期刊
THERANOSTICS
卷 8, 期 5, 页码 1361-1375出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.18299
关键词
Sarcoma-Targeting Peptide; Polypeptide Nanogel; Intracellular Drug Delivery; Necroptosis; Osteosarcoma Chemotherapy
资金
- National Natural Science Foundation of China [81202115, 51673190, 51603204, 51673187, 51520105004]
- Research Grant from Shanghai Hospital Development Center [SHDC12013107]
- Excellent Young Talent Program of Shanghai Municipal Commission of Health and Family Planning [XYQ2013108]
Purpose: Osteosarcoma is the most common primary bone cancer and is notorious for pulmonary metastasis, representing a major threat to pediatric patients. An effective drug targeting osteosarcoma and its lung metastasis is urgently needed. Design: In this study, a sarcoma-targeting peptide-decorated disulfide-crosslinked polypeptide nanogel (STP-NG) was exploited for enhanced intracellular delivery of shikonin (SHK), an extract of a medicinal herb, to inhibit osteosarcoma progression with minimal systemic toxicity. Results: The targeted, loaded nanogel, STP-NG/SHK, killed osteosarcoma cells by inducing RIP1-and RIP3-dependent necroptosis in vitro. Necroptosis is a novel cell death form that could be well adapted as an efficient antitumor strategy, the main obstacle of which is its high toxicity. After intravenous injection, STP-NG/SHK efficiently suppressed tumor growth and reduced pulmonary metastasis, offering greater tumor necrosis and higher RIP1 and RIP3 upregulation compared to free SHK or untargeted NG/SHK in vivo. Additionally, the treatment with NG/SHK or STP-NG/SHK showed minimal toxicity to normal organs, suggesting low systemic toxicity compared to free SHK. Conclusion: The STP-guided intracellular drug delivery system using the necroptosis mechanism showed profound anti-osteosarcoma activity, especially eliminated lung metastasis in vivo. This drug formulation may have great potential for treatment of osteosarcoma.
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