The research that is outlined in this proposal is aimed at creating a fundamentally new class of surfactants termed, umbrella - like amphiphiles (ULA's). The ultimate goal of this program is to develop these ULA's into novel carriers that can be used to promote the transport of polar, hydrophilic drugs across the plasma membrane of cells, thereby enhancing drug efficacy. Because antisense oligonucleotides (oligos) now show considerable promise for the treatment of life-threatening diseases such as cancer and AIDS, and because cellular entry has been identified as a- major hurdle which limits their therapeutic potential, this three-year program focuses sharply on the use of oligos as paradigms. It is emphasized that the ULA concept addresses the general problem of transporting hydrophilic drugs across the plasma membrane and that other viable ULA-drug conjugates should, in principal, be possible; e.g., hydrophilic peptides that function as DNA - regulating factors.
The specific aims of this research are: (i) to synthesize a homologous series of facial amphiphiles of varying flexibility and hydrophilicity, (ii) to covalently attach these amphilphiles to suitable bifunctional, trifunctional, and tetrafunctional molecular scaffolds derived from spermidine (iii) to characterize the conformational behavior of certain ULA- fluorescent probe conjugates in bulk solution and within lipid bilayers, and (iv) to synthesize prototype ULA- antisense oligonucleotide conjugates and to define their ability to diffuse, passively, across liposomal membranes.
| 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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