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PEGylated liposome-encapsulated rhenium-188 radiopharmaceutical inhibits proliferation and epithelial-mesenchymal transition of human head and neck cancer cells in vivo with repeated therapy.

ABSTRACT: Human head and neck squamous cell carcinoma (HNSCC) is usually treated with chemoradiotherapy, but the therapeutic efficacy could be hampered by intrinsic radioresistance and early relapse. Repeated administrations of rhenium-188 (¹⁸⁸Re)-conjugated radiopharmaceutical has been reported to escalate the radiation doses for better control of advanced human cancers. Here we found that high dosage of ¹⁸⁸Re-liposome, the liposome-encapsulated ¹⁸⁸Re nanoparticles exhibited significant killing effects on HNSCC FaDu cells and SAS cells but not on OECM-1 cells. To investigate the biological and pharmaceutical responses of high ¹⁸⁸Re-liposomal dosage in vivo, repeated doses of ¹⁸⁸Re-liposome was injected into the orthotopic tumor model. FaDu cells harboring luciferase reporter genes were implanted in the buccal positions of nude mice followed by intravenous injection of ¹⁸⁸Re-liposome. The Cerenkov luminescence imaging (CLI) was performed to demonstrate an increased accumulation of ¹⁸⁸Re-liposome in the tumor lesion of nude mice with repeated doses compared to a single dose. Repeated doses also enhanced tumor growth delay and elongated the survival of tumor-bearing mice. These observations were associated with significant loss of Ki-67 proliferative marker and epithelial-mesenchymal transition (EMT) markers in excised tumor cells. The body weights of mice were not significantly changed using different doses of ¹⁸⁸Re-liposome, yet repeated doses led to lower blood counts than a single dose. Furthermore, the pharmacokinetic analysis showed that the internal circulation of repeated ¹⁸⁸Re-liposomal therapy was elongated. The biodistribution analysis also demonstrated that accumulations of ¹⁸⁸Re-liposome in tumor lesions and bone marrow were increased using repeated doses. The absorbed dose of repeated doses over a single dose was about twofold estimated for a 1?g tumor. Together, these data suggest that the radiopharmacotherapy of ¹⁸⁸Re-liposome can enhance tumor suppression, survival extension, and internal circulation without acute toxicity using repeated administrations.

SUBMITTER: Chang CY

PROVIDER: S-EPMC6208374 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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PEGylated liposome-encapsulated rhenium-188 radiopharmaceutical inhibits proliferation and epithelial-mesenchymal transition of human head and neck cancer cells in vivo with repeated therapy.

Chang Chun-Yuan CY Chen Chao-Cheng CC Lin Liang-Ting LT Chang Chih-Hsien CH Chen Liang-Cheng LC Wang Hsin-Ell HE Lee Te-Wei TW Lee Yi-Jang YJ

Cell death discovery 20181031

Human head and neck squamous cell carcinoma (HNSCC) is usually treated with chemoradiotherapy, but the therapeutic efficacy could be hampered by intrinsic radioresistance and early relapse. Repeated administrations of rhenium-188 (188Re)-conjugated radiopharmaceutical has been reported to escalate the radiation doses for better control of advanced human cancers. Here we found that high dosage of 188Re-liposome, the liposome-encapsulated 188Re nanoparticles exhibi ...[more]

PMID: 30393570

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Project description:A pentapeptide macrocyclic ligand, KYCAR (lysyl-tyrosyl-cystyl-alanyl-arginine), has been designed as a potential chelating ligand for SPECT imaging and therapeutic in vivo agents. This study shows the synthesis and characterization of KYCAR complexes containing nonradioactive rhenium, 99mTc, or 188Re. The metal complexes were also biologically evaluated to determine in vivo distribution in healthy mice. The overall goals of this project were (1) to synthesize the Tc/Re pentapeptide complexes, (2) to identify spectroscopic methods for characterization of syn versus anti rhenium peptide complexes, (3) to analyze the ex vivo stability, and (4) to assess the biological properties of the [99mTc]TcO-KYCAR and [188Re]ReO-KYCAR complexes in vivo. Details on these efforts are provided below.MethodsNatRe/99mTc/188ReO-KYCAR complexes were synthesized, and macroscopic species were characterized via HPLC, IR, NMR, and CD. These characterization data were compared to the crystallographic data of ReO-KYC to assist in the assignment of diastereomers and to aid in the determination of the structure of the complex.ResultsThe radiometal complexes were synthesized with high purity (>95%). HPLC, IR, NMR and CD data on the macroscopic natReO-KYCAR complexes confirm the successful complexation as well as the presence of two diastereomers in syn and anticonformations. Tracer level complexes show favorable stabilities ex vivo for 2+ h.ConclusionMacroscopic metal complexes form diastereomers with the KYCAR ligand; however, this phenomenon is not readily observed on the tracer level due to the rapid interconversion. It was determined through pKa measurements that the macroscopic natReO-KYCAR complex is 0 at physiological pH. The [99mTc]TcO-KYCAR is stable in vitro while the [188Re]ReO-KYCAR shows 50% decomposition in PBS and serum. Biologically, the tracer level complexes clear through the hepatobiliary pathway. Some decomposition of both tracers is evident by uptake in the thyroid and stomach.

Dataset Information

PEGylated liposome-encapsulated rhenium-188 radiopharmaceutical inhibits proliferation and epithelial-mesenchymal transition of human head and neck cancer cells in vivo with repeated therapy.

Publications

PEGylated liposome-encapsulated rhenium-188 radiopharmaceutical inhibits proliferation and epithelial-mesenchymal transition of human head and neck cancer cells in vivo with repeated therapy.

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