Tumor-Targeted Chemo-Immunotherapy for Osteosarcoma Metastasis

摘要 这项建议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部转移性骨肉瘤的一种新的联合方案。它是 众所周知，复发性骨肉瘤几乎完全转移到肺部，对单药耐药。 药物和联合化疗。迫切需要免疫疗法等新的治疗选择 联合化疗以控制和消除这些肿瘤。我们假设肿瘤靶向 提供一种包括化疗药物(阿霉素，临床上常规用于治疗)的综合疗法 骨肉瘤)和免疫刺激剂(IL-12蛋白)将显示出更好的抗肿瘤效果 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RBC- 膜包裹纳米粒(ttRBC-NP)给药系统，然后测试其抗肿瘤效果 阿霉素(DOX)负载的ttRBC-NP，表示为ttRBC-NP(DOX)，使用术后自发形成的 转移性骨肉瘤小鼠肺模型。接下来，ttRBC-NP(DOX)将与肿瘤靶向联合使用 IL-12蛋白治疗，标记为ttIL-12，以检查在治疗转移瘤方面的潜在协同效应 骨肉瘤。此外，我们还将探讨这种肿瘤靶向的化学免疫疗法对肿瘤的影响。 以期破译其内在机制。总体而言，将实现两个具体目标 在这项建议中，包括：(I)合成ttRBC-NP(DOX)并测试其联合应用的抗肿瘤效果 TtIL-12蛋白治疗转移性骨肉瘤；以及(Ii)研究其潜在机制。 靶向联合治疗提高了对转移性骨肉瘤的抗肿瘤疗效。的成功之处 该项目将为转移性骨肉瘤提供一种新的有效治疗方案，通过将一种新的 以纳米粒子为基础的化疗与强大的IL-12蛋白治疗。这项工作也将推动 开发一种独特而稳健的仿生纳米颗粒输送技术在医学上的研究 利用天然红细胞膜覆盖并因此伪装合成药物纳米载体的平台 逃避免疫系统。这项工作还将显著提高对如何组合的理解 化学免疫治疗影响肿瘤微环境，从而提高抗肿瘤疗效。

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.