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 #
5P20GM103480-07
Application #
8730197
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Soni, Kruti S; Lei, Fan; Desale, Swapnil S et al. (2017) Tuning polypeptide-based micellar carrier for efficient combination therapy of ErbB2-positive breast cancer. J Control Release 264:276-287
Karuturi, Bala V K; Tallapaka, Shailendra B; Yeapuri, Pravin et al. (2017) Encapsulation of an EP67-Conjugated CTL Peptide Vaccine in Nanoscale Biodegradable Particles Increases the Efficacy of Respiratory Immunization and Affects the Magnitude and Memory Subsets of Vaccine-Generated Mucosal and Systemic CD8+ T Cells in a Diamet Mol Pharm 14:1469-1481
Fan, Wei; Zhang, Wenting; Jia, Yinnong et al. (2017) Investigation into the Biological Impact of Block Size on Cathepsin S-Degradable HPMA Copolymers. Mol Pharm 14:1405-1417
Chen, Shixuan; Ge, Liangpeng; Mueller, Aubrey et al. (2017) Twisting electrospun nanofiber fine strips into functional sutures for sustained co-delivery of gentamicin and silver. Nanomedicine 13:1435-1445
Chen, Shixuan; Ge, Liangpeng; Gombart, Adrian F et al. (2017) Nanofiber-based sutures induce endogenous antimicrobial peptide. Nanomedicine (Lond) 12:2597-2609
Jiang, Jiang; Chen, Shixuan; Wang, Hongjun et al. (2017) CO2-expanded nanofiber scaffolds maintain activity of encapsulated bioactive materials and promote cellular infiltration and positive host response. Acta Biomater :
Shrishrimal, Shashank; Kosmacek, Elizabeth A; Chatterjee, Arpita et al. (2017) The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues. Antioxidants (Basel) 6:
Souchek, Joshua J; Davis, Amanda L; Hill, Tanner K et al. (2017) Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells. Mol Cancer Ther 16:1819-1830
Smolsky, Joseph; Kaur, Sukhwinder; Hayashi, Chihiro et al. (2017) Surface-Enhanced Raman Scattering-Based Immunoassay Technologies for Detection of Disease Biomarkers. Biosensors (Basel) 7:
Lakshmanan, Imayavaramban; Salfity, Shereen; Seshacharyulu, Parthasarathy et al. (2017) MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53. Clin Cancer Res 23:3906-3917

Showing the most recent 10 out of 74 publications