The overall objective of the proposed research is to demonstrate the feasibility of a new tumor selective targeting approach - thermally triggered polyvalent targeting - that provides external control of affinity targeting to enhance the selective delivery of anticancer drugs to the tumor vasculature. This overall objective is motivated by the rationale that there is an urgent need for improved therapy of primary tumors, especially for tumors of the brain, pancreas, ovary and colon, where mortality is typically caused by the inability of therapy to control the primary tumor. The central hypothesis of the proposed research is that thermally triggered polyvalent targeting will: (1) enhance accumulation of the drug payload in solid tumors; (2) limit drug exposure in normal tissues; and (3) improve tumor therapy. In the proposed research, a thermally responsive polypeptide will be synthesized that self-assembles into a nanoscale structure - a polypeptide micelle with a diameter of ~60 nm - only within a tumor that is mildly heated (~42?C) by externally focused hyperthermia. These polypeptide micelles are designed to present multiple copies of a tumor endothelial specific targeting ligand on the exterior - corona - of the micelle. The polyvalent presentation of targeting ligands only in the tumor will increase its avidity and therefore selectively deliver the anticancer therapeutics to the tumor vasculature while sparing normal tissues. The modulation of both affinity and size at the nanoscale is a unique feature of these engineered nanostructures, and is the key to their performance. The thermally triggered micelle forming system consists of elastin-like polypeptides (ELPs) in an AB diblock architecture. ELPs are thermally responsive biopolymers that undergo a thermally triggered hydrophilic-hydrophobic phase transition above their transition temperature (Tt). A diblock ELP copolymer (ELPBC) will incorporate a vascular targeting ligand (L) at the end of its hydrophilic block and will be conjugated at the hydrophobic end to 211 Astatine (211At), a radionuclide which emits highly potent, short penetration a-particles. L-ELPBC-211At conjugates will self-assemble into polyvalent micelles at 40?C in heated tumors and target the tumor endothelium by a greater thermally triggered avidity of the micelle to tumor endothelium, leading to ablation of tumor vasculature. Thee significance of the proposed research is that it will be, to our knowledge, the first attempt to harness ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB007205-02
Application #
7391269
Study Section
Special Emphasis Panel (ZRG1-BCMB-L (50))
Program Officer
Henderson, Lori
Project Start
2007-04-01
Project End
2011-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
2
Fiscal Year
2008
Total Cost
$349,351
Indirect Cost
Name
Duke University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Bhattacharyya, Jayanta; Weitzhandler, Isaac; Ho, Shihan Bryan et al. (2017) Encapsulating a Hydrophilic Chemotherapeutic into Rod-like Nanoparticles of a Genetically Encoded Asymmetric Triblock Polypeptide Improves its Efficacy. Adv Funct Mater 27:
MacEwan, Sarah R; Chilkoti, Ashutosh (2017) From Composition to Cure: A Systems Engineering Approach to Anticancer Drug Carriers. Angew Chem Int Ed Engl 56:6712-6733
Wang, Jing; Dzuricky, Michael; Chilkoti, Ashutosh (2017) The Weak Link: Optimization of the Ligand-Nanoparticle Interface To Enhance Cancer Cell Targeting by Polymer Micelles. Nano Lett 17:5995-6005
Wang, Jing; MacEwan, Sarah R; Chilkoti, Ashutosh (2017) Quantitative Mapping of the Spatial Distribution of Nanoparticles in Endo-Lysosomes by Local pH. Nano Lett 17:1226-1232
Simon, Joseph R; Carroll, Nick J; Rubinstein, Michael et al. (2017) Programming molecular self-assembly of intrinsically disordered proteins containing sequences of low complexity. Nat Chem 9:509-515
Weinberger, Andreas; Walter, Vivien; MacEwan, Sarah R et al. (2017) Cargo self-assembly rescues affinity of cell-penetrating peptides to lipid membranes. Sci Rep 7:43963
Wang, Jing; Bhattacharyya, Jayanta; Mastria, Eric et al. (2017) A quantitative study of the intracellular fate of pH-responsive doxorubicin-polypeptide nanoparticles. J Control Release 260:100-110
Bhattacharyya, Jayanta; Ren, Xiu-Rong; Mook, Robert A et al. (2017) Niclosamide-conjugated polypeptide nanoparticles inhibit Wnt signaling and colon cancer growth. Nanoscale 9:12709-12717
MacEwan, Sarah R; Weitzhandler, Isaac; Hoffmann, Ingo et al. (2017) Phase Behavior and Self-Assembly of Perfectly Sequence-Defined and Monodisperse Multiblock Copolypeptides. Biomacromolecules 18:599-609
Schaal, Jeffrey L; Li, Xinghai; Mastria, Eric et al. (2016) Injectable polypeptide micelles that form radiation crosslinked hydrogels in situ for intratumoral radiotherapy. J Control Release 228:58-66

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