Tumor-Targeted Chemo-Immunotherapy for Osteosarcoma Metastasis

骨肉瘤转移的肿瘤靶向化学免疫治疗

• 批准号: 9926814
• 负责人: SHULIN LI
• 金额: $ 35.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926814
• 关键词: Antineoplastic Agents; Biology; Biomimetics; Blood Circulation; CD8-Positive T-Lymphocytes; Cell membrane; Cells; Clinic; Combined Modality Therapy; Doxorubicin; Drug Delivery Systems; Engineering; Erythrocytes; Gene Delivery; Goals; Homing; Immune; Immune system; Immuno-Chemotherapy; Immunotherapy; In Vitro; Interferon Type II; Interleukin-12; Joints; Lung; Lung Neoplasms; Medicine; Membrane; Metastatic Neoplasm to the Lung; Metastatic Osteosarcoma; Modeling; Mus; Nanotechnology; Neoplasm Metastasis; Operative Surgical Procedures; Paper; Peptides; Pharmaceutical Preparations; Property; Proteins; Publishing; Recurrence; Regimen; Research; Resistance; Resources; Site; Surface; System; Testing; Therapeutic; Toxic effect; Toxicity Tests; Treatment Efficacy; Treatment Protocols; Tumor Burden; University of Texas M D Anderson Cancer Center; Work; anti-tumor immune response; base; cancer therapy; chemotherapy; combinatorial; effective therapy; fusion gene; improved; in vivo; invention; nanocarrier; nanoparticle; nanoparticle delivery; nanotherapeutic; neoplasm immunotherapy; novel; osteosarcoma; public health relevance; success; synergism; synthetic drug; targeted delivery; tumor; tumor microenvironment

Abstract The primary objective of this proposal is to develop a non-invasive and effective tumor-targeted chemo- immunotherapy as a novel combination regimen for treating metastatic osteosarcoma tumors in the lungs. It is well known that recurrent osteosarcoma almost exclusively metastasizes to the lungs and is resistant to single- agent and combined chemotherapy. New treatment options such as immunotherapy are urgently needed for combination with chemotherapy to control and eliminate these tumors. We hypothesize that tumor-targeted delivery of a combination therapy that includes a chemo-drug (doxorubicin, routinely used in clinic to treat osteosarcoma) and an immune stimulant (IL-12 protein) will demonstrate an improved anti-tumor efficacy against metastatic osteosarcoma. To test this hypothesis, we will synthesize a novel tumor-targeted RBC- membrane-cloaked nanoparticle (ttRBC-NP) delivery system and then test the anti-tumor efficacy of the doxorubicin(DOX)-loaded ttRBC-NP, denoted ttRBC-NP(DOX), using a spontaneously formed post-surgery metastatic osteosarcoma mouse lung model. The ttRBC-NP(DOX) will next be combined with tumor-targeted IL-12 protein therapy, denoted ttIL-12, to examine potential synergistic effects on treating metastatic osteosarcoma. Furthermore, we will explore the impact of this tumor-targeted chemo-immunotherapy on tumor microenvironment in order to decipher the underlying mechanism. Overall, two specific aims will be pursued in this proposal, including: (i) to synthesize ttRBC-NP(DOX) and test its anti-tumor efficacy in combination with ttIL-12 protein therapy against metastatic osteosarcoma; and (ii) to study the underlying mechanisms by which the targeted combination therapy boosts anti-tumor efficacy against metastatic osteosarcoma. The success of this project will provide a new and effective treatment option for metastatic osteosarcoma by combining a novel nanoparticle-based chemotherapy with a powerful IL-12 protein therapy. This work will also advance the research of nanotechnology in medicine by developing a unique and robust biomimetic nanoparticle delivery platform that utilizes natural RBC membranes to coat and thus camouflage synthetic drug nanocarriers to evade the immune system. This work will also significantly improve the understanding of how combinatorial chemo-immunotherapy impacts the tumor microenvironment and thus enhances the anti-tumor efficacy.

摘要 该提案的主要目标是开发一种非侵入性和有效的肿瘤靶向化疗， 免疫疗法作为治疗肺转移性骨肉瘤肿瘤的新组合方案。是 众所周知，复发性骨肉瘤几乎只转移到肺部，并且对单- 药物和联合化疗。迫切需要新的治疗选择，如免疫治疗， 联合化疗来控制和消除这些肿瘤。我们假设肿瘤靶向 递送包括化疗药物（阿霉素，常规用于临床以治疗 骨肉瘤）和免疫刺激剂（IL-12蛋白）将显示出改善的抗肿瘤功效 对抗转移性骨肉瘤为了验证这一假设，我们将合成一种新的肿瘤靶向红细胞- 膜包裹的纳米颗粒（ttRBC-NP）递送系统，然后测试该纳米颗粒的抗肿瘤功效。 多柔比星（DOX）负载的ttRBC-NP，表示为ttRBC-NP（DOX），使用手术后自发形成的 转移性骨肉瘤小鼠肺模型。ttRBC-NP（DOX）接下来将与肿瘤靶向药物组合。 IL-12蛋白治疗，表示为ttIL-12，以检查对治疗转移性肿瘤的潜在协同作用。 骨肉瘤此外，我们将探讨这种肿瘤靶向化学免疫治疗对肿瘤的影响。 微环境，以破译潜在的机制。总体而言，将追求两个具体目标 在本方案中，包括：（i）合成ttRBC-NP（DOX）并测试其与 ttIL-12蛋白治疗转移性骨肉瘤;（ii）研究其潜在机制， 靶向联合治疗增强了针对转移性骨肉瘤的抗肿瘤功效。的成功 该项目将为转移性骨肉瘤提供一种新的有效的治疗选择， 基于纳米颗粒的化疗与强大的IL-12蛋白疗法。这项工作还将推动 通过开发独特和强大的仿生纳米颗粒递送，研究医学中的纳米技术 该平台利用天然RBC膜来涂覆并因此伪装合成药物纳米载体， 逃避免疫系统。这项工作还将大大提高对组合如何 化学免疫疗法影响肿瘤微环境，从而增强抗肿瘤功效。

项目成果

Preparation of particulate polymeric therapeutics for medical applications.

• DOI: 10.1002/smtd.201700147
• 发表时间: 2017-09
• 期刊: Small methods
• 影响因子: 12.4
• 作者: Zhu Jia;Ronnie H. Fang;Liangfang Zhang

Nanoparticle-modified microrobots for in vivo antibiotic delivery to treat acute bacterial pneumonia.

• DOI: 10.1038/s41563-022-01360-9
• 发表时间: 2022-11
• 期刊: Nature materials
• 影响因子: 41.2

Nanodelivery of STING agonists against cancer and infectious diseases.

• DOI: 10.1016/j.mam.2021.101007
• 发表时间: 2022-03
• 期刊: Molecular aspects of medicine
• 影响因子: 10.6
• 作者: Zhou J;Ventura CJ;Fang RH;Zhang L
• 通讯作者: Zhang L

Cell membrane-derived nanomaterials for biomedical applications.

• DOI: 10.1016/j.biomaterials.2017.02.041
• 发表时间: 2017-06
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Fang RH;Jiang Y;Fang JC;Zhang L
• 通讯作者: Zhang L

Remote Loading of Small-Molecule Therapeutics into Cholesterol-Enriched Cell-Membrane-Derived Vesicles.

• DOI: 10.1002/anie.201707598
• 发表时间: 2017-11-06
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Zhang X;Angsantikul P;Ying M;Zhuang J;Zhang Q;Wei X;Jiang Y;Zhang Y;Dehaini D;Chen M;Chen Y;Gao W;Fang RH;Zhang L
• 通讯作者: Zhang L