nm average diameter that immobilized an aptamer specific for LPS detection achieving a linear range of 0.1–10.24 ng mL−1 [93]. Thin nanoporous membranes of gold are best suited to the examination of surface plasmons as the analyte can get into the pores of NPG and can modify their dielectric atmosphere are detectable via absorption peaks in SPR whereas the species that adsorb onto the geometric surface of the pores of the film are equally detected by SPR measurements [94].
The electrodeposition of noble metals on support provides a unique possibility to obtain films of varying thickness and roughness. Many advanced electrodeposition techniques are known so far, and the field is actively developing with specific controllable nanostructural features leading to an increased number of grain boundaries for high catalytic performance [95]. It is interesting to see how the porous gold nanostructures can be electrodeposited on a solid support and the impact of electrodeposition parameters namely, potential and time of deposition, on the morphology and thickness of the film so formed. Detailed investigation on NPG surface pore size and the correlation with electrocatalytic activity has aimed to understand the growth mechanism of NPG [13]. The experimental results from the electrodeposition techniques have highlighted that the formation of a well-organized NPG film requires the appropriate electrochemistry and physics/mechanics interactions between the substrate and the deposits [96]. NPG morphology evolution is highly influenced by the topography of the substrate emphasizing the structure–property relationship and opening doors for such high-throughput combinatorial studies [46]. An exciting new field of research within the domain is the electrodeposition of hybrid thin films which has opened the gate to an unlimited number of new materials [97]. Electrodeposition, therefore, is a promising fabrication technique that has the potential of producing thin NPG films for effective drug delivery systems as precise control of the NPG pore and ligament dimensions can be achieved which in turn control the drug loading and release performance inside the body [98]. Electrodeposition is a distinct form of grain boundary engineering by which a material’s property can be enhanced to synthesize advanced materials both in bulk form and as thin films. It is a technologically viable production method for upgrading the mechanical, electrical, magnetic, and corrosion properties exhibited by metals [99].
The authors declare no conflict of interest.
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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. 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