Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-06-08
2003-06-17
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C424S078170
Reexamination Certificate
active
06579906
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the synthesis and characterization of a series of new compositions of matter, formulations, and applications of dendrimer biocide-silver nanocomposites as potent antimicrobial agents.
2. Description of the Related Art
Dendrimers are well defined, highly branched macromolecules that emanate from a central core. Commercially available dendrimers include polyamidoamine (“PAMAM”) dendrimers and polypropylene imine (“PPI”) dendrimers. Dendriditic architecture brings a very high number of functional groups in a compact space. Dendrimers in the present invention can for example be selected from the group consisting of polyamidoamine dendrimers, polylysine based dendrimers, polyethylene oxide based dendrimers, silicon based dendrimers, polyether based dendrimer and polypropylene imine dendrimers. A polylysine based dendrimers refers to a dendrimer in which the backbone or structure consists essentially of polylysine. A polyethylene oxide based dendrimers refers to a dendrimer in which the backbone or structure consists essentially of polyethylene oxide. A silicon based dendrimers refers to a dendrimer in which the backbone or structure consists essentially of silicon. A polyether based dendrimer refers to a dendrimer in which the backbone or structure consists essentially of polyether.
The advent of dendrimers represents a major breakthrough in synthetic chemistry. Dendrimers can be tailored to generate uniform or discrete functionalities and possess tunable inner cavities, surface moieties, sizes, molecular weights, and solvent interactions. Dendrimers can be synthesized by a convergent approach, see Tomalia, et al.,
Macromolecules,
20 at 1164 (1987), alternatively, dendrimers can also be synthesized by a divergent approach, see Tang, et al.,
Bioconjugate Chem.,
7 at 703-714 (1996).
In the divergent approach, growth of dendrimers starts from a multi-functional core. Through a series of reaction and purification steps, dendrimers grow radially outwards. At different stages of the synthesis, dendrimers are identified by generations. As the generation increases, the number of functional groups, the size of the dendrimer, and the molecular weight of the dendrimer increase. Commercially available dendrimers, such as polyamidoamine (PAMAM) dendrimers from Dendritech Inc. (Midland, Mich., USA) and polypropylene imine (PPI) dendrimers from DSM (Geleen, Netherlands) are synthesized by the divergent approach.
In the convergent approach, dendrons, as parts of dendrimers, are synthesized according to the divergent approach and these dendrons are then coupled to a multifunctional core. The advantage of the convergent approach is that the chemistry of each dendron can be different, and distinct functional groups can be integrated into dendrimers at precise sites. Due to the repetitive nature of the dendrimer synthesis and the extensive purification required, dendrimers are very expensive and not readily available. The combination of discrete numbers of functionalities in one molecule and high local densities of active groups has attracted a lot of attention, especially for biological applications. The unique architecture of dendrimers, they have been investigated for a wide variety of applications, such as gene delivery vesicles, Tang, et al.,
Bioconjugate Chem.,
7 at 703-714 (1996); Kukowska-Latallo, et al.,
Proc. Natl. Acad. Sci. USA,
93 at 4897-4902 (1996), catalysts, Zeng, F. Z.,
S. C. Chem. Rev.,
97 at 1681 (1997); Newkome, et al.,
Chem. Rev.,
99 at 1689-1746 (1999), drug delivery carriers, Liu, M.; Frechet, J. M.,
J. Proc. Am. Chem. Soc. Polym. Mater. Sci. Engr.,
80 at 167 (1999); Uhrich, K.,
TRIP,
5 at 388-393 (1997); Liu, H.; Uhrich, K. Proc,
Am. Chem. Soc. Div. Polym. Chem.,
38 at 1226 (1997), chromatography stationary phases, Matthews, et al.,
Prog. Polym. Sci.,
23 at 1-56 (1998), boron neutron capture therapy agents, Newkome, et al.,
Dendritic Macromolecules: Concepts, Syntheses, Perspectives
; VCH: Weinheim, Germany (1996); Newkome, G. R.,
Advances in Dendritic Macromolecules
; JAI Press: Greenwich, Conn., Vol. 2 (1995), and magnetic resonance imaging contrast agents. Tomalia,
D. A. Adv. Mater.,
6 at 529-539 (1994).
The dendriditic architecture of dendrimers provides a very high number of functional groups in a compact space. Because of this property, it is reasonable to expect that these novel molecules will play a major role in materials whose performance depends on high local concentration, such as drugs or antimicrobial agents.
The versatile chemistry of the dendrimers can also include metal atoms. The metal can be either an integral part of the dendrimer, such as in the building block, core, or terminal group, or it can associate with the dendrimer through interactions with branching units. These metals can be metal cations, metal salts, metal oxides or even elemental metal. Newkome and coworkers published a recent comprehensive review on dendrimers with metals (metallodendrimers) G. R. Newkome, E. He, C. N. Moorefield,
Chem. Rev.
1999, 99, 1689. Metal salts, such as silver, are known antimicrobial agents. Dendrimer nanocomposites, formed by dendrimers and antimicrobial salts, offer a new way to deliver or enhance the antimicrobial properties of these agents.
Balogh et al. synthesized dendrimer nanocomposites, dendrimers with inorganic silver or silver ions, and tested their antibacterial properties. Balogh, L.
Proc. Am. Chem. Soc. Div. Colloi. & Surf. Chem.,
54. (1999). For these dendrimer nanocomposites, the dendrimer itself does not have any antibacterial property. The activity comes from the silver/silver ions. In contrast, the quaternary ammonium functionalized dendrimers of the current invention derive antibacterial properties from the dendrimer itself. The dendrimers of the current invention are different from all previous investigations in that the surface groups of the dendrimers were transformed into quaternary ammonium groups. Unlike known QACs, the quaternary ammonium functionalized dendrimers of the current invention are more effective against Gram-negative bacteria such as
E. coli
and Gram-positive bacteria such as
S.aures.
SUMMARY OF THE INVENTION
The inventors have successfully synthesized novel dendrimer biocides. These dendrimer biocides are fully described in U.S. patent application Ser. No. 09/588,585, which is herein incorporated by reference for all purposes. The present invention is directed to novel dendrimer biocide-silver complexes, which are new nanocomposites synthesized from the dendrimer biocides of the U.S. patent application Ser. No. 09/588,585 and silver salts. The hybrid structures embodying the present invention provide even more potent antimicrobial properties.
The structure investigated in this study is not very clear. A tentative name of “dendrimer-silver nanocomposite” was used. The potent biocide properties of the dendrimer-silver nanocomposites according to the invention all came by surprise to the inventors.
In the copending patent application Ser. No. 09/588,585, the described dendrimer biocides are capable of killing anthrax spores. However, the inventors have unexpectedly found that the dendrimer biocide-silver nanocomposites have superior biocide properties. The synergy between the dendrimer biocide and the silver ion has great potential for denaturing spores. Because spores are a significant class of biological weapons, the present invention would be useful in combating biological warfare weapons.
Traditional antibiological warfare agents are known to be very reactive and extremely toxic. Such agents include chlorine, formaldehyde, and peroxygen. In contrast, the novel dendrimer biocide-silver nanocomposites of the present invention are nonreactive and are virtually nontoxic to human skin. Similar compounds have been used in hand-wash formulations. Thus, the invention may provide an effective antibiological warfare agent. Examples of uses for the present invention include a denaturing spray or soldier uniforms impreg
Chen Chris Z.
Cooper Stuart L.
Connolly Bove & Lodge & Hutz LLP
Hui San-ming
Travers Russell
University of Delaware
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