Mesothelioma, a malignancy associated with occupational exposure to asbestos is a devastating disease without attractive therapies. For decades, asbestos was used heavily in construction, industry, the Navy, even household products and appliances, and is still present in many homes, schools, and office buildings. The disease can arise from small exposures, and even as much as 50 years later. As a result, each year 3,000 Americans and many thousands more worldwide develop mesothelioma, and millions of us are at risk, creating a pressing need for new therapeutic strategies. Since mesothelioma is generally a regional disease within the pleura and peritoneum, aggressive surgery can resect most of solid viable tumor. However, microscopic residues and recurrence, especially in the peritoneal mesothelioma because of the complexity of the space and fragility of the organs, are increasingly recognized as major problems. Highly selective tumor location and targeting are needed. Our long term goal is to develop effective radioimmunotherapy (RIT) for human cancers by marrying radiotherapy with nanotechnology. The objective of this application is to engineer nano liposome as the dose delivery media to carry high payload of radionuclides for specific targeting of the methothelioma tumor cells by intraperitoneal administration. To accomplish, the first Aim is to identify optimal scFv antibodies targeting to malignant mesothelioma from a panel of 15 antibodies we have recently discovered. The native antibodies will be labeled with 99mTc for in vitro and in vivo evaluation of targeting. The remaining best 5 will be conjugated to nanosized liposome for further characterization in vitro and in vivo of the performance of these nanoparticle radioimmunoconjugates. The results will guide changes to the synthesis parameters in order to produce antibody liposome conjugates with promising properties for in vivo application.
The second aim will focus on the 177Lu labeling of the nanosized liposome conjugated with optimal antibody (177Lu-LP-scFv) to achieve high specific activity and characterize the targeting capability, stability and radiolysis in vitro. In vivo localization and biodistribution will be evaluated and optimized in animals bearing malignant peritoneal mesothelioma.
In Aim 3, the biodistribution and treatment efficacy of the best 177Lu-LP-scFv will then be evaluated in mice with malignant peritoneal mesothelioma xenografts. A variety of dosing schemes will also be tested. Execution of this project will provide effective and safe radioimmunotherapy of this aggressive disease. The novel antibody identified from in vivo screening will also have great potential to translate into specific marker for malignant mesothelioma and targeting vector for other targeted modality therapy. Additionally, the modular approach inherent in the nanoliposome simultalously loaded with targeting vector and high payload of cytotoxic agent holds promise as of potential template for multimodality intracavity locoregional therapies (e.g. photodynamic-radiotherapy) for malignant mesothelioma and other human cancers.
Malignant mesothelioma is a neoplasm of the mesothelial lining of the pleural or peritoneal cavity linked to prior exposure to asbestos. For decades, asbestos was used heavily in construction, industry, the Navy, even household products and appliances, and is still present in many homes, schools, and office buildings. The disease can arise from small exposures, and even as much as 50 years later with reported median survivals of only 18 to 24 months after diagnosis. As a result, each year more than 3,000 Americans and many thousands more worldwide develop mesothelioma, millions of us are at risk and projections suggest that the incidence will continue to rise, creating a pressing need for new therapeutic strategies. This project addresses key challenges of radioimmunotherapy (RIT) for the treatment of malignant mesothelioma. The goal for the study is to use nano liposome as the dose delivery media to carry high payload of radionuclides for specific targeting of the methothelioma tumor cells. If successfully completed, this novel method will create far-reaching applications in RIT, particularly for high-potent treatments of malignant mesothelioma. ? ? ?
|Huang, Tao; Hu, Pengcheng; Banizs, Anna B et al. (2017) Initial evaluation of Cu-64 labeled PARPi-DOTA PET imaging in mice with mesothelioma. Bioorg Med Chem Lett 27:3472-3476|
|Iyer, A K; He, J; Amiji, M M (2012) Image-guided nanosystems for targeted delivery in cancer therapy. Curr Med Chem 19:3230-40|
|Iyer, Arun K; Lan, Xiaoli; Zhu, Xiaodong et al. (2011) Novel human single chain antibody fragments that are rapidly internalizing effectively target epithelioid and sarcomatoid mesotheliomas. Cancer Res 71:2428-32|
|Iyer, Arun K; Su, Yang; Feng, Jinjin et al. (2011) The effect of internalizing human single chain antibody fragment on liposome targeting to epithelioid and sarcomatoid mesothelioma. Biomaterials 32:2605-13|
|Iyer, Arun K; He, Jiang (2011) Radiolabeled oligonucleotides for antisense imaging. Curr Org Synth 8:604-614|
|He, Jiang; Wang, Yong; Feng, Jinjin et al. (2010) Targeting prostate cancer cells in vivo using a rapidly internalizing novel human single-chain antibody fragment. J Nucl Med 51:427-32|
|He, Jiang; Wang, Yi; Dou, Shuping et al. (2010) Affinity enhancement pretargeting: synthesis and testing of a 99mTc-labeled bivalent MORF. Mol Pharm 7:1118-24|
|Christine, C W; Starr, P A; Larson, P S et al. (2009) Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 73:1662-9|