Rhenium-188 (
Re) is a high energy beta-emitting radioisotope with a short 16.9 h physical half-life, which has been shown to be a very attractive candidate for use in therapeutic nuclear medicine. ...The high beta emission has an average energy of 784 keV and a maximum energy of 2.12 MeV, sufficient to penetrate and destroy targeted abnormal tissues. In addition, the low-abundant gamma emission of 155 keV (15%) is efficient for imaging and for dosimetric calculations. These key characteristics identify
Re as an important therapeutic radioisotope for routine clinical use. Moreover, the highly reproducible on-demand availability of
Re from the
W/
Re generator system is an important feature and permits installation in hospital-based or central radiopharmacies for cost-effective availability of no-carrier-added (NCA)
Re. Rhenium-188 and technetium-99 m exhibit similar chemical properties and represent a "theranostic pair." Thus, preparation and targeting of
Re agents for therapy is similar to imaging agents prepared with
Tc, the most commonly used diagnostic radionuclide. Over the last three decades, radiopharmaceuticals based on
Re-labeled small molecules, including peptides, antibodies, Lipiodol and particulates have been reported. The successful application of these
Re-labeled therapeutic radiopharmaceuticals has been reported in multiple early phase clinical trials for the management of various primary tumors, bone metastasis, rheumatoid arthritis, and endocoronary interventions. This article reviews the use of
Re-radiopharmaceuticals which have been investigated in patients for cancer treatment, demonstrating that
Re represents a cost effective alternative for routine clinical use in comparison to more expensive and/or less readily available therapeutic radioisotopes.
Radionuclide therapy (RNT) based on the concept of delivering cytotoxic levels of radiation to disease sites is one of the rapidly growing fields of nuclear medicine. Unlike conventional external ...beam therapy, RNT targets diseases at the cellular level rather than on a gross anatomical level. This concept is a blend of a tracer moiety that mediates a site specific accumulation followed by induction of cytotoxicity with the short-range biological effectiveness of particulate radiations. Knowledge of the biochemical reactions taking place at cellular levels has stimulated the development of sophisticated molecular carriers, catalyzing a shift towards using more specific targeting radiolabelled agents. There is also improved understanding of factors of importance for choice of appropriate radionuclides based on availability, the types of emissions, linear energy transfer (LET), and physical half-life. This article discusses the applications of radionuclide therapy for treatment of cancer as well as other diseases. The primary objective of this review is to provide an overview on the role of radionuclide therapy in the treatment of different diseases such as polycythaemia, thyroid malignancies, metastatic bone pain, radiation synovectomy, hepatocellular carcinoma (HCC), neuroendocrine tumors (NETs), non-Hodgkin's lymphoma (NHL) and others. In addition, recent developments on the systematic approach in designing treatment regimens as well as recent progress, challenges and future perspectives are discussed. An examination of the progress of radionuclide therapy indicates that although a rapid stride has been made for treating hematological tumors, the development for treating solid tumors has, so far, been limited. However, the emergence of novel tumor-specific targeting agents coupled with successful characterization of new target structures would be expected to pave the way for future treatment for such tumors.
Peptide receptor radionuclide therapy (PRRT) is a site-directed targeted therapeutic strategy that specifically uses radiolabeled peptides as biological targeting vectors designed to deliver ...cytotoxic levels of radiation dose to cancer cells, which overexpress specific receptors. Interest in PRRT has steadily grown because of the advantages of targeting cellular receptors in vivo with high sensitivity as well as specificity and treatment at the molecular level. Recent advances in molecular biology have not only stimulated advances in PRRT in a sustainable manner but have also pushed the field significantly forward to several unexplored possibilities. Recent decades have witnessed unprecedented endeavors for developing radiolabeled receptor-binding somatostatin analogs for the treatment of neuroendocrine tumors, which have played an important role in the evolution of PRRT and paved the way for the development of other receptor-targeting peptides. Several peptides targeting a variety of receptors have been identified, demonstrating their potential to catalyze breakthroughs in PRRT. In this review, the authors discuss several of these peptides and their analogs with regard to their applications and potential in radionuclide therapy. The advancement in the availability of combinatorial peptide libraries for peptide designing and screening provides the capability of regulating immunogenicity and chemical manipulability. Moreover, the availability of a wide range of bifunctional chelating agents opens up the scope of convenient radiolabeling. For these reasons, it would be possible to envision a future where the scope of PRRT can be tailored for patient-specific application. While PRRT lies at the interface between many disciplines, this technology is inextricably linked to the availability of the therapeutic radionuclides of required quality and activity levels and hence their production is also reviewed.
Abstract Because of the broad incidence, morbidity and mortality associated with prostate-derived cancer, the development of more effective new technologies continues to be an important goal for the ...accurate detection and treatment of localized prostate cancer, lymphatic involvement and metastases. Prostate-specific membrane antigen (PSMA; Glycoprotein II) is expressed in high levels on prostate-derived cells and is an important target for visualization and treatment of prostate cancer. Radiolabeled peptide targeting technologies have rapidly evolved over the last decade and have focused on the successful development of radiolabeled small molecules that act as inhibitors to the binding of the N-acetyl-L-aspartyl-L-glutamate (NAAG) substrate to the PSMA molecule. A number of radiolabeled PSMA inhibitors have been described in the literature and labeled with SPECT, PET and therapeutic radionuclides. Clinical studies with these agents have demonstrated the improved potential of PSMA-targeted PET imaging agents to detect metastatic prostate cancer in comparison with conventional imaging technologies. Although many of these agents have been evaluated in humans, by far the most extensive clinical literature has described use of the68 Ga and177 Lu agents. This review describes the design and development of these agents, with a focus on the broad clinical introduction of PSMA targeting motifs labeled with68 Ga for PET-CT imaging and177 Lu for therapy. In particular, because of availability from the long-lived68 Ge (T1/2 = 270 days)/68 Ga (T1/2 = 68 min) generator system and increasing availability of PET- CT, the68 Ga-labeled PSMA targeted agent is receiving widespread interest and is one of the fastest growing radiopharmaceuticals for PET-CT imaging.
This review provides a comprehensive summary of the production of (177)Lu to meet expected future research and clinical demands. Availability of options represents the cornerstone for sustainable ...growth for the routine production of adequate activity levels of (177)Lu having the required quality for preparation of a variety of (177)Lu-labeled radiopharmaceuticals. The tremendous prospects associated with production of (177)Lu for use in targeted radionuclide therapy (TRT) dictate that a holistic consideration should evaluate all governing factors that determine its success.
While both "direct" and "indirect" reactor production routes offer the possibility for sustainable (177)Lu availability, there are several issues and challenges that must be considered to realize the full potential of these production strategies.
This article presents a mini review on the latest developments, current status, key challenges and possibilities for the near future.
A broad understanding and discussion of the issues associated with (177)Lu production and processing approaches would not only ensure sustained growth and future expansion for the availability and use of (177)Lu-labeled radiopharmaceuticals, but also help future developments.
Mouse haematopoietic stem cells (HSCs) undergo a postnatal transition in several properties, including a marked reduction in their self-renewal activity. We now show that the developmentally timed ...change in this key function of HSCs is associated with their decreased expression of Lin28b and an accompanying increase in their let-7 microRNA levels. Lentivirus-mediated overexpression of Lin28 in adult HSCs elevates their self-renewal activity in transplanted irradiated hosts, as does overexpression of Hmga2, a well-established let-7 target that is upregulated in fetal HSCs. Conversely, HSCs from fetal Hmga2(-/-) mice do not exhibit the heightened self-renewal activity that is characteristic of wild-type fetal HSCs. Interestingly, overexpression of Hmga2 in adult HSCs does not mimic the ability of elevated Lin28 to activate a fetal lymphoid differentiation program. Thus, Lin28b may act as a master regulator of developmentally timed changes in HSC programs with Hmga2 serving as its specific downstream modulator of HSC self-renewal potential.
Precise, analogue regulation of gene expression is critical for cellular function in mammals. In contrast, widely employed experimental and therapeutic approaches such as knock-in/out strategies are ...more suitable for binary control of gene activity. Here we report on a method for precise control of gene expression levels in mammalian cells using engineered microRNA response elements (MREs). First, we measure the efficacy of thousands of synthetic MRE variants under the control of an endogenous microRNA by high-throughput sequencing. Guided by this data, we establish a library of microRNA silencing-mediated fine-tuners (miSFITs) of varying strength that can be employed to precisely control the expression of user-specified genes. We apply this technology to tune the T-cell co-inhibitory receptor PD-1 and to explore how antigen expression influences T-cell activation and tumour growth. Finally, we employ CRISPR/Cas9 mediated homology directed repair to introduce miSFITs into the BRCA1 3'UTR, demonstrating that this versatile tool can be used to tune endogenous genes.
Space flight-induced physiological deconditioning resulting from decreased gravitational input, decreased plasma volume, and disruption of regulatory mechanisms is a significant problem in returning ...astronauts as well as in normal aging. Here we review effects of a promising countermeasure on cardiovascular systems of healthy men and women undergoing Earth-based models of space-flight. This countermeasure is produced by a centrifuge and called artificial gravity (AG). Numerous studies have determined that AG improves orthostatic tolerance (as assessed by various protocols) of healthy ambulatory men, of men deconditioned by bed rest or by immersion (both wet and dry) and, in one case, following spaceflight. Although a few studies of healthy, ambulatory women and one study of women deconditioned by furosemide, have reported improvement of orthostatic tolerance following exposure to AG, studies of bed-rested women exposed to AG have not been conducted. However, in ambulatory, normovolemic subjects, AG training was more effective in men than women and more effective in subjects who exercised during AG than in those who passively rode the centrifuge. Acute exposure to an AG protocol, individualized to provide a common stimulus to each person, also improved orthostatic tolerance of normovolemic men and women and of furosemide-deconditioned men and women. Again, men's tolerance was more improved than women's. In both men and women, exposure to AG increased stroke volume, so greater improvement in men vs. women was due in part to their different vascular responses to AG. Following AG exposure, resting blood pressure (via decreased vascular resistance) decreased in men but not women, indicating an increase in men's vascular reserve. Finally, in addition to counteracting space flight deconditioning, improved orthostatic tolerance through AG-induced improvement of stroke volume could benefit aging men and women on Earth.
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