Comparison of mean (
\r\n\tThe applications are those related to intelligent monitoring activities such as the quality assessment of the environmental matrices through the use of innovative approaches, case studies, best practices with bottom-up approaches, machine learning techniques, systems development (for example algorithms, sensors, etc.) to predict alterations of environmental matrices. The goal is also to be able to protect natural resources by making their use increasingly sustainable.
\r\n\r\n\tContributions related to the development of prototypes and software with an open-source component are very welcome.
\r\n\r\n\tThis book is intended to provide the reader with a comprehensive overview of the current state of the art in the field of Ambient Intelligence. A format rich in figures, tables, diagrams, and graphical abstracts is strongly encouraged.
",isbn:"978-1-83969-069-3",printIsbn:"978-1-83969-068-6",pdfIsbn:"978-1-83969-070-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"3fbf8f0bcc5cdff72aaf0949d7cbc12e",bookSignature:"Dr. Carmine Massarelli",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10391.jpg",keywords:"Embedded Systems, Technologies, Sensors, Remote Sensing, Smart Homes, Smart Cities, Integrated Monitoring Techniques, Agroecosystem, Smart Public Spaces, Computer Vision, Image Processing, Open-Source",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 12th 2020",dateEndSecondStepPublish:"November 9th 2020",dateEndThirdStepPublish:"January 8th 2021",dateEndFourthStepPublish:"March 29th 2021",dateEndFifthStepPublish:"May 28th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Environmental technologist expert in the development of Smart Technologies for water management and environmental monitoring, characterization, and monitoring of contaminated and degraded sites, integration of spatial data such as standard methodologies, interoperability, spectral data infrastructures.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"315689",title:"Dr.",name:"Carmine",middleName:null,surname:"Massarelli",slug:"carmine-massarelli",fullName:"Carmine Massarelli",profilePictureURL:"https://mts.intechopen.com/storage/users/315689/images/system/315689.jpg",biography:"Main activities:\n-development of Smart Technologies for water management and environmental monitoring;\n-characterization and monitoring of contaminated and degraded sites;\n-implementation of early warning systems and impact assessment systems also from multitemporal monitoring;\n-integration of spatial data: methodologies, standards, interoperability, spatial data infrastructures;\n-use of open source IT systems for the processing, analysis, and integration of remote sensing data with airborne and satellite sensors for thematic purposes such as characterization, control, and analysis of the territory in support of environmental policies relating to contaminated sites;\n-evaluation of the contamination of environmental matrices with specific tests and chemical analyses;\n-installation of airborne sensors and definition of flight parameters for Earth observation, CASI-1500 hyperspectral and TABI-320 thermal sensors;\n-acquisition of spectral signatures of objects through Fieldspec portable spectroradiometer and creation of databases in SQL language;\n-use of tools such as Ground Penetrating Radar for the advanced investigation of the subsoil with law enforcement agencies.",institutionString:"National Research Council",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Research Council",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"297737",firstName:"Mateo",lastName:"Pulko",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/297737/images/8492_n.png",email:"mateo.p@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:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"54978",title:"Effect of Uropathogenic Escherichia coli on Human Sperm Function and Male Fertility",doi:"10.5772/intechopen.68312",slug:"effect-of-uropathogenic-i-escherichia-coli-i-on-human-sperm-function-and-male-fertility",body:'Infertility is currently a highly prevalent disease, defined by the failure to achieve a successful pregnancy after 12 months or more of appropriate, unprotected intercourse or therapeutic donor insemination [1]. Approximately 50% of infertility cases are attributed to the male [2, 3] due to conditions such as varicocele, cryptorchidism, obstructive problems, hormonal disorders, ejaculatory dysfunction as well as infectious causes classified under male genital tract infection (MGTI).
MGTI accounts for 15% of male infertility cases [4]. MGTIs are an important problem in male reproductive health because they cause negative changes in semen parameters [5]. A consequence of MGTI is the inflammatory response evidenced by leukocytospermia, where a treatment with antibiotics and anti‐inflammatory drugs may be helpful to try to recover the patient’s fertilizing potential [6]. Principal causes of MGTI are bacteria such as Staphylococcus epidermidis, Streptococcus viridans, Staphylococcus aureus and Escherichia coli (E. coli), which have a negative effect on the fertilizing potential of a man and are strongly associated with MGTI [7, 8]. However, E. coli has been shown to exert greater damaging effects on human spermatozoa [7, 9–11].
E. coli is the causal agent in 65–80% of cases of chronic bacterial prostatis [12], and these bacteria have been isolated from semen in 69% of the patients with this pathology [13]. Moreover, E. coli causes diverse MGTIs such as urethritis, epididymitis and orchitis, and it is the most frequently isolated bacterium [4].
With this background, this chapter discusses the negative effect of E. coli on sperm quality and male fertility. The chapter will be developed by first addressing the uropathogenic E. coli strains associated with male infertility. Then, the evidence of the in vitro effects of E. coli on the male gamete will be analyzed. Evidences will be described, obtained after in vitro co‐incubation of normal human spermatozoa with E. coli and with polymorphonuclear leukocytes, emulating infection. Next, the effects of E. coli on human sperm functions observed by direct incubation of spermatozoa with bacteria and without leukocytes will be discussed. Also, evidence of the effects of the metabolic and soluble products of E. coli on human sperm function will be analyzed. To complete the picture of the evidence of the effects of this bacterium on male fertility, some studies on animal models will be reviewed.
Among the different pathogenic strains of E. coli, the uropathogenic strains are mainly associated with urinary tract infections (UTI). The pathogenic E. coli is classified according to the O antigens. Some of these have been associated with uropathogenic E. coli (UPEC) being the serotypes O1, O2, O4, O6, O7, O8, O16, O18, O25, and O75 preferentially associated with these strains [14]. Similarly, the most frequently O antigens associated among the serotypes isolated from patients with prostatitis are O1, O2, O4, O16, O18, O22, O25 and O75 serotypes [15], which coincide with E. coli strains isolated in cases of infections to the urinary tract. Regarding to the strains isolated from semen of infertile men, the described prevalent antigens are O1, O2, O4 and O6 [16]. These data indicate that the E. coli that infects the male reproductive tract is uropathogenic strain, which is not surprising considering the proximity of the urinary and reproductive tracts.
One way E. coli induces damage in spermatozoa is by mediating seminal leukocyte activation. The increased presence of leukocytes in semen, known as leukocytospermia, is defined by a concentration equal to or greater than 1 x 106 leukocytes per ml of semen [17]. Proinflammatory cytokines, which are usually released by leukocytes during the inflammatory response, are able to decrease sperm motility by themselves [5, 18, 19]. This damaging effect seems to be mediated by polymorphonuclear (PMN) leukocytes instead of by other leukocytes such as lymphocytes or monocytes [20]. The decrease in sperm quality is also mediated by reactive oxygen species (ROS) released by PMN after bacteria‐induced activation, with E. coli being able to induce a higher response of increased ROS production than other bacteria [9]. Other consequences of ROS released by leukocytes are lipid peroxidation, which affects sperm plasma membrane [21, 22], and early induction of sperm capacitation, which should normally occur later in the female reproductive tract [23].
The direct effect of E. coli on sperm was demonstrated through in vitro studies performed by directly incubating both cells. It has been demonstrated by several authors that E. coli coming into contact with spermatozoa causes decreased sperm motility [7, 24–26]. The decrease in sperm motility due to E. coli has been attributed for many years to an agglutinating effect on sperm [27]. Sperm agglutination can be caused by bacterial type 1 and P fimbriae; specifically, the type 1 fimbriae of E. coli cause a pattern of head‐head type agglutination because they bind mannose residues in the head region of sperm. Instead, type P fimbriae of E. coli cause a head‐tail agglutination pattern because they bind gal‐gal receptors present along the sperm [28].
Electron microscopy has revealed that this bacterium causes damage primarily in the head of spermatozoa, such as rupture of the plasma membrane, vesicle formation and rupture of the inner and outer membranes of the acrosome [29].
Consistent with the plasma membrane damages observed, another report showed that E. coli per se causes phosphatidylserine translocation, a cell death indicator [9]. From the point of view of sperm cell death, it was observed that E. coli endotoxins such as lipopolysaccharide (LPS), peptidoglycan and porins produce loss of sperm viability [30]. Moreover, it has been shown that LPS and porins cause sperm DNA fragmentation [31]. The effects of these endotoxins are mediated by the toll‐like receptor (TLR)‐2 and TLR‐4, both present in sperm. After TLR‐2 and TLR‐4 stimulation, sperm damage highlighting DNA fragmentation can be observed [32].
Another direct effect of E. coli is at the level of mitochondrial membrane potential (ΔΨm). The in vitro observation that contact with E. coli decreases the ΔΨm together with the motility in spermatozoa [33] was followed by another report showing, also in vitro, that E. coli directly reduces sperm ΔΨm and alters plasma membrane stability [34]. From the point of view of sperm function, it has been observed that ΔΨm is positively correlated with sperm motility in vivo [35, 36]. However, after contact with some strains of E. coli, which decrease sperm motility in vitro, they had no effect on ΔΨm [37]. This study also found that some E. coli isolated from different patients was unable to decrease sperm motility, remarkably even an O6, which is thought to be a highly uropathogenic strain in urinary tract infections [38]. These facts contrast with the notion that E. coli in general alters sperm function. These differences could be attributed to the fact that different strains bear specific but different characteristics from other E. coli strains. Evidence confirming this was observed in our work, when sperm were incubated with a hemolytic strain of E. coli. This strain caused a decrease in motility, ΔΨm, vitality and an increase in intracellular ROS in normal spermatozoa. These effects were not observed with other strains non‐hemolysis producers [39]. These differences among strains highlight the importance of knowing what kind of toxins are effectively produced by the E. coli strain infecting a patient, because it could indicate the level of sperm damage to be expected. As example, hemolytic E. coli strains produce the alpha‐hemolysin (HlyA) toxin [40], a calcium‐dependent pore‐forming toxin which has intracellular effects, inactivating pathways related to cell survival [41]. This toxin can be highly relevant, particularly if we consider that between 40 and 50% of E. coli strains isolated from patients with epididymitis release this toxin [42].
Evidence of E. coli effects on human spermatozoa shows that this bacterium impairs sperm quality, principally causing decreased motility; nevertheless, there are other consequences for sperm quality, specifically the incubation of sperm with E. coli decreases the ability of the male gamete to penetrate the oocyte, the most important step in the function of the spermatozoon [43].
The effects of E. coli soluble products on sperm have been studied using supernatants of E. coli culture as a source of bacterial metabolic product. It has been reported that although the direct contact with E. coli was able to alter sperm motility, the metabolic products of E. coli had no effect on decreasing motility in human spermatozoa [24]. However, after this report, it was shown that incubation with the soluble factors of E. coli reduced sperm motility and ΔΨm [33]. Added to this, the ability of E. coli soluble factors to decrease motility, viability, ΔΨm and increase ROS in spermatozoa can be prevented by lactobacilli. In an in vitro experiment, after adding lactobacilli to simulate the normal condition in the female genital tract, the harmful effects of E. coli soluble factors were inhibited [44].
Among the soluble factors of E. coli, a component called spermatozoa immobilization factor (SIF) was first described in 1977. The effect of SIF, as the name implies, is to immobilize spermatozoa, and this effect could be reversed by washing the spermatozoa [45]. Years later, an apparently similar SIF of 56 kDa was isolated and purified from supernatants of a strain of E. coli. SIF‐56 decreases sperm motility completely and almost instantaneously. It was also observed that SIF‐56 at very high concentrations can even induce sperm death [46]. Sperm immobilization mediated by SIF‐56 has been shown to depend on 115 kDa‐receptor present in sperm [47]. Another E. colisoluble factor described is the sperm agglutinating factor (SAF) of 71 kDa, which produces sperm agglutination, decreases ATPase activity and can cause sperm death [48]. A toxin candidate to be further investigated is HlyA, because this toxin is produced by E. coli strains most pathogenic to sperm both in vitro and in vivo [42].
In vitro investigations have the disadvantage of not necessarily representing what would happen in vivo. Hence, in vivo studies in animal models allow us to get closer to the reproductive reality of a man with accessory glands infected by E. coli. That is how the progressive reduction of testicular size with a consequent decrease in sperm count caused by the necrotic death of the testicular germ cell has been described in rats inoculated with E. coli [49]. After three days of injecting rats with HlyA producing E. coli, the epididymis had epithelial damage, leukocyte infiltration and edema and the sperm‐fertilizing potential was lost, because despite being motile, the spermatozoa had a premature acrosome reaction [50]. The above‐mentioned greater pathogenicity of the HlyA‐producing E. coli strains was reported in the work of Lang [50], where the E. coli strains that did not produce HlyA induced only slight damage to the epididymis. As already stated, sperm recognize peptidoglycans and LPS through TLR‐2 and TLR‐4, and this recognition event induces sperm cell death. This was confirmed by using knockout mice for both TLR‐2 and ‐4 and by observing that in these animals LPS or peptidoglycans did not induce sperm death [32].
Further evidence of the contribution of some E. coli strains to infertility was observed after inoculating the vaginal tract of rats with SAF‐producing strains. Control rats were inoculated with E. coli non‐SAF producers. It was observed that the rats inoculated with SAF-producing strains were incapable of pregnancy, demonstrating that these toxin‐producing strains affect fertility profoundly [51].
It is clear that E. coli has an important role in causing male infertility associated with genital tract infections. The main mechanism postulated for male infertility by E. coli is the profound damage to different sperm processes and function, either by direct contact and/or through secreted toxins.
While today there is a consensus that E. coli is an important causal agent of MGTI that may actually cause infertility, from the latest evidence presented above, it is clear that this would not be completely true for all UPEC. Due to these differences among the various strains, it seems important to develop molecular studies that can clarify what specific features of the E. coli strains are associated with the pathogenic effects on sperm or with an aggressive inflammatory response this point should be followed.
To date, there have only been a few studies at the molecular level to try to explain how E. coli causes infertility.
Knowledge of the molecular mechanisms by which E. coli damages sperm will make it possible to take measures to avoid its consequences on the fertilizing potential of men.
In recent years, 68Ga-radiopharmaceuticals gained more and more attention due to their steadily growing clinical application. Facilitated is this development by increasing interest in the application of its “theranostic twin” lutetium-177. Combining both, gallium-68 and lutetium-177, enables diagnostic molecular imaging followed by personalized treatment based on the diagnostic scan [1].
This concept is well established for treatment of neuroendocrine tumors (NETs) using peptide receptor radionuclide therapy (PRRT). This approach allows the targeted treatment of inoperable or metastatic NETs already proven in multiple clinical trials employing radiolabeled somatostatin analogs [2, 3, 4, 5, 6, 7, 8, 9]. Based on the data received, the U.S. Food and Drug Administration (FDA) recently approved 177Lu-labeled DOTA-TATE for PRRT treatment. However, not only for NETs, but also for other types of cancer (e.g. prostate cancer (PC)), lutetium-177 is of interest, reflected in numerous clinical trials registered at
Although, gallium-68 was already proposed for medical use by Gleason [10] its way to clinical application was not possible without the advancement of the primary generator design. Providing [68Ga]GaCl3 and containing only trace levels of the long-living mother radionuclide germanium-68 regarding 68Ga-activity, the commercially availability of generator simplified research and motivated developments with a view to a broad routine application. The launch of this new type of 68Ga-generator together with decades of research in chelation chemistry and drug discovery resulted in the design of 68Ga-radiopharmaceuticals of high affinity/selectivity for their biological targets [11, 12, 13].
The advantages of the generator availability and the easy one-step chelation chemistry ensured the relatively fast and broad application of the 68Ga-radiopharmaceuticals even in smaller institutions. However, exactly these advantages lead to problems in the supply today and require new developments in order to meet the growing demands.
What is the advantage of radiometals for an application in nuclear medicine? With carbon-11 and mostly fluor-18, two radionuclides for positron emission tomography (PET) are available, which can be used for radiolabeling without appreciably altering the biological properties of the compounds in addition to their favorable decay characteristics. However, the disadvantage of radiometals, the need for a chelator is also their advantage over fluor-18 and carbon-11.
Due to this, radiolabeling with radiometals is very easy, can be conducted in aqueous solution and with the right choice of chelator possible under mild conditions. That enables radiolabeling of temperature or organic solvent sensitive compounds (e.g. antibodies). Additionally, the choice of chelator provides the possibility of radiolabeling one compound with different radiometals. Thus, widespread application (PET, single photon emission computed tomography (SPECT), magnet resonance tomography (MRT) and therapy) of the compound only by exchange of the radiometal with minimum changes in biological behavior is possible. This facilitates patient-centered care from diagnosis via molecular imaging, over treatment planning, prognosis and monitoring utilizing one compound (Figure 1).
Depiction of the theranostic concept: utilizing one compound for a variety of applications in patient-centered care radiolabeled with different radionuclide.
Advantages in favor of gallium-68 compared with other appropriate radiometals are its favorable decay characteristics, its (commercial) availability and the possible combination with lutetium-177 as theranostic pair (Figure 2). Also gallium-68 possibly provides patient care in places where cyclotron-produced fluor-18 is not obtainable.
PET-images (A; C) and SPECT-images (B) of a patient with metastatic castrate-resistant prostate cancer (mCRPC) undergoing therapy with [177Lu]Lu-PSMA-617 with pre- and posttherapeutic 68Ga-PET-imaging using the diagnostic counterpart [68Ga]Ga-PSMA-11.
Currently gallium-68 is most widely used in the diagnosis of prostate cancer in the form of [68Ga]Ga-PSMA-11, respectively. [68Ga]Ga-PSMA-617 together with [177Lu]Lu-DOTA-PSMA-617 forms a theranostic couple, which is very well suited for the diagnosis or treatment of prostate cancer as the 68Ga/177Lu-radiolabelled tracers show a very similar biological behavior. Due to similarities in chemical behavior, identical (in case of PSMA-617) precursors can be radiolabelled using the same or similar equipment, synthesis and quality control methods [14].
The second, but longest known and best evaluated, 68Ga theranostic pair is used for neuroendocrine tumors in combination with various somatostatin analogs. The three most widely used analogs of somatostatin with gallium-68 are [68Ga]Ga-DOTA-TOC, [68Ga]Ga-DOTA-TATE, [68Ga]Ga-DOTA-LAN or [68Ga]Ga-DOTA-NOC [15]. As a therapeutic counterpart, yttrium-90 and lutetium-177 are used.
Besides these two main applications of gallium-68, a variety of studies work on the extension of the application scope.
For imaging of insulinoma pancreatic islets, several versions of 68Ga-radiopharmaceuticals based on Exendin-4, a glucagon-like protein-1 receptor agonist, exist and it was demonstrated that [68Ga]Ga-DOTA-exendin-4 localizes insulinoma significantly better than 111In-radiolabelled radiopharmaceuticals [16].
Integrin αvβ3 and gastrin-releasing peptide receptor (GRPR) are usually overexpressed in human breast cancer, prostate cancer, breast cancer, colorectal cancer, pancreatic cancer, glioma, lung cancer, ovarian cancers, endometrial cancers, renal cell cancer and gastrointestinal stromal tumors. An amphibian homolog of the mammalian gastrin-releasing peptide bombesin was intensively investigated, also radiolabelled with gallium-68, for imaging of GRPR. For integrin αvβ3, specific imaging probes usually use the peptide arginine-glycine-aspartic acid (RGD). For imagine of GRPR, several radiopharmaceuticals based on gallium-68 were proposed, in particular [68Ga]Ga-BBN-RGD for breast cancer imagine [17], [68Ga]Ga-NOTA-Aca-BBN for glioma imagine [18], [68Ga]-NOTA-DUPA-RM26 for prostate cancer imagine.
Another promising area of application of 68Ga-based radiopharmaceuticals is the labeling of human epidermal growth factor receptor family (HER2) [19] and carcinoembryonic antigen (CEA) [20].
Even though gallium-68 is a very convenient radionuclide for use in radiopharmacy, it is widespread in radiopharmaceuticals in comparison with other diagnostic isotopes. But usability and the commercially availability of generator simplified research and motivated developments with a view to a broad routine application.
Radiolabeling with radiometals is in some ways challenging. Due to the very low amount of substance, other metals present in the reaction mixture can be serious problem and noticeably effect the radiolabeling. These metallic impurities can compete with gallium-68 for the chelating function of the precursor and are compared with gallium-68 (1 GBq equals to 9.73×10−12 mol) even when present at low levels (<ppm) clearly in excess number. They are result of external influences (e.g. production of starting materials) or are an intrinsic generator property (e.g. matrix; decay product). To avoid additional or larger impurities than necessary, the following is recommended by the IAEA [21]:
Use plastic disposables/contact materials
Avoid contact with metals of your working equipment during preparation of reagents (e.g. pipettes, spatulas, vials, etc.)
Protect your working materials from direct contact with metals (e.g. surfaces, etc.)
Use chemicals and water with lowest metal content as possible (e.g. ultra-pure grade)
Do not use standard laboratory glassware (e.g. beakers, etc.)
Consider coating of your fume hood.
Gallium is located in group 13 in the 4th period. It has 31 known isotopes and 11 metastable isomers including the two natural occurring stable isotopes gallium-69 (60.11%) and gallium-71 (39.89%). Two gallium isotopes are applied in nuclear medicine for PET-imaging: gallium-67, which has the longest half-life (T1/2 = 3.26 d) of the instable 68Ga-isotopes, and gallium-68 (T1/2 = 67.71 min).
Ga(III) is a hard Lewis acid forming complexes coordinating four, five or six ligands. The most stable complexes are the last-mentioned with a octahedral coordination sphere in which oxygen, nitrogen and sulfur donor atoms form coordination bonds with Ga(III). To ensure the complex formation thorough pH, control is required to ensure deprotonation of the electron donor and to protect Ga(III) from forming Ga(OH)3 precipitating at pH 3–7 [22].
Gallium-68 is a positron emitter that decays with a half-life of 67.71 min and 89% positron branching to stable zinc-68. The transition is accompanied by low-abundant photon emission (1077 keV, 3.22%) [23]. Table 1 shows the mean and maximum energies of the positrons emitted in comparison to fluorine-18.
Positron emitter | Half-life | Eβ, max | |
---|---|---|---|
[MeV] | |||
Gallium-68 | 67.71 min | 0.829 | 1.899 |
Flourine-18 | 109.77 min | 0.250 | 0.634 |
Comparison of mean (
One of the reasons of the emerging application of gallium-68 in nuclear medicine is its cyclotron-independency and availability via radionuclide generator. Since the application of gallium-68 was a long time limited to research, advancements in generator design facilitated research on new 68Ga-radiopharmaceuticals as well as clinical use of the known.
Physical basis for radionuclide generators is the existence of the radioactive equilibria. The differentiation between radionuclide generations is based on the half-lives of the parent (1) and its daughter (2). Depending on the ratio between the two half-lives, three principal cases can be distinguished:
Transient equilibrium. Longer living parent but not more than factor 100: T1/2, 2 < T1/2,1 < 100.
Secular equilibrium. Much longer living parent: T1/2, 2 < < T1/2,1.
No equilibrium. Shorter living parent.
The basis for the 68Ge/68Ga-generator is the secular equilibrium between the parent radionuclide germanium-68 and its daughter gallium-68. Germanium-68 decays with T1/2 = 270.95 days via electron capture to gallium-68. This transition is subsequently followed by decay of gallium-68 to stable zinc-68. At equilibrium, the quantity of gallium-68 produced is equal to the quantity of gallium-68 decaying, while the parent activity does not significantly decrease over many half-lives of the daughter. The theoretical maximum activity or equilibrium state for a certain generator system can be obtained at the time t (Figure 3):
Build-up kinetics of gallium-68 on the generator column after initial elution.
For the 68Ge/68Ga system, equilibrium is reached after 14.1 h, representing maximum obtainable activity. Even if idle times of 12.5 half-lives are necessary to obtain maximum activities, the generators can be used more frequently. Within two half-lives of gallium-68 already 75% of the maximum value is build-up and could be used.
The 68Ge/68Ga-generator system introduced in the 1960s by Gleason [10] underwent a lot of changes until today. From the first gallium cow providing gallium-68 after liquid–liquid extraction [10], nowadays the generators, based on a solid matrix (inorganic or organic) providing “ionic” 68Ga3+ eluates. The first commercially available generator of this type was developed by Cyclotron Ltd., Obninsk, Russian Federation [25] eluting gallium-68 with 0.1 M HCl with initial elution yields of ~80% and 68Ge breakthrough of 0.001% [26]. Since the introduction of this generator in 1996 [26], a lot has happened on the market. Today several manufacturers produce 68Ge/68Ga-generators, including ones with GMP grade (e.g. Isotopen Technologien Garching (ITG)) or with approval (e.g. GalliPharm® Eckert & Ziegler in the EU with marketing authorization, in the USA with type II drug master file (DMF) on file with FDA).
Even though these generators represent considerable improvements in 68Ga-production, there are still some obstacles to direct radiolabeling with gallium-68. Beside the low radioactive and high [H+] concentration and 68Ge breakthrough, especially the presence of other trivalent metal ions is an inconvenience. As 1 GBq gallium-68 is equal to 9.73 pmol (9.73×10−12 mol), these metallic impurities, even present at low levels (<ppm), can be a serious problem as they can compete with gallium-68 for the chelating function of the precursor. In addition to the IAEA recommendations on externally introduced metallic contaminations [21], several procedures are available to reduce those metallic impurities, either intrinsic or externally introduced. These post-elution purification methods, so called post-processing’s, aim to improve the radioactive and [H+] concentration and the radionuclidic as well as chemical purity of the 68Ga-eluate. Beside fractionation of the eluate [11], anion-exchange (AEX) [13], cation-exchange (CEX) [27, 28, 29] and a combination thereof [30, 31] found to be suitable but only for fractionation but also are commercially used for cation-exchange.
Although 68Ge/68Ga-generators represent a convenient possibility for persistent patient care with 68Ga-radiopharmaceuticals, their 68Ga-activity available for radiolabeling underlies several restrictions resulting from generator design and physics. In conjunction with the sharp increase in demand in recent years, alternative production routes, preferably realizable with existing medical cyclotrons, moved into the focus.
Small to medium energy medical cyclotrons are suitable for 68Ga-production via the 68Zn(p,n)68Ga reaction using either a solid or a liquid target. Among the possible nuclear reactions [32, 33], it is the most reasonable leading to large production yields. For optimal results, the starting material zinc-68 as well as the proton energy needs to be selected with care to reduce co-production of long-living radioisotopes of gallium. Nevertheless, co-production of gallium-66 and gallium-67 is unavoidable due to the starting material and the excitation function of the 68Zn(p,2n)67Ga reaction [32, 33]. This has to be taken into account when producing gallium-68 via cyclotron for radiopharmaceutical application as both radioisotopes cannot be separated from the desired gallium-68.
For production of gallium-68 via cyclotron, either a solid or a liquid target can be used. For both target types, a lot of options exist leading to a several considerations to be made. Solid targets, for example, can be pressed, electroplated, foil or fused, all types having their advantages and disadvantages which are not mentioned here. In a first instance, the choice of target will mostly be done due to the actual conditions of the site. An existing production site for 18F-compounds which want to implement gallium-68 would probably choose the liquid target route, as the preconditions for a solid target (target holder, cooling, target transfer and target processing) are expensive and likely not available. Compared with that, the liquid target is a quick and inexpensive option to obtain gallium-68 when a generator is not reasonable. A detailed overview about all possible alternatives and their advantages/disadvantages is given by the IAEA [21].
After irradiation, the gallium-68 needs to be purified from target material either if a solid or liquid target was used. The quantity of zinc necessary for the target need to be removed as it and all other metal impurities may perturb the radiolabeling reaction of gallium-68. Intense research on this topic lead to several purification methods based on solvent extraction [34, 35], precipitation [36] and solid phase separation [37, 38, 39, 40, 41, 42, 43, 44] and suitable for automation.
Solid-phase extraction using a cation exchange resin or hydroxamate resin is most appropriate for an effective separation of gallium-68 from unwanted metals and can be easily combined with a second resin. This second purification step allows an additional reduction of [H+] concentration to facilitate further processing of the final product [21]:
Local conditions (expertise and equipment)
Separation time (should be as short as possible)
Acids (concentration and volume)
Availability of materials
Robustness of technique
Ease of automation
Possibility to recycle zinc-68 from target solution
The manual radiolabeling approach is a leftover from times, where gallium-68 was mainly used for research purpose, with lower 68Ga-activities and not in a clinical setting for patient care. It is widely used in research and development of new tracers [11, 12, 13, 29, 30, 45, 46, 47, 48, 49, 50, 51]. Its main advantage is full control over the complete process (pH, time and temperature) and the possibility to easily access radiolabeling kinetics.
Due to its general setup, this method is not suitable and indented for clinical use. Nevertheless, before the introduction of module systems or the cold kits, it was a long time, the only available method.
In general (Figure 4), the first step is the preparation of the reaction mixture by mixing [68Ga]GaCl3 with a suitable buffer in the required pH range and the radiolabeling precursor. Here, the purified cyclotron-produced, generator eluate or post-processed gallium-68 can be used.
Schematic description of the 68Ga-radiolabeling procedure (I) preparation of the reaction mixture by adding gallium-68 eluted from a generator or after post-processing to a mixture of a suitable buffer and precursor, (II) incubation of the reaction mixture for a certain time. If elevated temperatures are needed or not depends on the chelator, (III) purification step using solid phase extraction (SPE). For example, the 68Ga-radiopharmaceutical is trapped on a SPE C18-cartridge where it is washed with water to remove free gallium-68, germanium-68 and buffer, (IV) the purified product is finally eluted with diluted ethanol solution and formulated after sterile filtration in the product vial.
Then, the reaction vial is incubated to form the 68Ga-complex. Reaction period and reaction temperature are selected in accordance to the kinetics of the complex formation of gallium with the used chelator.
After the reaction, the reaction mixture can be purified using, for example, solid phase extraction from, for example, free gallium-68 and residual germanium-68 impurities.
In the final step, the 68Ga-radiopharmaceutical is sterile filtrated and formulated in the product vial (Table 2).
With the growing interest for gallium-68 not only for research but also for clinical routine and patient care the need for pharmacopeia compliant preparation of 68Ga-radiopharmaceuticals. This led to promotion of the automation of the traditional manual synthesis from which numerous semi- and fully automated devices have emerged. Today, those systems are designed with respect to Good Manufacturing Practice (GMP) Guidelines provided, for example, by the FDA, EU/EMA, ICH, WHO or others [55]. They use software and methods designed to minimize user interventions and utilize single-use consumables produced under GMP standard.
While the module production requires a fully equipped laboratory and quality control, it reduces radiation exposure of the operator the production process in terms of higher reliability and reduced variability [56, 57, 58].
Accordingly, the amount of contaminated waste materials is higher due to the procedure as well the complete quality control. Nevertheless, these systems are suitable for a variety of tracers and in most cases for more radionuclides not only for gallium-68 (e.g. Scintomics GRP series; Eckert & Ziegler Modular-Lab PharmTracer; Trasis AllInOne).
Recently, cold kits for radiolabeling entered the scene enable production of 68Ga-radiopharmaceuticals as easy as that of 99mTc-radiopharmaceuticals. This method allows the reconstitution of the pre-formulated cold kit with no previous post-processing of the eluate or subsequent purification of the final product. They are available in GMP quality and leaves only minimum quality control tests to the final user responsibility to verify the reconstitution procedure.
For example, the European Pharmacopeia (Ph. Eur.) states the marketing authorization (MA) holder of a licensed kit is responsible to ensure compliance of the kit with the requirements of its MA, while the final user carries the responsibility for the quality of the preparation and the handling. If the given instructions are not strictly followed or if one or more components used for the reconstitution do not have MA, it is the responsibility of the final user to demonstrate that the quality of the final preparation is suitable for the intended, use [26].
Therefore, preparation as well as quality control requires at least the equipment according to the instructions provided by the manufacturer. In addition, minimum contaminated waste materials remain. It has to be noted, according to the Ph. Eur. that applies only for licensed kits in combination with the generator mentioned in the instructions from the manufacturer. In contrast, unlicensed kits or a licensed kit used with an unlicensed generator or cyclotron produced gallium-68 also require full quality control according to the monograph. Additionally, local authorities may require more detailed quality control even for licensed kits.
Indeed, these cold kits contain relatively high amounts of precursor and additional filler materials. They still require manual handling and are only commercially available as single-dose kits for radiolabeling PSMA-11 (e.g. illumet™) and DOTA-TOC (e.g. NETSPOT®). In addition, the use of unpurified generator eluates requires very strict specifications for the generators in terms of 68Ge-breakthrough to ensure the quality of the final product. Nevertheless, there is a possibility for small sites to offer 68Ga-radiopharmaceuticals to their patients without great expense.
Quality defects of pharmaceutical can lead to serious consequences when they are applied. Consequently, the regulatory framework for production and quality control is very strict. In general, one main requirement in the production of pharmaceuticals is a comprehensive, integrated system of quality assurance. Its purpose is the monitoring and documentation of all processes as well as their functionality with respect to the rules of GMP.
Because radiopharmaceuticals are pharmaceutical preparations containing minimum one radionuclide for diagnostic or therapeutic purpose, in principle the same rules apply. Their quality control is intended to ensure that the quality meets the predefined specifications for the radiopharmaceutical. These specifications take into account the radionuclide, the precursor, the preparation process, the formulation and the intended administration route. Due to the nature of the contained radionuclides, not all necessary quality control tests can be performed before release for administration and require retrospective examination. In the available monographs, it is indicated if a test need not to be completed before release of the batch.
In the case of gallium-68, the short half-live and the limited available activities lead to further challenges. Here are sophisticated logistics for preparation and quality control essential.
In general, quality control of 68Ga-radiopharmaceuticals should include the following tests and information [59, 60, 61]:
Characters/appearance. Should discover any visible container defects. The quality of the final product in terms of absence of particular matter [62] and/or turbidity should be ensured as well as its correct appearance. Typically performed by visual inspection.
pH determination. Should ensure that the pH of the final product is in the necessary range for its purpose. For the final injectable formulation of a radiopharmaceutical, the pH should be closed to the physiologic value of 7.4. With regard to the relatively low volume of radiopharmaceuticals and depending on the injected volume and rate, a wider range (3.5–8.5) is applicable. Contrary to this, the pH of the radionuclide precursor gallium-68 should not exceed 2 to prevent the formation of unwanted 68Ga-colloids.
Radionuclidic identification. Identification of a radionuclide is generally conducted by determination of its half-life and/the nature and energy of its radiation emitted. For positron emitters like gallium-68 instead of energy and nature of the radiation, the identification is based on a γ-spectrum additional to their half-life determination (e.g. with dose calibrator).
Radiochemical identification. Identification of the desired radiochemical species via HPLC and/or TLC exploiting different chemical behavior of the different radiochemical species.
Radionuclidic purity. Due to the contribution or formation of other radionuclides during the production of gallium-68, their amount present in the final radiopharmaceutical must be determined. Depending on the production route of gallium-68, different limits for radionuclidic impurities may apply. The test for those long-living radionuclides need to be performed after complete decay of the sample using γ-spectrometry, representing a test performed after release of the batch.
Radiochemical purity. Should discover all chemical forms containing the radionuclide and determine their percentage of the total radioactivity of the product. These radiochemical impurities arise from the synthesis method, radiolysis or the radionuclide production and can lower the quality of the final diagnostic examination. Principally be determined by any suitable analytical method but with respect to the short half-life and radiation TLC and HPLC are normally used for quality control of 68Ga-radiopharmaceuticals.
Chemical purity. The chemical purity refers to the amount of the specified chemical form of a preparation if radioactivity is present or not [61]. Purity assessment is of special importance when diagnostic or therapeutic properties are directly linked to chemistry [63]. Therefore, particular attention is necessary for pharmacologically active impurities as they can affect the diagnostic value of the examination. The chemical purity of 68Ga-radiopharmaceuticals is normally ascertained with TLC and/or HPLC.
Residual solvents. Ph. Eur. as well as US pharmacopeia defines residual solvents as organic volatile chemicals used in the manufacture of drug substances/active substances, excipients or in the preparation of medicinal products (Eur. Ph. 5.4.; USP 467). As they represent a risk of health, they should be determined. Determination can be performed using gas chromatography (GC)
It has to be noted that the texts about residual solvents not cover solvents added by purpose or solvates. For those other limits and regulations may apply.
Microbiological contamination. Parenteral administered radiopharmaceuticals need to be compliant in terms of bacterial endotoxins or pyrogens as well as sterility
Bacterial endotoxins are known to cause a wide spectrum of nonspecific pathophysiological reactions (fever, changes in white blood cell counts, hypotension, disseminated intravascular coagulation, shock and death) leading to death when injected in most mammals [64]. Thanks to the development of more and more efficient systems today tests (LAL-test) for bacterial endotoxins (BET) can be completed before release of the batch of the 68Ga-radiopharmaceuticals.
In contrary, the test for sterility of 68Ga-radiopharmaceuticals via direct inoculation is necessarily retrospective nevertheless indispensable. Additionally, to the direct inoculation test the integrity of the sterile filter used for sterile filtration of the final product is performed. Due to the need for sterilization to obtain a sterile parenteral solution and the not applicability of autoclaving for short-living radiopharmaceuticals membrane filtration is normally the method of choice. The tests for the filter integrity (e.g. bubble point, diffusion rate, pressure hold) have the advantage that they can be completed before batch release.
Radioactivity content/concentration. Defines the activity, measured with a dose calibrator, within the volume of the final preparation.
Specific radioactivity. The specific radioactivity (activity of the radionuclide per unit mass either of the element or the desired chemical form) is calculated using the concentrations of radioactivity and the chemical form. Referring to the consensus nomenclature rules for radiopharmaceutical chemistry [65], the specific activity is expressed as measured activity per gram of compound (e.g. MBq/μg), while it is called molar activity when expressing the measured activity per mole of compound (MBq/nmol) [65]. As gallium-68 requires a complex ligand which is normally not fully removed during the final product purification, the measured specific or molar activity is lower than actual. Then the correct terms are apparent specific or molar activity [65].
The specific or molar activity is always given with reference date and time.
For gallium-68 obtained from a 68Ge/68Ga-generator, the Ph. Eur. contains a distinct monograph (#2464). This monograph specifies the quality characteristics of 68Ga chloride solutions for radiolabeling independently if obtained directly from a generator or after post-processing the generator eluate. If a further purification of the generator eluate is performed, this has to be stated on the label.
Use of generator-produced gallium-68 in the USA is regulated under 10 CFR 35. 1000 and 10 CFR 30.33 [66] (Table 3).
WHAT? | HOW? | LIMITS |
---|---|---|
Appearance | Visual inspection | Clear, colorless solution |
pH | pH indicator strips | <2 |
Radionuclide identity | Half-life determination | 62–74 min |
γ-spectrometry | 511, (1022), 1077, (18,839 keV | |
Radionuclidic purity | γ-spectrometry | <0.1% long living impurities |
<0.001% germanium-68 | ||
Radiochemical purity | TLC | >95% 68Ga(III) |
Chemical purity | ICP-AES/ICP-MS | <10 μg/GBq Fe |
<10 μg/GBq Zn | ||
Bacterial Endotoxins | LAL test | ≤175 EU/total volume |
Quality control specifications for diluted hydrochloric solutions of generator produced gallium-68 as defined by the Ph. Eur. (monograph #2464) [59].
For incoming starting materials, the GMP guidelines prescribe certain handling procedures to ensure their quality and suitability. For material acceptance of an incoming new 68Ge/68Ga-generator, minimum controls are needed. This include the conformation of the radionuclide identity, 68Ge-breakthrough and of activity stated in the Certificate of Analysis (CoA) all verified by activity measurement if possible [60]. Establishment of additional acceptance criteria may be required.
Nevertheless, the 68Ga-eluate used for radiolabeling should meet those specifications (Table 4), their verification is in clinical routine not possible for every production. This results from the different production routes of 68Ga-radiopharmaceuticals, which do not intend or allow an intervention for sampling of the eluate. Thus, the quality control of the starting material gallium-68 or of the final radiopharmaceuticals is allowed. This should include at least tests for 68Ge-breakthrough, radionuclidic purity, radiochemical purity and chemical purity.
Manufacturer | Type | Maximum nominal activity |
---|---|---|
Eckert & Ziegler (Germany) | GalliaPharm® | 2.4 GBq |
IGG100 | 2.4 GBq | |
Obninsk Cyclotron Ltd. (Russia) | 3.7 GBq | |
IRE Elit (Belgium) | Galio Eo® | 1.85 GBq |
Galli Ad® | 1.85 GBq | |
ITG (Germany) | 2 GBq | |
iThemba Labs (South Africa) | 1.85 GBq | |
Pars Isotopes (Iran) | Pars-GalluGEN | 2.59 GBq |
In all conscience a list of 68Ge/68Ga-generators available.
When produced via accelerator, the presence of the radioisotopes gallium-66 and gallium-67 is difficult to avoid due to zinc-66 and zinc-67 contaminating the target material. In return, germanium-68 is absent. Therefore, quality control and specifications for radionuclidic impurities are different to generator-produced gallium-68.
For gallium-68 obtained from a cyclotron, a new monograph (#3109) is already submitted for adoption to the Ph. Eur. [67]. This monograph specifies the quality characteristics of 68Ga-chloride solutions for radiolabeling obtained by irradiation of enriched zinc-68 in an accelerator with subsequent isolation of gallium-68 in acidic solution (Table 5).
WHAT? | HOW? | LIMITS |
---|---|---|
Appearance | Visual inspection | Clear, colorless solution |
pH | pH indicator strips | <2 |
Radionuclide identity | Half-life determination | 62–74 min |
γ-spectrometry | 511, (1022), 1077, (18,839 keV | |
Radionuclidic purity | γ-spectrometry | <0.1% long living impurities |
<2% gallium-66 & gallium-67 | ||
Radiochemical purity | TLC | >95% 68Ga(III) |
Chemical purity | ICP-AES/ICP-MS | <10 μg/GBq Fe |
<10 μg/GBq Zn | ||
Bacterial Endotoxins | LAL test | ≤175 EU/total volume |
Quality control specifications for diluted hydrochloric solutions of accelerator-produced gallium-68 as defined by a draft of a monograph for the Ph. Eur. Submitted for adoption (#3109) [67].
Similar to generator-produced gallium-68, quality control can be performed of the starting material obtained via cyclotron or on the final radiopharmaceutical. If quality control of the final radiopharmaceuticals performed, it should include at least tests for 68Ge-breakthrough, radionuclidic purity, radiochemical purity and chemical purity.
As an example for the specifications and limitations for a 68Ga-radiopharmaceutical quality control as requested by the monograph #2464 of the Ph. Eur. [68Ga]Ga-DOTA-TOC is provided [59]. It has to be noted, that monograph #2464 is currently under revision which can lead to different limits in feature (Table 6).
WHAT? | HOW? | LIMITS |
---|---|---|
Appearance | Visual inspection | Clear, colorless solution |
pH | pH indicator strips | < 2 |
Radionuclide identity | Half-life determination | 62 to 74 min |
γ-spectrometry | 511, (1022), 1077, (18,839 keV | |
Radionuclidic purity | γ-spectrometry | <0.1% long living impurities |
<0.001% germanium-68 | ||
Radiochemical purity | TLC | >91% |
TLC | <3% [68Ga]Ga in colloidal form | |
HPLC | <2% [68Ga]Ga3+ | |
Chemical purity | ICP-AES/ICP-MS | <10 μg/GBq Fe |
<10 μg/GBq Zn | ||
HPLC | <50 μg/V DOTA-TOC and metal complexes of DOTA-TOC | |
TLC | <200 μg/V HEPES | |
GC | <10% V/V and <2.5 g per administration | |
Bacterial endotoxins | LAL test | ≤175 EU/total volume |
Sterility | Direct inoculation | sterile |
Quality control specifications [68Ga]Ga-DOTA-TOC as given by the Ph. Eur. For generator-produced gallium-68 (monograph #2464) [59].
The quality control for a certain 68Ga-radiopharmaceutical depends on the production route of gallium-68, the synthesis route of the radiopharmaceutical as well as of the relevant legislation.
As descripted in Section 7.2, the respective production route leads to different radionuclidic impurities (germanium-68 vs. gallium-66 & gallium-67) that need to take into account for the final product specifications. However, this is not yet implemented in the pharmacopeias but is in part already in progress. For example, the monograph for [68Ga]Ga-DOTA-TOC (#2464) of the Ph. Eur. is currently in revision to take into account the cyclotron production of gallium-68 [68].
In general, the quality of the final radiopharmaceutical needs to fulfill all specifications given by the relevant legislation or pharmacopeia independent from the synthesis route. Nevertheless, it may be possible to dispense individual tests given, for example, for licensed kit preparations. For example, the Ph. Eur. states in its general notices “An article is not of Pharmacopoeia quality unless it complies with all the requirements stated in the monograph. This does not imply that performance of all the tests in a monograph is necessarily a prerequisite for a manufacturer in assessing compliance with the Pharmacopoeia before release of a product. The manufacturer may obtain assurance that a product is of Pharmacopoeia quality on the basis of its design, together with its control strategy and data derived, for example, from validation studies of the manufacturing process” [59]. Further details can be found in the general chapter on extemporaneous preparation of radiopharmaceuticals (5.19) and the general monograph radiopharmaceutical preparations (#0125) [59].
Nevertheless, the competent authorities may request further quality control testing. Therefore, it is strongly recommended, especially in case of doubt, to consult the competent authorities.
The implementation of a new radiopharmaceutical into the certain pharmacopeias is a protracted process. Therefore, several commonly used 68Ga-radiopharmaceuticals are not yet represented with own monographs in the pharmacopeias (e.g. [68Ga]Ga-PSMA-11). Nevertheless, such radiopharmaceuticals can be produced with consideration of the general notices, texts, monographs and along the lines of, for example, the monograph for [68Ga]Ga-DOTA-TOC. Again, in case of doubt, the competent authorities should be consulted.
Gallium-68 is a well-researched radionuclide with growing importance for clinical practice triggered by the development of new tracers expanding its application and the increasing demand for theranostic patient care.
Its availability via radionuclide generator in combination with comparably easy coordination chemistry enables a patient care even in places where the cyclotron-produced PET-radionuclides are unavailable and, in the case of NETs, enables patient care where no 18F-alternative exists.
This work was supported by the Ministry of Science and Higher Education of the Russian Federation project RFMEFI60719X0301.
The authors declare no conflict of interest.
AEX | anion-exchange |
API | active pharmaceutical ingredient |
BET | bacterial endotoxin test |
CEX | cation-exchange |
DMF | drug master file |
EU | European Union |
FDA | U.S. Food and Drug Administration |
GC | gas chromatography |
GMP | good manufacturing practice |
HCl | hydrochloric acid |
HPLC | high pressure liquid chromatography |
ICP-AES | inductively coupled plasma atomic emission spectroscopy |
ICP-MS | inductively coupled plasma mass spectrometry |
ITG | Isotopen Technologien Garching |
LAL-test | limulus amebocyte lysate test |
M | molarity (mol/liter) |
MA | marketing authorization |
mCRPC | metastatic castrate-resistant prostate cancer |
NET | neuroendocrine tumor |
PC | prostate cancer |
PET | positron emission tomography |
Ph. Eur. | European pharmacopeia |
pmol | picomol (10−12 mol). |
QC | quality control |
PRRT | peptide receptor radionuclide therapy |
SPE | solid phase extraction |
T1/2 | half-life |
TLC | thin layer chromatography |
USA | United States of America |
U.S. | United States |
USP | United States Pharmacopeia |
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\n\n\n\nCorresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
\n\nCSIC affiliated authors can also take advantage of a central Open Access fund (amounting to 10,000 EUR) to cover up to 50% of the rest of the OAPF until it expires. Effective for chapters accepted from January 1, 2020.
\n\nCorresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
\n\nCorresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
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\n\nThe Claremont Colleges are pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\nCorresponding authors will receive a 15% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
\n\nThe University of Massachusetts, Amherst is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\nCorresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
\n\nThe University of Surrey is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\nCorresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
\n\nMonographs Only
\n\n\n\nImportant: You must be a member or grantee of the above listed institutions in order to apply for their Open Access publication funds.
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