A major problem in cancer therapy is that anti-cancer agents do not adequately penetrate into tumor tissue. This proposal is based on recently identified tumor-homing peptides that specifically penetrate into tumors. These peptides contain both a tumor-specific homing sequence and a tissue-penetrating and cell-internalizing C-end Rule (CendR) motif. The CendR element in the tumor-penetrating peptides is cryptic, and proteolytically activated at the target site. Drug, fluorophore, and nanoparticle cargos attached to these peptides accumulate in tumors and penetrate deep into extravascular tumor tissue. Recent evidence produced with the prototype tumor-penetrating peptide, iRGD, indicates that it is not necessary to couple a cargo to the peptide for tumor-selective delivery; free iRGD activates a bulk transport pathway in the tumor which carries a co-injected drug or nanoparticle through the vascular wall and deep into the tumor tissue. This application proposes studies to provide detailed understanding of the tumor penetration process. Specifically, we propose (i) to define the molecular pathway of the transport pathway, (ii) to identify protease(s) that activate cryptic CendR elements in the tumor-penetrating peptides, (iii) to optimize the ability of the peptides to selectively increase tissue permeability in tumors, and (iv) to test selected peptide-anti-cancer drug combinations in treatment studies. The ability to specifically increase the accumulation of anti-cancer drugs in tumors is an advance of broad ramifications. It promises to make it possible to deliver drugs to tumors at higher concentrations than permitted by standard therapies. According to our results, the increase can be as high as 40 fold. Because the increase in drug concentration only occurs in tumors and not in normal tissues, the efficacy of the treatment is increased while the side effects remain the same. Alternatively, the dose could be reduced without compromising the efficacy of the treatment. As the adjuvant peptide and anti-cancer drug are not coupled to one another, a validated and an approved tumor-penetrating peptide could be used to augment any cancer drug - a major advance in cancer therapy could ensue.

Public Health Relevance

We have discovered peptides that specifically increase the accumulation of co-injected drugs in tumors, which enhances the anti-cancer activity of the drugs. The peptides activate an extravasation and tissue-penetration pathway. We propose to characterize this transport pathway and use the information to develop compounds that are optimal for the use of this system in tumor therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA152327-05
Application #
8815170
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
5
Fiscal Year
2015
Total Cost
$404,625
Indirect Cost
$197,125
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Jin, Yusung; Kim, Dokyoung; Roh, Hajung et al. (2018) Tracking the Fate of Porous Silicon Nanoparticles Delivering a Peptide Payload by Intrinsic Photoluminescence Lifetime. Adv Mater 30:e1802878
Kim, Byungji; Pang, Hong-Bo; Kang, Jinyoung et al. (2018) Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus. Nat Commun 9:1969
Sharma, Shweta; Mann, Aman P; Mölder, Tarmo et al. (2017) Vascular changes in tumors resistant to a vascular disrupting nanoparticle treatment. J Control Release 268:49-56
Cureton, Natalie; Korotkova, Iana; Baker, Bernadette et al. (2017) Selective Targeting of a Novel Vasodilator to the Uterine Vasculature to Treat Impaired Uteroplacental Perfusion in Pregnancy. Theranostics 7:3715-3731
Ruoslahti, Erkki (2017) Tumor penetrating peptides for improved drug delivery. Adv Drug Deliv Rev 110-111:3-12
Simón-Gracia, Lorena; Hunt, Hedi; Scodeller, Pablo et al. (2016) iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes. Biomaterials 104:247-57
King, Anna; Ndifon, Cornelia; Lui, Sylvia et al. (2016) Tumor-homing peptides as tools for targeted delivery of payloads to the placenta. Sci Adv 2:e1600349
Paasonen, Lauri; Sharma, Shweta; Braun, Gary B et al. (2016) New p32/gC1qR Ligands for Targeted Tumor Drug Delivery. Chembiochem 17:570-5
Liu, Xiangyou; Braun, Gary B; Zhong, Haizheng et al. (2016) Tumor-Targeted Multimodal Optical Imaging with Versatile Cadmium-Free Quantum Dots. Adv Funct Mater 26:267-276
Simón-Gracia, Lorena; Hunt, Hedi; Scodeller, Pablo D et al. (2016) Paclitaxel-Loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy. Mol Cancer Ther 15:670-9

Showing the most recent 10 out of 31 publications