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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Special Emphasis Panel (ZGM1)
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University of Nebraska Medical Center
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Souchek, Joshua J; Wojtynek, Nicholas E; Payne, William M et al. (2018) Hyaluronic acid formulation of near infrared fluorophores optimizes surgical imaging in a prostate tumor xenograft. Acta Biomater 75:323-333
Payne, William M; Svechkarev, Denis; Kyrychenko, Alexander et al. (2018) The role of hydrophobic modification on hyaluronic acid dynamics and self-assembly. Carbohydr Polym 182:132-141
Svechkarev, Denis; Kyrychenko, Alexander; Payne, William M et al. (2018) Probing the self-assembly dynamics and internal structure of amphiphilic hyaluronic acid conjugates by fluorescence spectroscopy and molecular dynamics simulations. Soft Matter 14:4762-4771
Chatterjee, Arpita; Zhu, Yuxiang; Tong, Qiang et al. (2018) The Addition of Manganese Porphyrins during Radiation Inhibits Prostate Cancer Growth and Simultaneously Protects Normal Prostate Tissue from Radiation Damage. Antioxidants (Basel) 7:
Fan, Wei; Zhang, Wenting; Alshehri, Sameer et al. (2018) Increasing time on target: utilization of inhibitors of cysteine cathepsins to enhance the tumor retention of receptor-targeted agents. Chem Commun (Camb) 54:11268-11271
Chen, Shixuan; Boda, Sunil Kumar; Batra, Surinder K et al. (2018) Emerging Roles of Electrospun Nanofibers in Cancer Research. Adv Healthc Mater 7:e1701024
Jiang, Jiang; Zhang, Yang; Indra, Arup K et al. (2018) 1?,25-dihydroxyvitamin D3-eluting nanofibrous dressings induce endogenous antimicrobial peptide expression. Nanomedicine (Lond) 13:1417-1432
Qi, Bowen; Crawford, Ayrianne J; Wojtynek, Nicholas E et al. (2018) Indocyanine green loaded hyaluronan-derived nanoparticles for fluorescence-enhanced surgical imaging of pancreatic cancer. Nanomedicine 14:769-780
Weng, Lin; Boda, Sunil Kumar; Wang, Hongjun et al. (2018) Novel 3D Hybrid Nanofiber Aerogels Coupled with BMP-2 Peptides for Cranial Bone Regeneration. Adv Healthc Mater 7:e1701415
Jiang, Jiang; Chen, Shixuan; Wang, Hongjun et al. (2018) CO2-expanded nanofiber scaffolds maintain activity of encapsulated bioactive materials and promote cellular infiltration and positive host response. Acta Biomater 68:237-248

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