11C-acetate positron emission tomography is more precise than 18F-fluorodeoxyglucose positron emission tomography in evaluating tumor burden and predicting disease risk of multiple myeloma
Abstract:The optimal method of tumor burden evaluation in newly diagnosed multiple myeloma (NDMM) is yet to be determined. This study aimed to compare the value of 11C-acetate positron-emission tomography (PET)/computed tomography (CT) (AC-PET and 18F-fluorodeoxyglucose PET/CT (FDG-PET) in the assessment of tumor burden in NDMM.
This study evaluated 64 NDMM patients between February 2015 and July 2018. AC-PET and FDG-PET were used to assess myeloma lesions. The clinical data, imaging results, and their correlations wer… Show more
“…In recent years, different groups have assessed the utility of myeloma-specific agents targeted to myeloma proteins such as CD38 and CXCR4. Metabolic tracers such as 18 F-FACBC ( 28 ) and 11 C-acetate ( 29 ) have also been explored as alternatives to 18 F-FDG. Although promising, the short 20-min radioactive half-life of 11 C makes it a challenging radionuclide for routine use.…”
Background: There remains an unmet need for molecularly targeted imaging agents in multiple myeloma (MM). The integrin, very late antigen-4 (VLA4), is differentially expressed in malignant MM cells as well as in the pathogenic inflammatory microenvironmental cells. [ 64 Cu]Cu-CB-TE1A1P-LLP2A ( 64 Cu-LLP2A) is a VLA4 targeted, high-affinity radiopharmaceutical with promising utility for managing patients diagnosed with MM. Here, we evaluated safety and human radiation dosimetry of 64 Cu-LLP2A for potential use in MM patients.Methods: Single dose [ nat Cu]Cu-LLP2A (Cu-LLP2A) tolerability and toxicity study was performed in CD-1 (Hsd:ICR) male and female mice. 64 Cu-LLP2A was synthesized in accordance with the good manufacturing practice compliant procedures. Three MM and six healthy participants underwent 64 Cu-LLP2A-PET/CT or PET/MR scans up to three time points to help determine tracer biodistribution, pharmacokinetics and radiation dosimetry. Time-activity curves were plotted for each participant. Mean organ absorbed doses and effective doses were calculated using the Organ Level INternal Dose Assessment (OLINDA) software. Tracer bioactivity was evaluated via cell binding assays and metabolites from human blood samples were analyzed with analytical radio-high performance liquid chromatography. When feasible, VLA4 expression was evaluated in the biopsy tissues using 14-color flow cytometry.Results: 150-fold mass excess of the desired imaging dose was tolerated well in male and female CD-1 mice (no observed adverse effect level (NOEL)). Time-activity curves from human imaging data showed rapid tracer clearance from blood via kidneys and bladder. The effective dose of 64 Cu-LLP2A in humans was 0.036 ± 0.006 mSv/MBq, and spleen had the highest organ uptake of 0.142 ± 0.034 mSv/MBq. Among all tissues, the red marrow demonstrated highest residence time. Image quality analysis supports early imaging time (4-5 h post injection of the radiotracer) as optimal. Cell studies showed statistically significant blocking for the tracer produced for all of the human studies (82.42 ± 13.47%). Blood metabolism studies confirmed a stable product peak (> 90%) up to 1 h post-injection of the radiopharmaceutical. No clinical or laboratory adverse events related to 64 Cu-LLP2A were observed in the human participants.Conclusions: 64 Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans.
“…In recent years, different groups have assessed the utility of myeloma-specific agents targeted to myeloma proteins such as CD38 and CXCR4. Metabolic tracers such as 18 F-FACBC ( 28 ) and 11 C-acetate ( 29 ) have also been explored as alternatives to 18 F-FDG. Although promising, the short 20-min radioactive half-life of 11 C makes it a challenging radionuclide for routine use.…”
Background: There remains an unmet need for molecularly targeted imaging agents in multiple myeloma (MM). The integrin, very late antigen-4 (VLA4), is differentially expressed in malignant MM cells as well as in the pathogenic inflammatory microenvironmental cells. [ 64 Cu]Cu-CB-TE1A1P-LLP2A ( 64 Cu-LLP2A) is a VLA4 targeted, high-affinity radiopharmaceutical with promising utility for managing patients diagnosed with MM. Here, we evaluated safety and human radiation dosimetry of 64 Cu-LLP2A for potential use in MM patients.Methods: Single dose [ nat Cu]Cu-LLP2A (Cu-LLP2A) tolerability and toxicity study was performed in CD-1 (Hsd:ICR) male and female mice. 64 Cu-LLP2A was synthesized in accordance with the good manufacturing practice compliant procedures. Three MM and six healthy participants underwent 64 Cu-LLP2A-PET/CT or PET/MR scans up to three time points to help determine tracer biodistribution, pharmacokinetics and radiation dosimetry. Time-activity curves were plotted for each participant. Mean organ absorbed doses and effective doses were calculated using the Organ Level INternal Dose Assessment (OLINDA) software. Tracer bioactivity was evaluated via cell binding assays and metabolites from human blood samples were analyzed with analytical radio-high performance liquid chromatography. When feasible, VLA4 expression was evaluated in the biopsy tissues using 14-color flow cytometry.Results: 150-fold mass excess of the desired imaging dose was tolerated well in male and female CD-1 mice (no observed adverse effect level (NOEL)). Time-activity curves from human imaging data showed rapid tracer clearance from blood via kidneys and bladder. The effective dose of 64 Cu-LLP2A in humans was 0.036 ± 0.006 mSv/MBq, and spleen had the highest organ uptake of 0.142 ± 0.034 mSv/MBq. Among all tissues, the red marrow demonstrated highest residence time. Image quality analysis supports early imaging time (4-5 h post injection of the radiotracer) as optimal. Cell studies showed statistically significant blocking for the tracer produced for all of the human studies (82.42 ± 13.47%). Blood metabolism studies confirmed a stable product peak (> 90%) up to 1 h post-injection of the radiopharmaceutical. No clinical or laboratory adverse events related to 64 Cu-LLP2A were observed in the human participants.Conclusions: 64 Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans.
“…For PET-based imaging, positron (ß +) emitting radionuclides are employed which ideally emits low-energy, short-range ß + with a 100% abundance and no higher energy prompts. These positrons instantly combine with an electron, the resulting electron–positron annihilation generates two γ ray photons that travel in diametrically opposite directions with identical energies of nearly 511 keV (Velikyan 2018 ; Kuntić et al 2016 ; Mattoli et al 2021 ; Garg et al 2021 ; Chen et al 2021 ) that are picked up by a circular array of detectors placed around the patient. Fig.…”
In the last three decades, radiopharmaceuticals have proven their effectiveness for cancer diagnosis and therapy. In parallel, the advances in nanotechnology have fueled a plethora of applications in biology and medicine. A convergence of these disciplines has emerged more recently with the advent of nanotechnology-aided radiopharmaceuticals. Capitalizing on the unique physical and functional properties of nanoparticles, radiolabeled nanomaterials or nano-radiopharmaceuticals have the potential to enhance imaging and therapy of human diseases. This article provides an overview of various radionuclides used in diagnostic, therapeutic, and theranostic applications, radionuclide production through different techniques, conventional radionuclide delivery systems, and advancements in the delivery systems for nanomaterials. The review also provides insights into fundamental concepts necessary to improve currently available radionuclide agents and formulate new nano-radiopharmaceuticals.
“…γ-emitters with an energy range between 100 and 370 keV and half-lives of a few minutes to several days are the ideal radionuclides for SPECT imaging . Ultrashort-lived high-energy β + emitters with half-lives from a few seconds to several hours and annihilation energy of 511 keV are used for PET imaging. − β – emitters account for the largest share of the global therapeutic radionuclide market. The main demand is for preparations based on iodine-131 ( 131 I), samarium-153 ( 153 Sm), rhenium-186 ( 186 Re), yttrium-90 ( 90 Y), and lutetium-177 ( 177 Lu) .…”
“…Snapshot of various biomedical applications of radionuclides. Radionuclides for nuclear imaging/diagnostics. − The gray color stands for the targeted radionuclides used for tumor imaging, while the blue color stands for the radionuclides used in PET and SPECT diagnostics, but are not used yet as nanotargeted radionuclides; yellow, in vitro diagnostics. Radionuclides for therapy: − Blue color stands for the radionuclides used in therapy with nanocarriers, gray color represents radionuclides used in traditional radiotherapy, and green color denotes brachytherapy radionuclides.…”
“…41 In 90% of cases of targeted radionuclide therapy in the clinic, 131 I and 90 Y isotopes are used. 42 The 188 Re radionuclide is one of most promising generator-type therapeutic β − emitters, with the energy of β − emission of 1.96 MeV (25.6%) and 2.12 MeV (71.1%) and a half-life of 17 h. 43 In clinical practice, radiopharmaceuticals based on 188 Re are used for the treatment of prostate and breast cancers. With the development of radiopharmaceuticals based on the generator-type 188 Re, a rapid expansion of its usage can be expected.…”
Nuclear medicine is expected to make
major advances in cancer diagnosis
and therapy; tumor-targeted radiopharmaceuticals preferentially eradicate
tumors while causing minimal damage to healthy tissues. The current
scope of nuclear medicine can be significantly expanded by integration
with nanomedicine, which utilizes nanoparticles for cancer diagnosis
and therapy by capitalizing on the increased surface area-to-volume
ratio, the passive/active targeting ability and high loading capacity,
the greater interaction cross section with biological tissues, the
rich surface properties of nanomaterials, the facile decoration of
nanomaterials with a plethora of functionalities, and the potential
for multiplexing several functionalities within one construct. This
review provides a comprehensive discussion of nuclear nanomedicine
using tumor-targeted nanoparticles for cancer radiation therapy with
either pre-embedded radionuclides or nonradioactive materials which
can be extrinsically triggered using various external nuclear particle
sources to produce in situ radioactivity. In addition,
it describes the prospect of combining nuclear nanomedicine with other
modalities to enable synergistically enhanced combination therapies.
The review also discusses advances in the fabrication of radionuclides
as well as describes laser ablation technologies for producing nanoradiopharmaceuticals,
which combine the ease of production with exceptional purity and rapid
biodegradability, along with additional imaging or therapeutic functionalities.
From a practical standpoint, these attributes of nanoradiopharmaceuticals
may provide distinct advantages in diagnostic/therapeutic sensitivity
and specificity, imaging resolution, and scalability of turnkey platforms.
Coupling image-guided targeted radiation therapy with the possibility
of in situ activation of nanomaterials as well as
combining with other therapeutic modalities using a multifunctional
nanoplatform could herald an era of exciting technological and therapeutic
advances to radically transform the landscape of nuclear medicine.
The review concludes with a discussion of current challenges and presents
the authors’ views on future opportunities to stimulate further
research in this rewarding field of high societal impact.
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