Diagnostic PET Imaging of Mammary Microcalcifications Using ⁶⁴Cu-DOTA-Alendronate in a Rat Model of Breast Cancer

Abstract

The development of improved breast cancer screening methods is hindered by a lack of cancer-specific imaging agents and effective smallanimal models to test them. The purpose of this study was to evaluate 64 Cu-DOTA-alendronate as a mammary microcalcification-targeting PET imaging agent, using an ideal rat model. Our long-term goal is to develop 64 Cu-DOTA-alendronate for the detection and noninvasive differentiation of malignant versus benign breast tumors with PET. Methods: DOTAalendronate was synthesized, radiolabeled with 64 Cu, and administered to normal or tumor-bearing aged, female, retired breeder SpragueDawley rats for PET imaging. Mammary tissues were subsequently labeled and imaged with light, confocal, and electron microscopy to verify microcalcification targeting specificity of DOTA-alendronate and elucidate the histologic and ultrastructural characteristics of the microcalcifications in different mammary tumor types. Tumor uptake, biodistribution, and dosimetry studies were performed to evaluate the efficacy and safety of 64 Cu-DOTA-alendronate. Results: 64 Cu-DOTA-alendronate was radiolabeled with a 98% yield. PET imaging using aged, female, retired breeder rats showed specific binding of 64 Cu-DOTA-alendronate in mammary glands and mammary tumors. The highest uptake of 64 Cu-DOTA-alendronate was in malignant tumors and the lowest uptake in benign tumors and normal mammary tissue. Confocal analysis with carboxyfluorescein-alendronate confirmed the microcalcification binding specificity of alendronate derivatives. Biodistribution studies revealed tissue alendronate concentrations peaking within the first hour, then decreasing over the next 48 h. Our dosimetric analysis demonstrated a 64 Cu effective dose within the acceptable range for clinical PET imaging agents and the potential for translation into human patients. Conclusion: 64 Cu-DOTA-alendronate is a promising PET imaging agent for the sensitive and specific detection of mammary tumors as well as the differentiation of malignant versus benign tumors based on absolute labeling uptake.

Combining Diagnostic Imaging and Pathology for Improving Diagnosis and Prognosis of Cancer

“…In addition, in these studies, it was shown that microcalcifications made of hydroxyapatite are actively produced by cancer osteoblast-like cells (OLCs) in a process similar to what occurs during physiological bone matrix formation [38–40]. On the basis of this evidence, molecular imaging could be used to discriminate cancer from any other type of lesion by studying the metabolic activity of breast tissues associated with the presence of microcalcifications as shown by Ahrens et al in a mouse model [41].…”

[68Ga]Ga-THP-Pam: A Bisphosphonate PET Tracer with Facile Radiolabeling and Broad Calcium Mineral Affinity

“…18 F is produced by cyclotrons, which are expensive and complex instruments but can produce [ 18 F]­NaF in large quantities without any further need for complicated radiosynthetic procedures . On the other hand, PET BPs rely on the use of radiometals and hence are bifunctional chelators that generally involve multistep syntheses and radiosynthetic procedures, which may require an automated synthesis module for clinical translation. ,− ,− The most promising radionuclide in the development of PET BPs is 68 Ga ( t 1/2 = 68 min; β + = 89%). This radiometal benefits from not only a short radiation decay half-life that minimizes radiation dose to patients but also availability from both cyclotrons and benchtop generators that can be installed in any radiopharmacy, allowing cyclotron-independent PET radiotracers on-site .…”

Chemical Self-Assembly of Multifunctional Hydroxyapatite with a Coral-like Nanostructure for Osteoporotic Bone Reconstruction

“…55−57 On the other hand, Fe 3 O 4 NPs have been demonstrated to promote OB proliferation and differentiation because of their innate magnetic properties. 58,59 However, previous research has shown that unconjugated AL is rapidly cleared from the blood (95% in 6 h), 60,61 and monodisperse Fe 3 O 4 NPs are easily uptaken by the reticuloendothelial system, 62 which reduces their therapeutic efficacy. In the current study, loading of AL and Fe 3 O 4 onto HA crystals prevented short burst release of functional components into the defect site; hence, the long-term release of bioactive molecules and the sustained magnetic stimulation by MNPs accelerated healing of osseous defects in osteoporotic situation.…”

“…AL is a powerful antiresorptive agent that is widely used for the treatment of systemic metabolic bone diseases. Many studies have claimed that AL could inhibit bone resorption via suppression of OC formation and function; meanwhile, it may also improve OB activity and osseointegration between implants and the native bone. − On the other hand, Fe 3 O 4 NPs have been demonstrated to promote OB proliferation and differentiation because of their innate magnetic properties. , However, previous research has shown that unconjugated AL is rapidly cleared from the blood (95% in 6 h), , and monodisperse Fe 3 O 4 NPs are easily uptaken by the reticuloendothelial system, which reduces their therapeutic efficacy. In the current study, loading of AL and Fe 3 O 4 onto HA crystals prevented short burst release of functional components into the defect site; hence, the long-term release of bioactive molecules and the sustained magnetic stimulation by MNPs accelerated healing of osseous defects in osteoporotic situation.…”