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.
Relevancy Statement The 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. This project will also explore the impact of this tumor-targeted combination therapy on tumor microenvironment in order to decipher the underlying mechanism. The success of this project will provide a new and effective treatment option for osteosarcoma metastasis, advance the research of nanotechnology in medicine in general, and improve the understanding of how targeted combination therapy can boost anti-tumor efficacy.
|Jiang, Yao; Chekuri, Sanam; Fang, Ronnie H et al. (2018) Engineering biological interactions on the nanoscale. Curr Opin Biotechnol 58:1-8|
|Luk, Brian T; Jiang, Yao; Copp, Jonathan A et al. (2018) Biomimetic Targeting of Nanoparticles to Immune Cell Subsets via Cognate Antigen Interactions. Mol Pharm 15:3723-3728|
|Angsantikul, Pavimol; Thamphiwatana, Soracha; Zhang, Qiangzhe et al. (2018) Coating nanoparticles with gastric epithelial cell membrane for targeted antibiotic delivery against Helicobacter pylori infection. Adv Ther (Weinh) 1:|
|Fang, Ronnie H; Kroll, Ashley V; Gao, Weiwei et al. (2018) Cell Membrane Coating Nanotechnology. Adv Mater 30:e1706759|
|Hu, Jiemiao; Sun, Chuang; Bernatchez, Chantale et al. (2018) T-cell Homing Therapy for Reducing Regulatory T Cells and Preserving Effector T-cell Function in Large Solid Tumors. Clin Cancer Res 24:2920-2934|
|Wei, Xiaoli; Ying, Man; Dehaini, Diana et al. (2018) Nanoparticle Functionalization with Platelet Membrane Enables Multifactored Biological Targeting and Detection of Atherosclerosis. ACS Nano 12:109-116|
|Gao, Weiwei; de Ávila, Berta Esteban-Fernández; Zhang, Liangfang et al. (2018) Targeting and isolation of cancer cells using micro/nanomotors. Adv Drug Deliv Rev 125:94-101|
|Ying, Man; Zhuang, Jia; Wei, Xiaoli et al. (2018) Remote-Loaded Platelet Vesicles for Disease-Targeted Delivery of Therapeutics. Adv Funct Mater 28:|
|Escajadillo, Tamara; Olson, Joshua; Luk, Brian T et al. (2017) A Red Blood Cell Membrane-Camouflaged Nanoparticle Counteracts Streptolysin O-Mediated Virulence Phenotypes of Invasive Group A Streptococcus. Front Pharmacol 8:477|
|Fang, Ronnie H; Jiang, Yao; Fang, Jean C et al. (2017) Cell membrane-derived nanomaterials for biomedical applications. Biomaterials 128:69-83|
Showing the most recent 10 out of 19 publications