This research is aimed at developing a fundamentally new concept in surfactant chemistry that has been termed, """"""""molecular amphomorphism"""""""". In essence, molecular amphomorphism is the ability of a molecule to interconvert between two different forms in response to changes in microenvironment. The immediate objectives of this research are to synthesize a variety of """"""""umbrella-like"""""""" amphiphiles that exhibit amphomorphic properties, and to analyze their effects on the membrane permeation behavior of attached polar agents. The broad, long-term objective of this program is to exploit the concept of molecular amphomorphism from the standpoint of drug delivery; i.e., to create umbrella-like amphiphiles that promote the permeation of polar agents (e.g., peptides and antisense oligonucleotides) across cellular membranes, thereby improving their therapeutic potential.
The specific aims of this research are: (i) to synthesize a broad series of """"""""umbrella-like"""""""" amphiphiles derived from cholic acid, deoxycholic acid, spermine and spermidine, (ii) to prepare corresponding umbrella- peptide and umbrella-antisense oligonucleotide conjugates, (iii) to characterize the permeability properties of each umbrella-peptide and umbrella-antisense oligonucleotide conjugate with respect to bilayers constructed from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and (iv) to define the effectiveness of molecular umbrellas in promoting the cellular entry of antisense oligonucleotides.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM051814-05
Application #
6019036
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert
Project Start
1994-12-01
Project End
2002-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Lehigh University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Bethlehem
State
PA
Country
United States
Zip Code
18015
Janout, Vaclav; Cline, Lauren L; Feuston, Bradley P et al. (2014) Molecular umbrella conjugate for the ocular delivery of siRNA. Bioconjug Chem 25:197-201
Cline, Lauren L; Janout, Vaclav; Fisher, Michael et al. (2011) A molecular umbrella approach to the intracellular delivery of small interfering RNA. Bioconjug Chem 22:2210-6
Janout, Vaclav; Regen, Steven L (2009) Bioconjugate-based molecular umbrellas. Bioconjug Chem 20:183-92
Petrov, Ravil R; Chen, Wen-Hua; Regen, Steven L (2009) Thermally gated liposomes: a closer look. Bioconjug Chem 20:1037-43
Mehiri, Mohamed; Chen, Wen-Hua; Janout, Vaclav et al. (2009) Molecular umbrella transport: exceptions to the classic size/lipophilicity rule. J Am Chem Soc 131:1338-9
Chen, Wen-Hua; Janout, Vaclav; Kondo, Masaharu et al. (2009) A fine line between molecular umbrella transport and ionophoric activity. Bioconjug Chem 20:1711-5
Kondo, Masaharu; Mehiri, Mohamed; Regen, Steven L (2008) Viewing membrane-bound molecular umbrellas by parallax analyses. J Am Chem Soc 130:13771-7
Mehiri, Mohamed; Jing, Bingwen; Ringhoff, Danielle et al. (2008) Cellular entry and nuclear targeting by a highly anionic molecular umbrella. Bioconjug Chem 19:1510-3
Liu, Guozheng; Hnatowich, Donald J (2008) A semiempirical model of tumor pretargeting. Bioconjug Chem 19:2095-104
Madan, Rebecca Pellett; Mesquita, Pedro M M; Cheshenko, Natalia et al. (2007) Molecular umbrellas: a novel class of candidate topical microbicides to prevent human immunodeficiency virus and herpes simplex virus infections. J Virol 81:7636-46

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