Diabetic retinopathy (DR) is a multifactorial manifestation associated with microvascular complications and is the fourth leading cause of visual impairment and blindness world-wide. Current day treatment of DR relies heavily on invasive techniques such as intravitreal injections of therapeutic agents. Unfortunately, intravitreal injections are associated with various complications such as intraocular bleeding, endophthalmitis, pain and discomfort resulting in poor patient compliance. To date, there has been no non-invasive drug delivery system reported for DR treatment. To address this, we developed a core-shell nanoparticle-based delivery system consisting of a hydrophobic polycaprolactone core and a hydrophilic Pluronic® F68 shell, loaded with triamcinolone acetonide and evaluated its efficacy in a DR rat model. After being administered as eye drops, the drug loaded nanoparticles significantly improved structural (retinal thickness and vascular health) and functional activity (rod and cone function) of retina as compared to DR controls that were treated with the drug alone or placebo nanoparticles. Furthermore, drug loaded nanoparticles reduced retinal inflammation as evidenced by a decrease in NF-κB, ICAM-1 and TNFα expression after 20 days of treatment. Similarly, a reduction in glial cell hyperplasia as evidenced by reduced GFAP expression, and a decrease in microvascular complications as evidenced by a decrease in VEGF secretion and microvascular tuft formation were observed in rat retinas after 40 days of treatment. The combined reduction in retinal inflammation and vascular abnormalities, both hallmarks of DR, demonstrates the potential of the nanoparticulate delivery system for use as a topical formulation for treating DR.
The eye consists of sensitive, compactly adjoined tissue structures which act as strong physical (static) and physiological (dynamic) barriers that prevent entry of foreign bodies into the eye. Together, these barriers reduce the bioavailability of topically and intraocularly administered medicaments thus demanding frequent drug administration for the treatment of chronic eye diseases. Hence, development of drug delivery systems (DDS) that can be retained in ocular tissues for longer durations can help to reduce the frequency of drug administration, whereas, delivery systems that traverse through ocular barriers may offer higher bioavailability of administered drugs to otherwise inaccessible ocular tissues. These objectives can be partially/fully achieved using nanoparticulate/colloidal DDS. Colloidal DDS, due to their nanodimensions, undergo internalization by cells which enables transport of drugs through ocular barriers. Furthermore, nanoparticles can prolong duration of drug release and can increase residence time of entrapped cargo molecules in ocular tissues. Together, these aspects facilitate a higher bioavailability, prolonged therapeutic effect and reduced frequency of drug administration for the effective treatment of chronic ocular diseases. Hence, nanocarriers have been widely explored for ophthalmic drug delivery applications. In this review, we discuss the anatomy of ocular tissues along with their barrier properties. We then discuss ocular diseases along with the various routes of drug administration and pathways of drug transport in the eye. The next section discusses the influence of physicochemical properties of therapeutic molecules on their ocular distribution and conventional and advanced (nanoparticulate/colloidal DDS) drug formulations that are used for the treatment of ocular diseases.
We investigated efficacy of nitric oxide (NO) against Leishmania donovani. NO is a mediator of host response to infection, with direct parasiticidal activity in addition to its role in signalling to evoke innate macrophage responses. However, it is short-lived and volatile, and is therefore difficult to introduce into infected cells and maintain inracellular concentrations for meaningful periods of time. We incorporated diethylenetriamine NO adduct (DETA/NO), a prodrug, into poly(lactide-co-glycolide) particles of ∼200 nm, with or without amphotericin B (AMB). These particles sustained NO levels in mouse macrophage culture supernatants, generating an area under curve (AUC0.08-24h) of 591.2 ± 95.1 mM × h. Free DETA/NO resulted in NO peaking at 3 h and declining rapidly to yield an AUC of 462.5 ± 193.4. Particles containing AMB and DETA/NO were able to kill ∼98% of promastigotes and ∼76% of amastigotes in 12 h when tested in vitro. Promastigotes and amastigotes were killed less efficiently by particles containing a single drug– either DETA/NO (∼42%, 35%) or AMB (∼90%, 50%) alone, or by equivalent concentrations of drugs in solution. In a pre-clinical efficacy study of power >0.95 in the hamster model, DETA/NO particles were non-inferior to Fungizone® but not Ambisome®, resulting in significant (∼73%) reduction in spleen parasites in 7 days. Particles containing both DETA/NO and AMB were superior (∼93% reduction) to Ambisome®. We conclude that NO delivered to the cytosol of macrophages infected with Leishmania possesses intrinsic activity and adds significantly to the efficacy of AMB.
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