期刊
THERANOSTICS
卷 8, 期 11, 页码 3164-3175出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.22164
关键词
PEG; Polyethylene glycol; anti-PEG antibodies; liposome; LipoDox; ELISA
资金
- Ministry of Science and Technology, Taiwan [MOST 106-2632-B-037-003, MOST 106-2320-B-041-001, MOST106-2314-B-037-019, MOST106-2311-B-037001-MY2, MOST 107-2321-B-037-003]
- National Health Research Institutes, Taiwan [NHRI-EX107-10729EI]
- Academia Sinica, Taiwan [AS-107-TP-B11]
- Program for Translational Innovation of Biopharmaceutical Development Technology Supporting Platform Axis [107-0210-01-19-04]
- Grant of Biosignature in Colorectal Cancers, Academia Sinica, Taiwan
- KMU-KMUH Co-Project of Key Research from Kaohsiung Medical University, Taiwan [KMU-DK107001]
- Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Taiwan
Rationale: Increasing frequency of human exposure to PEG-related products means that healthy people are likely to have pre-existing anti-PEG antibodies (pre-alpha PEG Ab). However, the influence of pre-alpha PEG Abs on the pharmacokinetics (PK) and therapeutic efficacy of LipoDox is unknown. Methods: We generated two pre-alpha PEG Ab mouse models. First, naive mice were immunized with PEGylated protein to generate an endogenous alpha PEG Ab titer (endo alpha PEG). Second, monoclonal alpha PEG Abs were passively transferred (alpha PEG-PT) into naive mice to establish a alpha PEG titer. The naive, endo alpha PEG and alpha PEG-PT mice were intravenously injected with (111)in-labeled LipoDox to evaluate its PK. Tumor-bearing naive, endo alpha PEG and alpha PEG-PT mice were intravenously injected with (111)in-labeled LipoDox to evaluate its biodistribution. The therapeutic efficacy of LipoDox was estimated in the tumor-bearing mice. Results: The areas under the curve (AUC)(last) of LipoDox in endo alpha PEG and alpha PEG-PT mice were 11.5- and 15.6-fold less, respectively, than that of the naive group. The biodistribution results suggested that pre-alpha PEG Ab can significantly reduce tumor accumulation and accelerate blood clearance of In-111-labeled LipoDox from the spleen. The tumor volumes of the tumor-bearing endo alpha PEG and alpha PEG-PT mice after treatment with LipoDox were significantly increased as compared with that of the tumor-bearing naive mice. Conclusions: Pre-alpha PEG Abs were found to dramatically alter the PK and reduce the tumor accumulation and therapeutic efficacy of LipoDox. Pre-alpha PEG may have potential as a marker to aid development of personalized therapy using LipoDox and achieve optimal therapeutic efficacy.
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