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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA200574-05
Application #
9926814
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Sommers, Connie L
Project Start
2016-06-15
Project End
2021-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Ying, Man; Zhuang, Jia; Wei, Xiaoli et al. (2018) Remote-Loaded Platelet Vesicles for Disease-Targeted Delivery of Therapeutics. Adv Funct Mater 28:
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
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

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