Alendronate conjugate for targeted delivery to bone-forming prostate cancer.

Autor: Damasco JA; Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. Electronic address: jdamasco@fortislife.com., Yu G; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. Electronic address: gyu1@mdanderson.org., Kumar A; Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; Department of Biomedical Engineering, Rice University, Houston, TX 77004, USA. Electronic address: ak105@rice.edu., Perez J; Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. Electronic address: jdperez1@up.edu.ph., Lirag RCM; Department of Chemistry, Physics, and Engineering, Cameron University-Duncan, Duncan, OK 73533, USA. Electronic address: rlirag@cameron.edu., Whitley EM; Department of Veterinary Medicine and Surgery, And The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. Electronic address: emwhitley24@gmail.com., Lin SH; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; The University of Texas MD Anderson Cancer Center UT Health Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: slin@mdanderson.org., Melancon MP; Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; The University of Texas MD Anderson Cancer Center UT Health Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: mmelancon@mdanderson.org.
Jazyk: angličtina
Zdroj: Talanta [Talanta] 2023 May 01; Vol. 256, pp. 124308. Date of Electronic Publication: 2023 Jan 27.
DOI: 10.1016/j.talanta.2023.124308
Abstrakt: Bone is the primary metastasis site for lethal prostate cancer, often resulting in poor prognosis, crippling pain, and diminished functioning that drastically reduce both quality of life and survivability Uniquely, prostate cancer bone metastasis induces aberrant bone overgrowth, due to an increase of osteoblasts induced by tumor-secreted bone morphogenetic protein 4 (BMP4). Conjugating drugs to substances that target the tumor-induced bone area within the metastatic tumor foci would be a promising strategy for drug delivery. To develop such a strategy, we conjugated a near infrared (NIR) fluorescent probe, the dye Cy5.5, to serve as a surrogate for drugs, with alendronate, which targets bone. Characterization, such as infrared spectroscopy, confirmed the synthesis of the Cy5.5-ALN conjugate. The maximum absorbance of free Cy5.5, which was at 675 nm, did not change upon conjugation. Alendronate targeted the bone component hydroxyapatite in a dose-dependent manner up to 2.5 μM, with a maximum of 85% of Cy5.5-ALN bound to hydroxyapatite, while free Cy5.5 alone had 6% binding. In in vitro cell binding studies, Cy5.5-ALN bound specifically with mineralized bone matrix of differentiated MC3T3-E1 cells or 2H11 endothelial cells that were induced to become osteoblasts through endothelial-to-osteoblast transition, the underlying mechanism of prostate-cancer-induced bone formation. Neither Cy5.5-ALN nor free Cy5.5 bound to undifferentiated MC3T3-E1 or 2H11 cells. Bone-targeting efficiency studies in non-tumor-bearing mice revealed accumulation over time in the spine, jaw, knees, and paws injected with Cy5.5-ALN, and quantification showed higher accumulation in femurs than in muscle at up to 28 days, while the free Cy5.5 dye was observed circulating without preferential accumulation and decreased over time. There was a linear relationship with fluorescence when the injected concentration of Cy5.5-ALN was between 0.313 and 1.25 nmol/27 g of mouse, as quantified in mouse femurs both in vivo and ex vivo. Ex vivo evaluation of bone-targeting efficiency in nude mice was 3 times higher for bone-forming C4-2b-BMP4 tumors compared to non-bone-forming C4-2b tumors (p-value <0.001). Fluorescence microscopy imaging of the tumors showed that Cy5.5-ALN co-localized with the bone matrix surrounding tumor-induced bone, but not with the viable tumor cells. Together, these results suggest that a drug-ALN conjugate is a promising approach for targeted delivery of drug to the tumor-induced bone area in the metastatic foci of prostate cancer.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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