Objective: A major barrier to the advancement of diagnostic and therapeutic nanomedicines has been the non-target retention caused by the accumulation of the drug delivery systems in organs associated with the mononuclear phagocyte system, particularly the liver and spleen. The focus of this proposal is on the development of 177Lu-DOTA-Metabolically Active Linkers (MALs) that substantially reduce the non-target retention of diagnostic and radiotherapeutic HPMA copolymers, thereby leading to an increase in the tumor to- non-target ratios. We propose to design and develop MALs that enzymatically cleave in the presence of Cathepsins B and S, which are known to be highly expressed in the liver and spleen. Cleavage of the MALs will generate low molecular weight radiometabolites which are expected to clear more effectively from nontarget tissue while still achieving significant retention in tumors. For therapeutic applications, this enhanced clearance from non-target tissues will substantially decrease non-target toxicity. If successful, the MAL stratagem will be easily integrated into a wide variety of nanomedicine platforms to substantially enhance the efficacy and translational potential of these agents for treating cancer and other diseases. Study Design:
The first aim of this proposal is to synthesize, purify, characterize and radiolabel the 177Lu- DOTA-MAL-HPMA copolymers. Upon synthesizing the agents, the intemalization, efflux and metabolism properties of the agents will be investigated in human macrophage and the HPAC pancreatic cancer cell line.
The second aim of the proposal will focus on the initial in vivo evaluation of the 177Lu-DOTA-MAL-HPMA copolymers. These studies will include biodistribution, human dose estimation, in vivo metabolism and microSPECT/CT imaging studies. Lastly, the third aim will evaluate the therapeutic potential of the 177Lu- DOTA-MAL-HPMA copolymers alone and in combination with current pancreatic cancer chemotherapeutic regimens. As part of the therapeutic evaluation, maximum tolerated dose determinations and histopathological analysis will be performed to gauge therapeutic efficacy and toxicity.

Public Health Relevance

Currently, the five-year survival rate for patients diagnosed with pancreatic cancer is less than 5%. Our goal is to design peptides that substantially lower the non-target toxicity of cancer-targeted drug delivery systems. This decrease in non-target toxicity would allow for the administration of higher therapeutic doses as well as lead to an increase in efficacy, safety and potential of the drug delivery system for clinical translation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
2P20GM103480-06
Application #
8601981
Study Section
Special Emphasis Panel (ZGM1-TWD-Y (C2))
Project Start
Project End
Budget Start
2013-09-15
Budget End
2014-05-31
Support Year
6
Fiscal Year
2013
Total Cost
$224,463
Indirect Cost
$75,318
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Macha, M A; Rachagani, S; Pai, P et al. (2015) MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. Oncogene 34:1698-708
Macha, Muzafar A; Seshacharyulu, Parthasarathy; Krishn, Shiv Ram et al. (2014) MicroRNAs (miRNAs) as biomarker(s) for prognosis and diagnosis of gastrointestinal (GI) cancers. Curr Pharm Des 20:5287-97
Gutti, Tanuja L; Knibbe, Jaclyn S; Makarov, Edward et al. (2014) Human hepatocytes and hematolymphoid dual reconstitution in treosulfan-conditioned uPA-NOG mice. Am J Pathol 184:101-9
Yi, Xiang; Manickam, Devika S; Brynskikh, Anna et al. (2014) Agile delivery of protein therapeutics to CNS. J Control Release 190:637-63
Alakhova, Daria Y; Kabanov, Alexander V (2014) Pluronics and MDR reversal: an update. Mol Pharm 11:2566-78
Savalia, Krupa; Manickam, Devika S; Rosenbaugh, Erin G et al. (2014) Neuronal uptake of nanoformulated superoxide dismutase and attenuation of angiotensin II-dependent hypertension after central administration. Free Radic Biol Med 73:299-307
Shi, Wen; Ogbomo, Sunny M; Wagh, Nilesh K et al. (2014) The influence of linker length on the properties of cathepsin S cleavable (177)Lu-labeled HPMA copolymers for pancreatic cancer imaging. Biomaterials 35:5760-70
Gupta, Suprit; Batra, Surinder; Jain, Maneesh (2014) Antibody labeling with radioiodine and radiometals. Methods Mol Biol 1141:147-57
Nukolova, Natalia V; Oberoi, Hardeep S; Zhao, Yi et al. (2013) LHRH-targeted nanogels as a delivery system for cisplatin to ovarian cancer. Mol Pharm 10:3913-21
Zhou, Zhengyuan; Wagh, Nilesh K; Ogbomo, Sunny M et al. (2013) Synthesis and in vitro and in vivo evaluation of hypoxia-enhanced 111In-bombesin conjugates for prostate cancer imaging. J Nucl Med 54:1605-12

Showing the most recent 10 out of 16 publications