Purpose: Uveal melanoma (UM) is a rare yet the most common and aggregative primary intraocular malignancy in adults. At present, there is no effective treatment for advanced UM and consequently, the mortality rate of UM has remained high over the past few decades. In order to improve prognosis and survival of UM patients, it is critical to sustained inhibit tumor progression and metastasis as early as possible after the initial presentation/diagnosis of the disease. The main objective of the present study is to investigate a novel therapeutic strategy against UM through the development of a bioinspired in situ gelling delivery system that is capable of sustained releasing anti-UM therapeutics in the posterior segment of the eye where most UM occurs, to inhibit UM progression and metastasis.
Methods: Curcumin, a small molecule hypoxia-inducible factor 1α (HIF-1α) pathway inhibitor that plays a pivotal role in the UM tumor progression and metastasis, was selected as the model compound. The in situ gelling delivery system composed of biopolymers such as hyaluronic acid (HA) and collagen, major components of the vitreous humor, was prepared using a simple one-step polymerization approach without the use of toxic chemical reaction catalysts. The composition/components of the in situ gelling hydrogel system was optimized to achieve desired gelling temperature (35-37°C) and gelling duration. In order to improve the vitreous transport and distribution of the anti-UM therapeutic to its target site (the choroid), curcumin was encapsulated into biodegradable nanoparticles using poly(lactic-co-glycolic acid) (PLGA) polymer and lyophilized to form dry nanoparticles. Formulation and preparation parameters, as well as cryoprotectant of curcumin loaded nanoparticles were studied. The curcumin nanoparticle formulation that can retain initial nanoparticle characteristics (such as particle size and polydispersity index) following reconstitution, were incorporated into the optimized in situ gelling hydrogel system. Physicochemical properties (e.g. drug loading, and particle size) as well as in vitro performance (e.g. release characteristics and anti-UM efficacy) of the developed curcumin nanoparticle/in situ gelling composite were investigated.
Results: Following the formulation optimization, an in situ gelling formulation that formed a hydrogel at 37C in 3 minutes was obtained (Figure 1A). The curcumin nanoparticle formulation with 5% (w/w) drug loading remained its particle size (157.0 ± 2.75 nm), PDI (0.08 ± 0.009), and Zeta potential (-21.03 ± 3.94 mV) following reconstitution when sucrose was used as the cryoprotectant. As shown in Figure 1B, curcumin nanoparticles with narrow particle size distribution were evenly distributed into the in situ gelling hydrogel matrix. The in vitro anti-UM efficacy study using human melanoma cell line (MP38) demonstrated that the developed curcumin nanoparticle/hydrogel composite was able to improve cellular uptake and subsequent anti-UM effect against the human UM cells (MP38) (Figure 2). Furthermore, it was observed that the blank nanoparticles and blank composite did not affect cell viability in vitro.
Conclusion: The developed in situ gelling delivery system gelled at 37C within 3 minutes, and was able to sustained release curcumin against UM cells in vitro. This novel in situ gelling delivery system demonstrates promise for the treatment of the rare and devastating intraocular malignancy in adults.