Sarcoma-Targeting Peptide-Decorated Polypeptide Nanogel Intracellularly Delivers Shikonin for Upregulated Osteosarcoma Necroptosis and Diminished Pulmonary Metastasis.,Theranostics

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Sarcoma-Targeting Peptide-Decorated Polypeptide Nanogel Intracellularly Delivers Shikonin for Upregulated Osteosarcoma Necroptosis and Diminished Pulmonary Metastasis.
Theranostics ( IF 12.4 ) Pub Date : 2018-02-02 , DOI: 10.7150/thno.18299
Suoyuan Li _{1,

2} , Tao Zhang ₁ , Weiguo Xu ₃ , Jianxun Ding ₃ , Fei Yin ₄ , Jing Xu ₄ , Wei Sun ₁ , Hongsheng Wang ₄ , Mengxiong Sun ₁ , Zhengdong Cai _{1,

4} , Yingqi Hua _{1,

4}

Affiliation

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.

中文翻译：

肉瘤靶向肽修饰的多肽纳米凝胶在细胞内提供紫草素，用于上调骨肉瘤坏死和减少肺转移。

目的骨肉瘤是最常见的原发性骨癌，并且因肺转移而臭名昭著，对儿科患者构成重大威胁。迫切需要针对骨肉瘤及其肺转移的有效药物。设计在这项研究中，利用肉瘤靶向肽修饰的二硫键交联的多肽纳米凝胶（STP-NG）来增强紫草素（SHK）（一种草药提取物）的细胞内递送，从而以最小的全身毒性抑制骨肉瘤的进展。结果靶向的负载型纳米凝胶STP-NG / SHK通过在体外诱导RIP1和RIP3依赖性坏死病杀死骨肉瘤细胞。坏死病是一种新型的细胞死亡形式，可以很好地适应作为一种有效的抗肿瘤策略，其主要障碍是其高毒性。静脉注射后与体内游离SHK或非靶向NG / SHK相比，STP-NG / SHK有效抑制肿瘤生长并减少肺转移，提供更大的肿瘤坏死和更高的RIP1和RIP3上调。此外，用NG / SHK或STP-NG / SHK处理对正常器官的毒性最小，这表明与游离SHK相比，全身毒性较低。结论采用坏死性机制的STP指导的细胞内药物递送系统显示出强大的抗骨肉瘤活性，尤其是在体内消除了肺转移。该药物制剂可能具有治疗骨肉瘤的巨大潜力。NG / SHK或STP-NG / SHK处理对正常器官的毒性最小，表明与游离SHK相比，全身毒性较低。结论采用坏死性机制的STP指导的细胞内药物递送系统显示出强大的抗骨肉瘤活性，尤其是在体内消除了肺转移。该药物制剂可能具有治疗骨肉瘤的巨大潜力。NG / SHK或STP-NG / SHK的治疗对正常器官的毒性最小，表明与游离SHK相比，全身毒性较低。结论采用坏死性机制的STP指导的细胞内药物递送系统显示出强大的抗骨肉瘤活性，尤其是在体内消除了肺转移。该药物制剂可能具有治疗骨肉瘤的巨大潜力。

更新日期：2018-05-01

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