دورية أكاديمية
أعرض في EDS

Systemic delivery of a Gli inhibitor via polymeric nanocarriers inhibits tumor-induced bone disease.

التفاصيل البيبلوغرافية
العنوان: Systemic delivery of a Gli inhibitor via polymeric nanocarriers inhibits tumor-induced bone disease.
المؤلفون: Vanderburgh JP; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA., Kwakwa KA; Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA., Werfel TA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA., Merkel AR; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Gupta MK; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA., Johnson RW; Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Guelcher SA; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA; Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Duvall CL; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA., Rhoades JA; Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: julie.sterling@vumc.org.
المصدر: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2019 Oct; Vol. 311-312, pp. 257-272. Date of Electronic Publication: 2019 Sep 05.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Publishers Country of Publication: Netherlands NLM ID: 8607908 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4995 (Electronic) Linking ISSN: 01683659 NLM ISO Abbreviation: J Control Release Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Amsterdam : Elsevier Science Publishers, 1984-
مواضيع طبية MeSH: Antineoplastic Agents/*administration & dosage , Bone Neoplasms/*drug therapy , Drug Carriers/*administration & dosage , Mammary Neoplasms, Animal/*drug therapy , Nanoparticles/*administration & dosage , Pyridines/*administration & dosage , Thiophenes/*administration & dosage, Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacokinetics ; Apoptosis/drug effects ; Bone Neoplasms/secondary ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Carriers/chemistry ; Drug Carriers/pharmacokinetics ; Drug Liberation ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Mammary Neoplasms, Animal/pathology ; Mesenchymal Stem Cells/drug effects ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Nude ; Nanoparticles/chemistry ; Osteogenesis/drug effects ; Polymers/administration & dosage ; Polymers/chemistry ; Polymers/pharmacokinetics ; Pyridines/chemistry ; Pyridines/pharmacokinetics ; Thiophenes/chemistry ; Thiophenes/pharmacokinetics ; Zinc Finger Protein Gli2/antagonists & inhibitors ; Zinc Finger Protein Gli2/genetics
مستخلص: Solid tumors frequently metastasize to bone and induce bone destruction leading to severe pain, fractures, and other skeletal-related events (SREs). Osteoclast inhibitors such as bisphosphonates delay SREs but do not prevent skeletal complications or improve overall survival. Because bisphosphonates can cause adverse side effects and are contraindicated for some patients, we sought an alternative therapy to reduce tumor-associated bone destruction. Our previous studies identified the transcription factor Gli2 as a key regulator of parathyroid hormone-related protein (PTHrP), which is produced by bone metastatic tumor cells to promote osteoclast-mediated bone destruction. In this study, we tested the treatment effect of a Gli antagonist GANT58, which inhibits Gli2 nuclear translocation and PTHrP expression in tumor cells. In initial testing, GANT58 did not have efficacy in vivo due to its low water solubility and poor bioavailability. We therefore developed a micellar nanoparticle (NP) to encapsulate and colloidally stabilize GANT58, providing a fully aqueous, intravenously injectable formulation based on the polymer poly(propylene sulfide) 135 -b-poly[(oligoethylene glycol) 9 methyl ether acrylate] 17 (PPS 135 -b-POEGA 17 ). POEGA forms the hydrophilic NP surface while PPS forms the hydrophobic NP core that sequesters GANT58. In response to reactive oxygen species (ROS), PPS becomes hydrophilic and degrades to enable drug release. In an intratibial model of breast cancer bone metastasis, treatment with GANT58-NPs decreased bone lesion area by 49% (p<.01) and lesion number by 38% (p<.05) and resulted in a 2.5-fold increase in trabecular bone volume (p<.001). Similar results were observed in intracardiac and intratibial models of breast and lung cancer bone metastasis, respectively. Importantly, GANT58-NPs reduced tumor cell proliferation but did not alter mesenchymal stem cell proliferation or osteoblast mineralization in vitro, nor was there evidence of cytotoxicity after repeated in vivo treatment. Thus, inhibition of Gli2 using GANT58-NPs is a potential therapy to reduce bone destruction that should be considered for further testing and development toward clinical translation.
(Published by Elsevier B.V.)
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معلومات مُعتمدة: R25 GM062459 United States GM NIGMS NIH HHS; S10 RR027631 United States RR NCRR NIH HHS; R01 CA163499 United States CA NCI NIH HHS; I01 BX001957 United States BX BLRD VA; R00 CA194198 United States CA NCI NIH HHS; P30 CA068485 United States CA NCI NIH HHS; U01 CA091664 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: Bone metastasis; Breast cancer; GANT58; Gli2; Nanoparticle; PTHrP
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Drug Carriers)
0 (GANT58)
0 (Polymers)
0 (Pyridines)
0 (Thiophenes)
0 (Zinc Finger Protein Gli2)
تواريخ الأحداث: Date Created: 20190909 Date Completed: 20201021 Latest Revision: 20201021
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC7007697
DOI: 10.1016/j.jconrel.2019.08.038
PMID: 31494183
قاعدة البيانات: MEDLINE
الوصف
تدمد:1873-4995
DOI:10.1016/j.jconrel.2019.08.038