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An anionic amphiphilic dendrimer is reported that possesses increased cytotoxicological potency against prokaryotic cells compared to eukaryotic cells. The half maximal effective concentration (EC 50 ) for the dendrimer against Bacillus subtilis, a Gram-positive bacterial strain, was measured to be 4.1×10 −5 M, while that against human umbilical vein endothelial cells (HUVEC) was more than 36x greater at a value of 1.5×10 −3 M. EC 50 ratios for two commercial amphiphiles, sodium dodecyl sulfate (SDS) and Triton X-100, in addition to a similar synthesized dendritic structure were at most only 3.8x greater. Furthermore, the observed EC 50 values appear to be correlated to the critical aggregation constant (CAC) in solution suggesting a mechanism of action for these anionic amphiphilic dendrimers related to their supramolecular structures.Dendritic macromolecules, due to their structure, unique properties, and precise compositions, are of significant interest 1 and are finding uses in an ever-increasing number of medical applications. 2 This is especially evident in the drug delivery area where the dendritic structure enables the attachment of a multitude of drugs or targeting moieties as well as the opportunity to control pharmacokinetics through alterations in generation number. 3 Our interest lies in the synthesis and evaluation of dendritic macromolecules composed of building blocks that are natural metabolites or known to be biocompatible for ocular tissue repair, 4 cartilage tissue engineering, 5 and drug delivery. 6 In an ongoing effort to expand the biomedical applications of dendrimers and our understandings of the resulting structure-activity relationships, we are investigating anionic dendritic macromolecules as antibacterial agents. Herein, we report the antibacterial activity of an anionic amphiphilic dendrimer and the striking selectivity in its E-mail: mgrin@bu.edu. There is a significant global need for new antibacterials and alternative mechanisms of action given the rise in resistance among bacteria. 7 Of the various known antibacterial agent classes, amphiphilic compounds act through perturbation and disruption of the prokaryotic membrane. 8 We hypothesized that amphiphilic anionic dendrimers may exhibit antibacterial activity with minimal eukaryotic cell cytotoxicity, since dendrimers with terminal anionic charges are generally non-cytotoxic and have low toxicity in zebrafish whole animal development studies. 9 On the other hand, cationic dendrimers, some of which have antibacterial properties if the positive charge is properly shielded, 10 have repeatedly shown cytotoxicity against a variety of eukaryotic cell lines. 3e,11 In addition, there are many reports of linear polycationic agents but only a few descriptions of linear polyanionic antibacterial agents (e.g., sulfonated polystyrene). 12 Consequently, we synthesized a series of surface-block anionic amphiphilic dendrimers composed of succinic acid, glycerol, and myristic acid possessing various numbers of acid and alkyl functionali...

Biomaterials used in implants have traditionally been selected based on their mechanical properties, chemical stability, and biocompatibility. However, the durability and clinical efficacy of implantable biomedical devices remains limited in part due to the absence of appropriate biological interactions at the implant interface and the lack of integration into adjacent tissues. Herein, we describe a robust peptide-based coating technology capable of modifying the surface of existing biomaterials and medical devices through the non-covalent binding of modular biofunctional peptides. These peptides contain at least one material binding sequence and at least one biologically active sequence and thus are termed, “Interfacial Biomaterials” (IFBMs). IFBMs can simultaneously bind the biomaterial surface while endowing it with desired biological functionalities at the interface between the material and biological realms. We demonstrate the capabilities of model IFBMs to convert native polystyrene, a bioinert surface, into a bioactive surface that can support a range of cell activities. We further distinguish between simple cell attachment with insufficient integrin interactions, which in some cases can adversely impact downstream biology, versus biologically appropriate adhesion, cell spreading, and cell survival mediated by IFBMs. Moreover, we show that we can use the coating technology to create spatially resolved patterns of fluorophores and cells on substrates and that these patterns retain their borders in culture.

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A bifunctional peptide coating was designed, synthesized, and evaluated as a potential pro-healing stent coating. The bifunctional peptide consisted of a short 28-mer sequence that on the N-terminus, has a motif with affinity for polystyrene binding, and at the C-terminus, a motif that was shown to selectively bind human endothelial cells but not platelets. Results showed that the selective coating, a polystyrene binding peptide terminated in RRETAWA (FFSFFFPASAWGSSGSSGK(biotin)CRRETAWAC), bound endothelial cells quantitatively as well as the common RGD motif, but unlike RGD, it did not show any preference for platelet adherence. Follow-up work examining the difference in cell line selectivity between endothelial cells, whose binding should be encouraged, and smooth muscle cells, whose binding should be deprecated in a stenting application, did identify a temporal preference of the RRETAWA-terminated peptide coating for endothelial cells. However, the in vivo implications of this apparent selectivity need to be examined in more detail before definitive conclusions can be drawn. The positive in vitro results encourage the continued development of other novel coatings that mimic biological structures and/or signaling capabilities to direct cellular processes on the surface of synthetic materials.