This proposal describes the design and development of versatile amphiphilic dendrimer-based supramolecular assemblies, in aqueous milieu, that disassemble in response to specific proteins as stimuli. There have been great advances in stimuli-sensitive supramolecular assemblies; however, these have primarily focused on systems that respond to changes in factors such as pH, temperature, or redox conditions, which are secondary imbalances in biology. The most direct and primary indicator of imbalance in biology involves change in protein activity. Therefore, generating supramolecular assemblies that respond to proteins is exciting. Our primary objective is to obtain a better understanding of the structural factors that control the assembly/disassembly events in response to the concentration of a specific protein or activity of an enzyme. The structural requirements for achieving control over these assembly/disassembly events are quite stringent. This proposal describes the first, concerted approach to achieve controlled disassembly of dendrimer-based amphiphilic assemblies in response to a specific protein stimulus, in order to understand those structural requirements. We take three complementary approaches to disassemble the dendrimer assemblies through interaction with proteins: (i) where the protein non-covalently binds to specific ligand functionalities in the dendrimer; (ii) where the proteins induce a covalent modification of the functionalities of the dendrimers; and (iii) where two enzymes with opposing functional group transformation capabilities render the supramolecular assemblies perform work only in the presence of a biological energy source. The proposed research will result in a novel, protein- responsive supramolecular platform with implications in several biomedical applications.

Public Health Relevance

This project describes new strategies for stimuli-responsive disassembly of supramolecular assemblies formed from facially amphiphilic dendrimers and oligomers, specifically protein-based stimuli. Since disassembly can cause concurrent guest release, this will ultimately provide novel protein-responsive therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065255-16
Application #
9594151
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fabian, Miles
Project Start
2003-03-01
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
16
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Massachusetts Amherst
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
153926712
City
Hadley
State
MA
Country
United States
Zip Code
Gordon, Mallory R; Zhuang, Jiaming; Ventura, Judy et al. (2018) Biodistribution Analysis of NIR-Labeled Nanogels Using in Vivo FMT Imaging in Triple Negative Human Mammary Carcinoma Models. Mol Pharm 15:1180-1191
Gao, Jingjing; Liu, Xiaochi; Secinti, Hatice et al. (2018) Photoactivation of Ligands for Extrinsically and Intrinsically Triggered Disassembly of Amphiphilic Nanoassemblies. Chemistry 24:1789-1794
Raghupathi, Kishore; Thayumanavan, Sankaran (2017) Nano-Armoring of Enzymes: Rational Design of Polymer-Wrapped Enzymes. Methods Enzymol 590:381-411
Zhuang, Jiaming; Garzoni, Matteo; Torres, Diego Amado et al. (2017) Programmable Nanoassemblies from Non-Assembling Homopolymers Using Ad?Hoc Electrostatic Interactions. Angew Chem Int Ed Engl 56:4145-4149
Munkhbat, Oyuntuya; Garzoni, Matteo; Raghupathi, Krishna R et al. (2016) Role of Aromatic Interactions in Temperature-Sensitive Amphiphilic Supramolecular Assemblies. Langmuir 32:2874-81
Rangadurai, Poornima; Molla, Mijanur Rahaman; Prasad, Priyaa et al. (2016) Temporal and Triggered Evolution of Host-Guest Characteristics in Amphiphilic Polymer Assemblies. J Am Chem Soc 138:7508-11
Bai, Wei; Jiang, Ziwen; Ribbe, Alexander E et al. (2016) Smart Organic Two-Dimensional Materials Based on a Rational Combination of Non-covalent Interactions. Angew Chem Int Ed Engl 55:10707-11
Li, Longyu; Song, Cunfeng; Jennings, Matthew et al. (2015) Photoinduced heterodisulfide metathesis for reagent-free synthesis of polymer nanoparticles. Chem Commun (Camb) 51:1425-8
Gordon, Mallory R; Canakci, Mine; Li, Longyu et al. (2015) Field Guide to Challenges and Opportunities in Antibody-Drug Conjugates for Chemists. Bioconjug Chem 26:2198-215
Yuan, Conghui; Chang, Ying; Mao, Jie et al. (2015) Supramolecular assembly of crosslinkable monomers for degradable and fluorescent polymer nanoparticles. J Mater Chem B 3:2858-2866

Showing the most recent 10 out of 59 publications