Dendrimer-encapsulated camptothecins: increased solubility, cellular uptake, and cellular retention affords enhanced anticancer activity in vitro.

A biocompatible polyester dendrimer composed of the natural metabolites, glycerol and succinic acid, is described for the encapsulation of the antitumor camptothecins, 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)] is also reported, and low nmol/L IC(50) values are measured. Cellular uptake and efflux measurements in MCF-7 cells show an increase of 16-fold for cellular uptake and an increase in drug retention within the cell when using the dendrimer vehicle.

Dendritic supramolecular assemblies for drug delivery.

Dendritic supramolecular assemblies were formed in water with Reichardt's dye or the anticancer drug 10-hydroxycamptothecin and the dendritic macromolecule, ([G4]-PGLSA-OH)2-PEG3400.

Novel tissue adhesives to secure laser in situ keratomileusis flaps.

PURPOSE: To evaluate 2 novel biodendrimer tissue adhesives in sealing and securing laser in situ keratomileusis (LASIK) flaps. SETTING: Duke University Eye Center, Durham, North Carolina, USA. METHODS: Laser in situ keratomileusis flaps were created in 10 human eye-bank eyes using the Hansatome microkeratome system (Bausch & Lomb). These eyes were divided into 2 groups. Flaps in the first group (n=4) were secured with a laser-activated biodendrimer adhesive along the flap edge. In the second group (n=6), the flaps were secured with a self-gelling dendritic adhesive. Dry Merocel sponges (Medtronic Solan) were used to test the strength of flap adherence in both groups. Further testing was performed in the second group. The hinges of these flaps were cut with a scalpel blade and fluorescein dye was injected under the flap to observe potential dye leakage along the flap edge. RESULTS: Laser in situ keratomileusis flaps sealed with both adhesives were secure with no flap dislocation. There was no leakage of fluorescein dye observed in the second group. Both adhesives were easy to apply, clear when dry, and had a soft rubbery consistency. CONCLUSIONS: Two novel biodendrimer adhesives successfully sealed and secured LASIK flaps. These adhesives may prove to be an effective alternative for treating LASIK flap complications such as epithelial ingrowth or flap dislocation.

New dendritic adhesives for sutureless ophthalmic surgical procedures: in vitro studies of corneal laceration repair.

OBJECTIVE: To compare a biodendrimer adhesive with a conventional suture for repairing linear and stellate corneal lacerations. METHODS: A keratome knife was used to create 4.1-mm full-thickness linear incisions (n = 36) and 3 x 4-mm full-thickness stellate incisions (n = 25) in the central cornea of enucleated human eyes. The incisions were sealed with either a suture or the biodendrimer adhesive. The globes were inflated with balanced salt solution, and the increase in intraocular pressure was monitored via a cardiac transducer until fluid leaked from each eye. This intraocular pressure reading from the transducer was recorded at the sight of any leakage through the wound (leakage pressure). By using the Wilcoxon rank sum test, the median leakage pressure was compared for each closure method, separately for each wound group. By using the 1-sided 1-sample t test, each mean leakage pressure value was compared with 34 mm Hg, which is the intraocular pressure under certain stressful physiologic conditions (eg, coughing and the Valsalva maneuver). RESULTS: For globes that underwent a linear incision, the mean leakage pressure was 78.7 mm Hg for the sutured group and 109.6 mm Hg for the adhesive group. Globes that underwent a stellate incision had a mean leakage pressure of 57.8 mm Hg for the sutured group and 78.7 mm Hg for the adhesive group. All of these pressures showed a statistical significance from 34 mm Hg via a 1-sided 1-sample t test. CONCLUSIONS: The difference in leakage pressures for all 4 groups was statistically significant relative to 34 mm Hg. This suggests that either method of closure, adhesive or suture, can withstand physiologic increases in intraocular pressure postoperatively and that biodendrimer adhesives are able to seal large corneal lacerations.Clinical Relevance The use of biodendrimer adhesives to repair a corneal wound constitutes a viable alternative clinical procedure to conventional sutures.

Biodendrimer-based hydrogel scaffolds for cartilage tissue repair.

Photo-crosslinkable dendritic macromolecules are attractive materials for the preparation of cartilage tissue engineering scaffolds that may be optimized for in situ formation of hydrated, mechanically stable, and well-integrated hydrogel scaffolds supporting chondrocytes and chondrogenesis. We designed and synthesized a novel hydrogel scaffold for cartilage repair, based on a multivalent and water-soluble tri-block copolymer consisting of a poly(ethylene glycol) core and methacrylated poly(glycerol succinic acid) dendrimer terminal blocks. The terminal methacrylates allow mild and biocompatible photo-crosslinking with a visible light, facilitating in vivo filling of irregularly shaped defects with the dendrimer-based scaffold. The multivalent dendrimer constituents allow high crosslink densities that inhibit swelling after crosslinking while simultaneously introducing biodegradation sites. The mechanical properties and water content of the hydrogel can easily be tuned by changing the biodendrimer concentration. In vitro chondrocyte encapsulation studies demonstrate significant synthesis of neocartilaginous material, containing proteoglycans and type II collagen.

Dendritic macromers as in situ polymerizing biomaterials for securing cataract incisions.

Dendritic macromers are attractive macromolecules for hydrogel formation since high cross-linking densities at low polymer concentration can be obtained, varied physical properties can be observed based on the macromer structure, and low viscous aqueous solutions can be injected in an in vivo site of irregular shaped to form a well-integrated polymer network. A peptide dendron possessing terminal cysteine residues was synthesized and characterized. When this peptide dendron was mixed with poly(ethylene glycol dialdehyde) in aqueous solution at pH = 7.4, a hydrogel spontaneously formed as a consequence of thiazolidine linkages between the macromers. Such in situ polymerized hydrogels are of interest for tissue engineering and wound-repair applications. To evaluate the potential use of this hydrogel sealant in ophthalmic surgeries, a 3-mm clear corneal incision (i.e., the wounds created during a typical cataract surgery) was successfully sealed.

Hybrid dendritic-linear polyester-ethers for in situ photopolymerization.

Novel first through fourth generation hybrid dendritic-linear copolymers, composed entirely of building blocks known to be biocompatible or degradable to natural metabolites in vivo, are described. Specifically, these copolymers are composed of poly(ethylene glycol), glycerol, and succinic acid and are synthesized using a divergent approach in high yield. A photo-cross-linkable derivative of this copolymer successfully seals 4.1 mm corneal lacerations. The mechanism of tissue repair is likely one of physical entrapment where an interpenetrating network (IPN) is formed between the cross-linked copolymer and the tissue.

Dendritic molecular capsules for hydrophobic compounds.

Reichardt's dye, a highly solvatochromic dye, was encapsulated within poly (glycerol succinic acid) ([Gn]-PGLSA-OH) dendrimers to investigate the interior environment of these dendritic macromolecules. The absorption maximum for the encapsulated Reichardt's dye in water was indicative of a relatively high dielectric constant present within the dye/dendrimer complex. (1)H NMR of the encapsulated complex showed the presence of aromatic protons from Reichardt's dye along with the aliphatic protons of the dendrimer. Additionally, there were substantial changes in T(1) and T(2) times of the encapsulated dye when compared with the free dye, and (1)H NOESY spectra for the complex showed a significant number of intermolecular NOE cross-peaks. These data reveal the close through-space proximity of the dye to the dendrimer and the restricted motion of the encapsulated dye. To demonstrate the potential use of these macromolecules as drug delivery vehicles, the poorly water-soluble anticancer drug 10-hydroxycamptothecin (10HCPT) was encapsulated within a carboxylated PGLSA dendrimer ([G4]-PGLSA-COONa). Cytotoxicity assays with human breast cancer cells showed a significant reduction of cell viability, demonstrating that 10HCPT retains activity upon encapsulation.