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- Elgqvist, Jörgen, 1963
(författare)
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Targeted alpha therapy: part I.
- 2011
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Ingår i: Current radiopharmaceuticals. - : Bentham Science Publishers Ltd.. - 1874-4729 .- 1874-4710. ; 4:3
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Tidskriftsartikel (refereegranskat)abstract
- The possibility of pinpointing biological targets, and thereby potentially targeting and eradicating small tumors or even single cancer cells, is a tantalizing concept that has been discussed since the magic-bullet concept was first presented by Paul Erlich in the beginning of the 20th century in connection with his work on tissue staining for histological examinations and the work by Kohler and Milstein on antibody production published in 1975. This concept now seems feasible through the use of highly specific targeting constructs, chemical labeling of radioactive substances to these targeting constructs that results in high specific activities, radioimmunocomplexes with good stability even after injection, and the use of radionuclides emitting alpha( α)-particles having exceedingly high ionizing density and, therefore, a high probability of killing cells along its track in tissue. However, problems such as limited or delayed diffusion of the α-radioimmunocomplex and inhomogeneous activity distributions in the targeted tumors, resulting in inhomogeneous absorbed dose distributions, are challenges that need to be addressed. These challenges need to be overcome before TAT becomes a standard treatment for diseases such as micrometastatic cancer. Hopefully, when enough funding will be provided and, hence, more treatment strategies of TAT will reach the clinical level the importance to conduct controlled, randomized trials with sufficient patient numbers, enabling statistical significance to occur must be emphasized in order to be able to properly compare and evaluate different approaches. In this issue, of the two hot-topic issues for targeted alpha therapy, articles discuss the recent developments in radionuclide availability, biomolecular targeting, labeling chemistry, and dosimetry for the most promising α-particle emitters. In the first article, Zalutsky et al. discuss the possibilities and limitations of using the promising α-particle emitter, 211At, and emphasize the need for funding new cyclotrons and prioritizing beam-times of already existing cyclotrons to improve the availability of 211At. Haddad et al. describe the status of the ARRONAX project through which a number of important nuclear medicine radionuclides will be produced, including some of those suitable for TAT. Relevant targeting constructs and their associated antigens used today and candidates for use in the future are discussed by Olafsen et al. in the third article. The next article, by Scott Wilbur, discusses chemical and radiochemical issues of radiolabeling using α-particle emitting radionuclides, e.g. factors that are important in selecting chelation or bonding reagents during the development of α-particle emitting radiopharmaceuticals. Lindegren at al. continue the discussion of chemical considerations in the following article, but focuses on pre-targeting techniques, which will hopefully enhance both the activity distribution in the targeted tumor and the tumor-to-normal tissue absorbed dose ratio. The two final articles discuss different aspects of the dosimetry related to α-particles. The article by Sgouros et al. discusses how knowledge of the microscopic distribution of α-particle emitters is necessary to perform correct dosimetry, as well as the importance of the translation of activity distributions obtained in pre-clinical studies to the human situation, which requires micro-scale models of the source-target geometry at human dimensions according to the authors. Chouin et al. focus in the following article on the microdosimetry of α-particles. The authors present basic concepts and some applications of the microdosimetry for TAT, and conclude microdosimetry should only be considered when alternative approaches fail to provide an account of a given biological endpoint. The intention of this particular hot-topic issue is to present an up-to-date overview of key areas in the research field of TAT, i.e. radionuclides available, targeting constructs, labeling chemistry, and dosimetry. This issue will hopefully be followed by similar ones jointly produced by contributions from the research community active in the field, of which most researchers are participating in these two particular issues, i.e. Targeted Alpha Therapy - Part I and II.
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- Olafsen, Tove, et al.
(författare)
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Protein targeting constructs in alpha therapy.
- 2011
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Ingår i: Current radiopharmaceuticals. - : Bentham Science Publishers Ltd.. - 1874-4729 .- 1874-4710. ; 4:3, s. 197-213
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Tidskriftsartikel (refereegranskat)abstract
- The progress in the field of targeted α-particle therapy (TAT) has to a great extent been enhanced by developments in both recombinant DNA technology and radionuclide labeling chemistry. Advances in genomics and proteomics have promoted an increase in the identification of novel targets and molecules that can define different diseases, such as cancer. In radioimmunotherapy (RIT), the primary goal is to improve delivery to and therapeutic efficacy of the cancer cells, whilst minimizing toxicity. Different approaches have been investigated to achieve this, such as reducing the size of the carrier, pretargeting, multidosing, locoregional administration and using a cocktail of radiolabeled monoclonal antibodies for targeting multiple antigens simultaneously. Some of these approaches have been encouraging, but translation of TAT into the clinic has been slow, in part because of the limited availability and the short physical half-lives of some of the available α-particle emitters. The clinical studies carried out to date have been promising, although many challenges remain in order to make TAT safe and economically feasible. In this paper a number of different targeting constructs used hitherto that may be promising carriers for TAT in the future are presented and discussed. The constructs include enzymatic cleaved antibody fragments (Fab and F(ab˙)2 fragments); genetically engineered antibody fragments (scFv monomer, dimer (i.e. diabody) and tetramer, CH2 domain deleted antibody fragments); other protein targeting constructs such as affibodies and peptides as well as liposomal delivery.
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- Palm, Stig, 1964, et al.
(författare)
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Patient-specific alpha-particle dosimetry
- 2011
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Ingår i: Current radiopharmaceuticals. - : Bentham Science Publishers Ltd.. - 1874-4729 .- 1874-4710. ; 4:4, s. 329-35
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Tidskriftsartikel (refereegranskat)abstract
- Alpha-particle therapy has received increased attention during the last few years because of the development of new targeting constructs and new labeling techniques and the availability of suitable α-particle - emitting radionuclides. This work provides an overview of methods that have been used in clinical trials in estimating the absorbed dose to tumors and healthy tissue in patients following such α-particle therapy. Similarities and differences compared to conventional therapies using β¯-particle emitters are presented. The specific challenges of establishing accurate dosimetry for α- particles in the individual patient are also discussed, as is the effect that improved patient-specific dosimetry might have on the overall efficacy of this type of therapy.
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- Tolmachev, Vladimir
(författare)
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Radiobromine-labelled tracers for positron emission tomography : possibilities and pitfalls
- 2011
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Ingår i: Current radiopharmaceuticals. - : Bentham Science Publishers Ltd.. - 1874-4710. ; 4:2, s. 76-89
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Tidskriftsartikel (refereegranskat)abstract
- The use of positron emission tomography (PET) for radionuclide imaging provides better sensitivity, better spatial and temporal resolution and better quantification accuracy in comparison with single photon emission computed tomography (SPECT). One limitation of PET is the predominant use of short-lived (with half-life up to 2 h) radionuclides. Extension of PET utility might be achieved by the use of more long-lived, "non-conventional" positron emitters. Two positron-emitting isotopes of bromine, 75Br (T1/2 = 96.7 min) and 76Br (T1/2 = 16.2 h), can be considered as labels for targeting proteins and peptides, and for small molecules, which have an optimal imaging time outside the time frame provided by conventional biogenic positron emitters. Variety of tracers might be labelled by electrophilic bromination of activated phenolic rings, electrophilic bromodestannylation and halogen exchange. A major problem is that in vivo metabolism of tracers might lead to formation of radiobromide as a main radiocatabolite. Radiobromide is very slowly excreted, and is distributed in the extracellular space creating high background. Careful tracer design optimisation is required to avoid this obstacle in the introduction of bromine isotopes into PET practice.
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