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.
| 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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