ABSTRACT
Glaucoma is the second most leading cause of blindness [6]. It is a progressive optic neuropathy and has been commonly associated with elevated intraocular pressure (IOP) [7]. The conventional drug delivery system for treatment of glaucoma comprises of ocular drops and has been linked with numerous disadvantages such as natural anatomical barrier (low residence time), poor patient compliance, and local and systemic side effects [8]. Several sustained release drug delivery systems for anti-glaucoma drugs have been proposed that include intraocular implants [9], ophthalmic inserts [10], nano-and microparticles [11], liposomes [12], nanoemulsions [13], and contact lenses [14]. However, due to potential benefits of nanoparticles (NPs) over other delivery systems, further research is focused on finding new drugs and developing better nanoformulations. One such study introduced latanoprost (an ester prodrug of prostaglandin F2a with an efficiency to lower the IOP). Latanoprost acid (LA) is the pharmacologically active component of latanoprost. LA was entrapped in biocompatible and biodegradable nanoparticles formed using polylactide-poly(ethylene glycol) (PLA-PEG) copolymers. The in vivo studies revealed that LA-loaded NPs proved to be a promising system for curing glaucoma without inducing any side effects [15].Topical drug delivery is considered as the easiest method for ophthalmic drug delivery and has gained patient compliance over time. Once a drug is topically applied, due to the natural tear drainage and blinking action of the eye there is a 10-fold reduction in drug concentration in eye within 4-20 min [16]. Thus, the residence time of the drug in precorneal space and penetration to ocular tissue is reduced to 5-6 min and 1% to 3%, respectively [17]. The mucoadhesive nanoparticles that interact with the mucosal layer of cornea have been a big success in ophthalmic drug delivery, as they can increase the drug residence time in precorneal space up to 20 min [18]. The best advantage of using NPs is that their surface can be modified as per requirement. Thus, surface modifications in NPs can significantly increase the bioavailability, corneal penetration, and conjunctival uptake of drug-loaded NPs [19]. It has also been established that due to the above-mentioned reasons the therapeutic efficacy of drugs loaded in polymeric NPs is significantly increased [20]. Eudragit S, methyl methacrylate methacrylic acid, and chitosan are some
of the mucoadhesive polysaccharides that can prolong their presence on the ocular surface [21].Chitosan is known to increase transepithelial absorption by reversal opening of tight junctions [22]. Poly-b amino ester (PbAE) is a biodegradable and biocompatible cationic polymer that is recently being used for nanoparticle synthesis for ophthalmic drug delivery [23]. Another new mucoadhesive polymer Durasite (cross-linked, poly acryclic acid, Inspire Pharmaceuticals, Durham, NC) has been designed to increase the drug residence time in precorneal space in order to improve the effect of topical delivery [24]. There have been several limitations associated with the use of nanoformulations such as, mucoadhesive polymers in solution get hydrated and their mucoadhesivity is reduced [25], other nonmucoadhesive polymers are not retained on eye for significant period; therefore, alternative drug delivery approaches such as nano-gels have been developed. Levofloxacin nanoparticle-laden in situ gel is one such system that has been used to enhance ocular retention [26]. Other studies are focused on improving the properties of mucoadhesive polymers by mixing other polymers, e.g., Cationic chitosan and anionic dextran sulfate have been used to form mucoadhesive chitosan-dextran sulfate nanoparticles with enhanced retention capability [27]. Aptamers (functional nucleic acid ligands) with enhanced specificity towards the target antigen are the current and advanced therapeutics that have been commonly used in nanodelivery systems in cancer and eye and inflammatory diseases [28]. Chimerization of aptamers enhances their capability by diversifying their use in targeted therapy [29]. In a recent approach, an epithelial cell adhesion molecule (EpCAM) aptamer (EpDT3)-doxorubicin (Dox) conjugate was used to target cancer stem cells using retinoblastoma (RB) cell line as a model [30]. RB is most common cancer found in the retina of children under the age of 2-3 years [31]. It was found that the EpDT-3-Dox conjugate selectively induced apoptosis in cancer as well as cancer stem cells and did not harm the non-cancerous cells. Apart from aptamers, other nucleic acid-based therapeutics such as the RNA interference (RNAi) approach has also gained huge success in inhibiting invasiveness of RB cells [32]. Therefore, the current therapeutic approach has shifted from conventional nanoparticle-based therapy to highly targeted aptamers, mucoadhesive polymer mixtures, nanoemulsions, and nanogels.
