Dendrimers are globular monodisperse polymers composed of branched repeating units emitting from a central core. We are synthesizing, characterizing, and evaluating a new class of dendritic polymers termed "Biodendrimers." These dendrimers are comprised of building blocks known to be biocompatible or degradable in vivo to natural metabolites. We have reported the synthesis of these macromolecules using either a divergent or convergent strategy. The introduction of biocompatible building blocks augments the favorable physical properties of dendrimers, and facilitates the design and development of new materials for drug delivery and tissue engineering applications.

Hydrogel-based tissue adhesives are attractive materials for sealing corneal wounds compared to sutures since these materials can not only close the injury, but also serve as a temporary scaffold until new corneal tissue remodels the wound. The current surgical practice of using monofilament nylon sutures inflicts additional trauma to the wound and can be associated with a number of post-operative complications including microbial keratitis, extended healing time, and astigmatism. Recently, we have reported two new biodendrimer-based tissue adhesives for repairing corneal wounds. The first adhesive is a photocrosslinkable hybrid ABA dendritic-linear copolymer composed of glycerol, succinic acid, and polyethylene glycol. This photoactivated adhesive was used successfully to seal ex vivo and in vivo full-thickness corneal lacerations and to secure ex vivo laser in-situ keratomileusis (LASIK) flaps.

The second type of tissue adhesive developed is one that self-gels upon mixing at the wound site to provide a hydrogel patch. We recently reported the synthesis of peptide dendrons, the formation of a crosslinked hydrogel via multiple chemical ligation reactions, and the use of these hydrogel adhesives to seal ex vivo clear corneal incisions (i.e., the wound created during a typical cataract procedure), to repair ex vivo corneal lacerations, and to secure ex vivo corneal transplants using a reduced number of sutures. This chemical ligation crosslinking strategy for hydrogel formation is favorable since it is a mild reaction that can be performed in aqueous solution (pH 7.4 and 37 ^oC), in the presence of functional groups, and does not generate any side-reaction products.

The container properties of dendrimers lend to their use as vehicles for drug delivery. Recently, we have reported biocompatible polyester dendrimers composed of glycerol and succinic acid for the encapsulation of two anticancer agents: 10-hydroxycamptothecin and 7-butyl-10-aminocamptothecin. The cytotoxicity of the dendrimer-drug complex toward four different human cancer cell lines (human breast adenocarcinoma (MCF-7), colorectal adenocarcinoma (HT-29), non-small cell lung carcinoma (NCI H460), and glioblastoma (SF-268)) was determined, and low IC₅₀s were measured. Cellular uptake and efflux measurements in MCF-7 cells show an increase of 16-fold and a 50% increase in drug retention within the cell when using the dendrimer vehicle.

The design of supramolecular assemblies that mimic molecular organization and compartmentalization observed in biological systems is of wide spread interest. The most familiar examples are the phosphocholine lipid bilayers, which constitute prokaryotic and eukaryotic cell membranes. These natural diacyl phosphocholines spontaneously organize to form spherically self-closed liposomes in solution. We have synthesized nucleoside-amphiphiles bearing a phosphocholine moiety and these new amphiphiles possess the molecular recognition information of nucleic acids and the compartmentalization characteristics of lipids. These nucleoside-based phosphocholines readily self-assemble into hydrogels and DNA-hydrogel networks in aqueous solution as well as organogels in nonaqueous solutions.

In the extracellular matrix, chemical cues are present that control all aspects of cell biology. These surface-bound and soluble factors provide the necessary adhesion and signaling for normal cellular activity, and without such matrix support, the cells will apoptose. Implanted medical device surfaces lack the molecular features that provide guidance to the surrounding cells to afford optimal in vivo integration and function. Controlling the interface between the material and biological realms that occurs at the surface of these devices would have important implications for a range of medical technologies from sensors to orthopaedic implants. To achieve these goals we have developed a non-covalent coating, which we have termed an Interfacial Biomaterial (IFBM) that can direct biological processes at the interface between the surfaces of synthetic and biological materials. The approach entails identifying specific and high affinity adhesion peptides via phage display technology, and then, via chemical synthesis, assembling two or more peptides with known adhesion domains to create a multi-functional interfacial biomaterial. These multi-functional materials are amenable to coating and patterning techniques suggesting their use for applications ranging from proteomics to tissue engineering. In addition to cell adhesive coatings, we have recently reported cell-repellent or cytophobic coatings, and the use of these coatings to reduce the adhesion of two distinct mammalian cell lines and pathogenic Staphylococcus aureus strains. Interfacial biomaterials are new coating materials that provide a strategy to regulate biological processes at the critical interfacial site between two similar or dissimilar materials or biologics.

Gene therapy offers the potential to cure a wide-range of diseases by delivering a missing gene or a functional substitute of a defective gene. Presently, the gene transfection activity is low with synthetic vectors, reflecting inefficiencies in the overall transfection pathway that includes: DNA-synthetic vector complexation, endocytosis, endosomal escape, nuclear entry, and finally expression. Our research effort is focused on improving the release of the negatively-charged DNA from the DNA-amphiphile supramolecular complex. Recently we have reported a new approach which entails the use of a charge-reversal amphiphile that transforms from a cationic (+1) to an anionic amphiphile (+1) intracellularly. This functional synthetic vector performs two roles: first, it binds and then releases DNA, and second, as an anionic multiply-charged amphiphile, it destabilizes bilayers. This gene delivery system which undergoes an electrostatic transition intracellularly shows enhanced gene transfection efficiency.

A variety of ophthalmic conditions can yield perforations or lacerations of the cornea. Corneal lacerations represent ophthalmic emergencies that if not treated promptly and effectively can lead to blindness. Treatment options for corneal lacerations include suturing, patch grafting, penetrating keratoplasty, keratoprostheses, and biological glues (e.g., cyanoacrylate). Sutureless procedures using biological glues are advantageous since these techniques immediately restore the integrity of the globe and decrease the risk of additional surgical complications. We have synthesized, characterized, and evaluated a novel photocrosslinkable hyaluronic acid-based adhesive for repairing ex vivo and in vivo full thickness corneal lacerations.

Phospholipids are a major component of all prokaryotic and eukaryotic membranes. The chemical structure of the phospholipid dictates the self-assembled bilayer structure formed as well as the membrane physical and mechanical properties. We are interested in the effect of vesicle structure and mechanical property when ribose is substituted for the conventional glycerol backbone. We have synthesized and characterized a series of carbohydrate-based lipids possessing chain lengths from C₁₂ to C₂₀. Structural and mechanical property studies indicate that below the phase transition a lamellar crystalline phase is present and above the T_m, a fragile lamellar fluid state exists. Our results are likely to provide new insight for tailoring vesicle properties for pharmaceutical, cosmetic, and other industrial applications.

The preparation of nanoscale structures is an important step in the study of fundamental chemical and physical processes at unusually small dimensions. Typically, these structures are composed of inorganic semiconductors or transition metals, but these materials can suffer from a lack of processability and adaptability. Conducting polymers are one promising class of materials with unique physical and chemical properties for nanodevice development. The electrochemical and photochemical properties of these thermally and environmentally stable polymers can be tailored for specific applications including organic light-emitting diodes, electrochromic displays, and photo- and electrochemical device components. We are using the electrochemical dip-pen nanolithography to fabricate polymeric nanostructures. Recently, we have prepared nanoscale polymeric nanolines and nanoscale junctions from aniline, ethylenedioxythiophene (EDOT), and pyrrole.

Electrochemical methods to detect specific nucleic acid sequences of hereditary diseases, genetic abnormalities, and viral or bacterial pathogens, are of widespread importance to providing correct medical diagnosis and treatment. We have recently reported two new electrochemical DNA assays. The first exploits a hairpin to duplex transition on a gold electrode. When a complementary DNA target strand binds to the hairpin, the hairpin opens, and the ferrocene redox probe is separated from the electrode affording a decrease in the observed current. In the second approach, a simplified “2-piece” reagentless electrochemical assay for DNA detection was constructed. In this design, a conformational change occurs when a surface-immobilized, ferrocene-labeled oligodeoxynucleotide-poly(ethylene glycol) triblock macromolecule binds a target DNA strand. Specifically, the DNA-PEG-DNA macromolecule folds or wraps around the target DNA bringing the ferrocene probe in close proximity to the electrode surface affording an electrochemical response (see figure). These two electrochemical DNA sensors monitor electron-transfer dynamics which are altered as a consequence of a large structural rearrangement induced by hybridization.

Oligodeoxynucleotides (ODNs) modified with functional reporter groups have diverse and important research and clinical applications including primers for DNA sequencing, hybridization probes for detecting DNA, anti-sense and antigene oligonucleotides for therapy, and spectroscopic probes for DNA structure and function studies.

We are developing synthetic strategies to site-specifically label ODNs with spectroscopic and/or redox-active transitional metal or organic chromophores. The first approach involves synthesizing the labeled phosphoramidite for subsequent incorporation into the nucleic acid strand using standard DNA synthesis protocols. The second approach entails derivatizing the ODN during solid-phase synthesis using Pd(0) cross-coupling chemistry.

In DNA, the effects of oligodeoxynucleotide sequence, base-pairing, p-stacking, as well as the donor-acceptor distance and driving force on electron-transfer rates are of interest, and experiments are being performed to address many of these issues. Using our synthetic skills, we have prepared DNA duplexes labeled with electron-transfer probes. We observed an electron-transfer reaction between phenothiazine (PTZ), the electron donor, and the photoexcited acceptor chromophore, *Ru(bpy)₂(4-m-4'-pa-bpy)²⁺.

We are synthesizing and characterizing new Pt(II) dimine dithiolate or catecholate chromophores possessing bulky electron-donating or electron-withdrawing sulfur or oxygen ligands. We are also characterizing the nonlinear optical (NLO) activity of a series of Pt(diimine) complexes to develop NLO structure-property relationships.

Special Thanks to Boston University, Whitaker Foundation, American Chemical Society PRF-G, American Heart Association, Pew Foundation, Sloan Foundation, and Dreyfus Foundation, and Orthopedic Research Education Foundation, National Science Foundation, Army Office of Research, Glen Research, 3M, Johnson & Johnson, National Institutes of Health (Eye Institute), and National Institutes of Health (NBIB).