Vesicular carriers are lamellar structures made up of amphiphilic molecules surrounded by an aqueous compartment. From the early 1980s, vesicular carriers, particularly liposomes and niosomes, have gained wide attention by researchers for their use as ocular drug delivery carriers (Stratford et al. 1983; Kaur et al. 2004). Liposomes are biocompatible and biodegradable vesicles comprising of an aqueous volume surrounded by a phospholipid bilayer (Agarwal et al. 2014). Niosomes are structurally similar to liposomes; however, bilayers are made up of nonionic surfactant instead of phospholipids (Moghassemi and Hadjizadeh 2014). Vesicular carriers are useful for the delivery of both hydrophilic and hydrophobic drugs which are encapsulated in the core or bilayer, respectively. These carriers have been widely explored to overcome the problems of conventional ocular therapy. Vesicles can vary in size from nanometers to micrometers, can be uni- or multilamellar, and can vary considerably in size, surface charge, lipid composition, and fluidity of the bilayers. Drug encapsulation by these carriers results in improved pharmacokinetics, stability, precorneal residence time, and transcorneal permeation. Because of their unique features, liposomes and niosomes are a promising means of delivering ocular drugs for the treatment of both anterior and posterior segment eye disorders. Topical bioavailability can be improved by maximizing corneal drug absorption, minimizing precorneal drug loss, and continuous delivery of ophthalmic drugs to the ocular tissues. When applied topically, vesicles can attach to the hydrophobic corneal epithelium (Schaeffer and Krohn 1982). Effect of vesicle type, charge, and size on precorneal retention and transcorneal permeation is well investigated and generally follows the order of (+)SUV > (+)MLV = (−)SUV > SUV > MLV > free drug. It has been shown that positively charged vesicles composed of cationic lipids such as stearylamine, didodecyldimethylammonium bromide, and 1,2-dioleyl-3-trimethyl ammonium propane have higher binding affinity to the corneal surface than neutral or negatively charged vesicles (Velpandian et al. 1999; Law et al. 2000; Hathout et al. 2007). Several experiments using animal models have shown that cationic liposome-entrapped drugs have improved ocular bioavailability compared to their free drug counterparts. Cationic vesicles also exert adjuvant immunity when they are used as a delivery system for protein vaccines and DNA (Yan et al. 2007). Moreover, the performance of liposomes and niosomes can be further improved by their surface modification. Surface modification of vesicles with carbopol, chitosan, and its derivative, N-trimethyl chitosan, not only improve the physicochemical stability but also prolong precorneal retention and enhance bioavailability over uncoated counterparts and drug solutions (Li et al. 2009; Mehanna et al. 2010; Abdelbary 2011; Li et al. 2012). In a recent study, coating of liposome with mucoadhesive silk fibroin has shown to improve cellular uptake and therapeutic efficacy (Dong et al. 2015). Liposomes incorporated into hydrogels or soft contact lenses or complexed with either chitosan nanoparticle or noisome has been used to improve precorneal retention and to extend optimal ocular pharmacodynamics over a prolonged period (Nagarsenker et al. 1999).

Topical administration for posterior segment delivery is the greatest challenge and opportunity of ocular liposomal drug delivery. It has been shown that liposomal drug can reach the neural retina and ganglion cells after topical administration (Masuda et al. 1996; Davis et al. 2014). Liposome formulation variables might be used to tune the delivery properties to the ocular tissues. It is very unlikely that large-sized liposomes could permeate in the tight corneal barrier. Blood vessel-mediated liposomal delivery to the posterior segment can be achieved only if the liposomes are able to distribute to the ocular tissues. For this purpose, the size of the liposomes is critically important due to the limited size of choroidal and conjunctival fenestrations. Hironaka et al. demonstrated that liposomes with a size of 105–125 nm reach the retina (Hironaka et al. 2009). In another study, size-dependent distribution of liposomes to different posterior segment tissues was seen. Liposomes with the diameter less than 80 nm produced by microfluidization permeated to the retinal pigment epithelium, whereas liposomes with the diameter of 100 nm or more were distributed to the choroidal endothelium (Lajunen et al. 2014). However, active targeting using transferring or phospholipid-binding protein annexin A5 was shown to be necessary for liposome retention to the target tissue (Hironaka et al. 2009; Davis et al. 2014). Direct intravitreal injection of liposomes is a more definitive method of posterior segment drug delivery than topical administration, but it is more invasive and associated with greater risks of infection and bleeding. Despite some advantages that make vesicular carrier a potentially useful system for ocular drug delivery, the utility of these carriers may be limited by a short shelf life, limited drug loading, difficulty associated with thorough sterilization, and long-term side effects. Additionally, vesicles may not be able to release the entire payload of active drug relative to a free solution form. Therefore, all these factors should be taken into account while developing vesicular formulation for ophthalmic application.

Nanoparticles (NPs) are colloidal carriers with a size range of 10–1000 nm. For ocular delivery, nanoparticles are generally composed of proteins, natural or synthetic polymers such as gelatin, modified starch, albumin, sodium alginate, chitosan, hyaluronic acid, carbopol, poly (lactic-co-glycolic acid) (PLGA), poly-ε-caprolactone (PCL), Eudragit® (RS100 and RL100), and poly-(butylcyanoacrylate) (PBCA). Drug-loaded NPs can be nanospheres or nanocapsules. In nanospheres, drug is uniformly distributed throughout polymeric matrix, while in nanocapsules, drug is enclosed inside the polymeric shell. NPs were considered to offer the possibility of a more facile delivery and transport across tissues, and consequently their potential for delivery to both anterior and posterior ocular tissues started to be studied (Khar et al. 2010; Jain et al. 2012). In 1986, an early attempt to use NPs was done with PBCA NPs loaded with highly lipophilic drug, progesterone (Li et al. 1986). After topical application to rabbit eyes, a decreased progesterone concentration in tissues, compared to control solutions, was observed attributed to greater affinity of progesterone for the NP polymer. The lesson learned from these experiments was that it is important to optimize the physicochemical relations between the polymers and drug to obtain an efficient carrier. Later, Juberias et al., used PECL nanocapsules loaded with 1 % cyclosporine (CsA) in a rat model of corneal transplantation rejection. By using PECL nanocapsules, toxic effects of CsA were avoided along with improved ocular penetration; however, corneal graft rejection was not prevented by the CsA-loaded PECL NPs (Juberías et al. 1998). The failure was not considered to be a consequence of negative interactions between the polymer and the drug. Improved formulations using polymers with known biocompatibility and biodegradability, such as PLGA, were developed later and shown to be more effective than commercial formulations (Vega et al. 2006; Garg et al. 2014). Recently, NPs with mucoadhesive properties have been developed to improve precorneal residence time. NPs prepared from chitosan, hyaluronic acid, carbopol, and sodium alginate are commonly employed to improve precorneal residence time of nanoparticles (Kao et al. 2006; Motwani et al. 2008; Ibrahim et al. 2010; Contreras-Ruiz et al. 2010; Ameeduzzafar et al. 2014; Chhonker et al. 2015).

Out of these, chitosan NPs or chitosan-coated NPs are most widely explored for improving precorneal residence. Chitosan is a natural polysaccharide with interesting features, such as biocompatibility and biodegradability, mucoadhesiveness, and the ability to transiently enhance the permeability of ocular barriers. Chitosan NPs are able to interact with the ocular surface and get through the corneal and conjunctival epithelium without causing toxicity. Several studies using chitosan NPs, chitosan/carbopol NPs, chitosan/lecithin NPs, and chitosan/alginate NPs have demonstrated improved pharmacokinetics and pharmacodynamic activity of encapsulated drugs (Motwani et al. 2008). The surface characteristics of the nanocarriers also have an influence on the interaction with the ocular surface structures. For instance, chitosan-coated PECL NPs enter the corneal epithelium in vivo more efficiently than uncoated PECL or polyethylene glycol-coated PECL NPs (de Campos et al. 2003). The transport pathways by which NPs penetrate the ocular surface tissues are of great interest. For NPs composed of hydrophobic polymers such as PECL or PLGA, uptake via transcellular route has been proposed, whereas for NPs composed of hydrophilic polymers such as chitosan, paracellular route has been proposed. These results moved us to explore different biomaterial combinations intended specifically for the ocular surface tissues. Consequently, we joined PLGA and chitosan to form a new matrix-based nanosystem that we termed “nanoplex” (Jain et al. 2010a, b, 2011; Warsi et al. 2014). The theoretical advantages of these nanoplexes are encapsulation of both hydrophilic and hydrophobic drugs, better control over drug release, prolonged corneal retention, and penetration (Jain et al. 2010a, b). We tested nanoplex formulation, showing their potential for ocular administration. In an in vivo study using rabbit eye, we investigated the interaction of nanoplexes with ocular mucosa. Confocal microscopy of the cornea revealed both paracellular and transcellular uptake of the nanoplex. The uptake mechanism postulated was adsorptive-mediated endocytosis and opening of tight junctions between epithelial cells. Results demonstrated prolonged precorneal retention of nanoplexes. Further, these carriers were found to be well tolerated (Jain et al. 2011).

NPs have also been lucratively employed as an alternative strategy for prolonged drug delivery to the posterior segment ocular tissues. For posterior segment delivery, disposition of NPs depends on the size and surface property. Following periocular administration into Sprague–Dawley rats, NPs in the range of 200–2000 nm were retained at the site of administration for at least 2 months. On the other hand, NPs with size 20 nm were cleared rapidly from periocular tissues (Amrite and Kompella 2005; Amrite et al. 2008). Therefore, it can be concluded that for transscleral drug delivery to the back of the eye, NPs with low clearance by blood and lymphatic circulations and slow drug release are suitable delivery carriers. Following intravitreal injection, NPs migrate through the retinal layers and tend to accumulate in the RPE cells. Following single intravitreal injection, the PLA NPs were retained in rat RPE tissues up to 4 months, suggesting great potential for achieving steady and continuous delivery to the back of the eye using NPs. In another study using PLGA NPs, authors concluded that NPs provide sustained delivery of dexamethasone for the treatment of posterior segment eye diseases (Pan et al. 2015). The surface property of nanoparticles is a key factor affecting their distribution from vitreous humor to retinal layers following intravitreal injection. Koo et al. found that polyethyleneimine/glycol chitosan NPs and human serum albumin/glycol chitosan NPs easily penetrated the vitreal barrier and reached at the inner limiting membrane but could not penetrate to the deeper retinal layers. On the other hand, negatively charged human serum albumin/hyaluronic acid NPs could penetrate the whole retina structures and reach the outer retinal layers such as the photoreceptor layer and RPE which was attributed to interaction between anionic surface and Müller cells (Koo et al. 2012). Therefore, the anionic NPs could be promising drug delivery carrier for the treatment of choroid and retinal disorders. Additionally, molecules such as folate and hyaluronic acid have been proposed as a targeting strategy. Specifically, folate-decorated NPs have shown increased uptake in retinal pigment epithelium cells in vitro (Suen et al. 2013). On the other side, the inclusion of hyaluronan into chitosan NPs was explored as a strategy to target the CD44 receptors expressed by epithelial corneal and conjunctival cells (Contreras-Ruiz et al. 2011). Few other reports highlighted the importance of polymeric NPs to deliver drug and genes to the retina more specifically to the RPE cells (de la Fuente et al. 2008; Khar et al. 2010). More recently, novel pentablock copolymeric NPs have been developed using biodegradable polyglycolic acid, polyethylene glycol, polylactic acid, and polycaprolactone polymers. Results indicated that pentablock polymeric NPs can serve a platform for sustained delivery of therapeutic proteins in the treatment of posterior segment diseases (Patel et al. 2014).

Dendrimers are globular, nanostructured polymers (~1–100 nm), which have received significant attention as ocular drug delivery systems, due to their well-defined size, tailorable structure, and potentially favorable ocular biodistribution. Dendrimers have tree-like branched architecture formed by repetitive branched molecules surrounding a central core allowing them to act as efficient carriers for nucleic acids and water insoluble drugs. Because of their electrophoretic, dimensional length scaling and other biomimetic properties, similar to globular proteins, dendrimers display good ocular tolerance. The large number of surface functional groups on dendrimers can lead to multivalent interactions, with a potential for mucoadhesive properties that could lead to a reduction in tear washing and dilution and improved precorneal residence. The most commonly used dendrimers in ocular delivery are poly-(amidoamine) (PAMAM), polypropylenimines (PPI), and phosphorus dendrimers (Yavuz et al. 2013). Although the mechanisms of interaction of the dendrimers with the ocular mucosa have not been fully disclosed, it has been reported that anionic high-generation PAMAM dendrimers can act as permeability enhancers and they are mainly internalized by caveolin-mediated process, whereas neutral and cationic low-generation dendrimers promote higher permeability and are endocytosed by clathrin-mediated pathway (Perumal et al. 2008; Spataro et al. 2010; Durairaj et al. 2010; Kambhampati and Kannan 2013). Various research groups have shown enhanced bioavailability of pilocarpine (Vandamme and Brobeck 2005), tropicamide (Vandamme and Brobeck 2005), puerarin (Yao et al. 2010), brimonidine (Holden et al. 2012), and timolol maleate (Holden et al. 2012) after topical application of PAMAM dendrimer formulation. Phosphorus dendrimers are reported to be beneficial in the delivery of carteolol to aqueous humor (Spataro et al. 2010). Dendrimer glucosamine and dendrimer glucosamine 6-sulfate conjugates have shown to have synergistic immunomodulatory and antiangiogenic effect (Shaunak et al. 2004).