Ponnapakkam Tulasi, Anbalagan Muralidharan, Stratford Robert E, Zou Binghao, Blair Robert, Rowan Brian G, Gensure Robert
Xavier University of Louisiana, New Orleans, LA 70125, USA.
Department of Structural And Cellular Biology, Tulane University, School of Medicine, New Orleans, LA 70112, USA.
Toxicol Rep. 2025 Jul 12;15:102085. doi: 10.1016/j.toxrep.2025.102085. eCollection 2025 Dec.
The present study evaluates the acute toxicological profile and drug distribution of a novel bone-targeted parathyroid hormone-related peptide (PTHrP) antagonist for bone metastatic breast cancer. [W2]PTH(1-33)-CBD was created by fusing PTHrP antagonist peptide to the bacterial collagen-binding domain (CBD) of ColG collagenase from Clostridium histolyticum to target the drug to type 1 collagen in bone. Acting as an inverse agonist at the PTH/PTHrP receptor, [W2]PTH(1-33)-CBD induced apoptosis in breast cancer cells and reduced tumor burden in mouse tibia. Female C57BL/6 mice were injected with vehicle, 320 µg/kg, or 1000 µg/kg [W2]PTH(1-33)-CBD as a single injection. Animal behavior, body weight, mortality, and biochemical and organ toxicity assays showed no significant changes during 28-day study period. [W2]PTH(1-33)-CBD distribution assessed by immunohistochemistry confirmed localization to bone, skin, and kidney. No significant changes in liver enzymes or serum protein were observed. Treatment reduced serum calcium and increased creatinine, but kidney histology showed no toxicity. Histological analysis of the kidneys showed no alterations, indicating no toxicity. Histological analysis of spleen, lungs, skin, and bone showed no pathological changes. Pharmacokinetic analysis was done after a single injection of 1000 µg/kg dose (via subcutaneous and intravenous) to female Sprague Dawley rats to determine how the body metabolizes [W2]PTH(1-33)-CBD. Serum was collected at various time points, and drug analysis was performed. Exposure from both routes was similar, indicating complete absorption of [W2]PTH(1-33)-CBD following SC. No clinically significant biochemical or histopathological changes were observed at these doses, thus establishing a safety profile for treatment with novel [W2]PTH(1-33)-CBD.
本研究评估了一种新型骨靶向甲状旁腺激素相关肽（PTHrP）拮抗剂用于骨转移性乳腺癌的急性毒理学特征和药物分布情况。[W2]PTH(1-33)-CBD是通过将PTHrP拮抗剂肽与溶组织梭菌的ColG胶原酶的细菌胶原结合域（CBD）融合而产生的，以使药物靶向骨中的I型胶原。作为PTH/PTHrP受体的反向激动剂，[W2]PTH(1-33)-CBD诱导乳腺癌细胞凋亡并减轻小鼠胫骨中的肿瘤负担。雌性C57BL/6小鼠单次注射赋形剂、320μg/kg或1000μg/kg[W2]PTH(1-33)-CBD。动物行为、体重、死亡率以及生化和器官毒性检测显示，在28天的研究期内没有显著变化。[W2]通过免疫组织化学评估的PTH(1-33)-CBD分布证实其定位于骨、皮肤和肾脏。未观察到肝酶或血清蛋白有显著变化。治疗使血清钙降低，肌酐升高，但肾脏组织学显示无毒性。肾脏的组织学分析未显示改变，表明无毒性。脾脏、肺、皮肤和骨的组织学分析未显示病理变化。对雌性Sprague Dawley大鼠单次注射1000μg/kg剂量（经皮下和静脉注射）后进行药代动力学分析，以确定机体如何代谢[W2]PTH(1-33)-CBD。在不同时间点收集血清并进行药物分析。两种给药途径的暴露情况相似，表明皮下注射后[W2]PTH(1-33)-CBD完全吸收。在这些剂量下未观察到临床上显著的生化或组织病理学变化，从而确立了新型[W2]PTH(1-33)-CBD治疗的安全性概况。
