vehicles in the field of ocular therapeutics due to their ability to enhance drug levels within ocular tissues. However, safety of chitosan nanoparticles after repeated administrations should be ensured since chitosan is known to disrupt epithelial tight junctions (Schipper et al. 1997).

A multicomponent nanoparticle comprised of PLGA and chitosan has recently been investigated for the delivery of a plasmid encoding the plasminogen kringle 5 (PK5) protein, an angiogenic inhibitor for the treatment of diabetic retinopathy (Park et al. 2009). The PLGA–chitosan nanoparticles were prepared by addition of ethyl acetate to PLGA and addition of chitosan chloride to a polyvinyl acetate (1% w/v) solution. The K5 plasmid was then added to the chitosan solution for complexation and DNA condensation. The chitosan–plasmid solution was then mixed with the PLGA solution for 4 min and then water was added to the mixture and allowed to stir for 3 h. Centrifugation was then completed to purify the nanoparticles and lastly, lyophillization was conducted to obtain a dry powder. The PLGA– chitosan nanoparticles (~260 nm) were injected intravitreally into a rat eye and PK5 gene expression was detected up to 4 weeks after injection. The nanoparticle formulation was also capable of decreasing cell viability of bovine retinal capillary endothelial cells, but had no effect on ARPE-19 cells. In vivo, the nanoparticles diminished the neovascular area and preretinal vascular cells when intravitreally injected. PLGA–chitosan nanoparticles provide for effective means to treat diabetic retinopathy by inhibiting neovascularization.

11.2.6  Dendrimers

Dendrimers are organic chemical structures with macromorphology consisting of branched tree-like structures. Dendrimer morphology comprises a core, which serves as the initiation site of branching. The core is then branched out to create the linkage between the core and the branches. The ends of each branch typically carry surface functional groups, which can serve as binding locations for drug molecules, targeting molecules, or imaging agents. Various organic compounds can be used in the synthesis of dendrimers depending on the functionalization and physiochemical properties desired. Some commonly synthesized dendrimers are based on polyamido amine (PAMAM) and poly-propylene imine (PPI). PAMAM dendrimers are especially desirable in designing drug delivery systems since the amine functional group can be easily tethered to a drug. Dendrimer morphology and size can vary depending on the number and type of building blocks used.

The use of dendrimers for ocular delivery was proposed at least 5–10 years ago (Robinson and Mlynek 1995; Vandamme and Brobeck 2005) and several investigators are still discovering the benefits of dendrimers. Similar to other drug delivery devices, dendrimers can be designed to have desirable properties such as controlled release and enhanced bioavailability or tissue penetration. Dendrimers have been designed to cross cellular barriers such as epithelial cells in the gastrointestinal tract (Wiwattanapatapee et al. 2000). Enhanced permeation was reported across canine

kidney cells (Tajarobia et al. 2001) as well as Caco-2 monolayers (Jevprasesphant et al. 2004). In addition, dendrimers have been shown to improve the cell permeability of ibuprofen by reducing the time it takes the cell to uptake ibuprofen from 3 to 1 h (Kolhea et al. 2003). In 2005, Vandamme and Brobeck determined which physiochemical parameters (molecular weight, size, number of amines, carboxyl, and hydroxyl groups) contribute to the controlled release properties of the PAMAM dendrimer in rabbit eye (Vandamme and Brobeck 2005). Fluorescently labeled PAMAM dendrimer preparations (25 mL each) was instilled into the center of the rabbit cornea and concentrations of the dendrimer at specific time points up to 24 h were determined. PAMAM dendrimers with an amine group functionalization at generation 2 had lowest corneal mean residence time (MRT) of 100 min and the presence of a carboxyl group or a hydroxyl group at generation 2 had the highest corneal MRT of 300 min. The corneal MRT of the amine-functionalized PAMAM dendrimer was increased to 203 min if the amine was placed at generation 4. The corneal MRT is a function of the molecular weight and functional group since enhanced MRT was observed with an increase in molecular weight and with hydroxyl or carboxyl functionalization.

PAMAM dendrimers, although smaller than 10 nm in their molecular form, can form lose aggregates in buffers at physiological pH that can be separated by filtration. In the periocular region of the eye, while 20 nm particles disappear rapidly within a few hours, 200 nm particles remain almost completely at the site of administration for at least 2 months (Amrite and Kompella 2005). Thus, administration of larger nanoparticles will retain the drug better at the site of administration in the periocular space. Using this concept Kang et al. prepared PAMAM dendrimers of carboplatin with a particle size of approximately 260 nm and administered them in the subconjunctival space of a murine model for retinoblastoma (Kang et al. 2009). With this approach, nanoparticle formulation was shown to be much superior to equivalent carboplatin solution at the end of 22 days following a single dose.

For efficient cellular response by a particular drug that is associated with a drug delivery device, it is typically desired for the drug delivery vehicle enter cells by crossing biological membranes. One possible mechanism to evade this hurdle is to synthesize dendrimers that have specific functional groups that enhance cell uptake. A polyguanidilyated dendrimer termed dendritic guanidilyated translocator (DPT) by Durairaj and Kompella in 2009 was recently shown to increase gatifloxacin (GFX) solubility, activity, permeability, and tissue retention (Durairaj and Kompella 2009; Durairaj et al. 2010). DPT enhanced solubility for GFX in a dose-dependent manner. Within 5 min, preservative-free DPT–GFX rapidly entered human corneal epithelium cells (HCE). DPT–GFX formulation increased the sclera–choroid–RPE (SCRPE) transport of GFX by 40%. Further, DPT–GFX formulation was shown to be as efficient or superior to GFX alone in antibacterial activity. In rabbit single and multiple dosing studies, DPT–GFX (1.2% w/v GFX) was well tolerated and resulted in about 13and 2-fold greater tissue exposure of the drug compared to preservative containing commercial formulation of GFX (0.3%). Further, drug levels persisted longer in various tissues with DPT formulation. Thus, DPT formulations may reduce the frequency of dosing of GFX.