Surface-Modified Melphalan Nanoparticles for Intravitreal Chemotherapy of Retinoblastoma

Abstract

The goal of this work was to design and assess the ability of unmodified and surfacemodified poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to enhance cell association, provide efficacy in retinoblastoma cells, and overcome current administration challenges, including hydrolysis and precipitation, of intravitreal administration. METHODS. A single emulsion method was used to encapsulate Coumarin 6, to enable NP visualization via fluorescence microscopy. Melphalan NPs were synthesized using an adapted double-emulsion method to reduce melphalan loss during fabrication. Melphalan loading and release were quantified against a free melphalan standard. The cellular association and internalization of unmodified and surface-modified NPs were determined using flow cytometry, and the efficacy of melphalan NPs was quantified in retinoblastoma cells. RESULTS. The highest cell association was observed with TET1 and MPG-NPs after 24 hours administration; however, a significant fraction of NPs were associated with the cell surface, instead of undergoing internalization. MPG-NPs fabricated with the low saturation process were most efficacious, while all surface-modified NPs improved efficacy relative to unmodified NPs when formulated using the highly saturated process. Similar effects were observed as a function of NP dose, with TET1 and MPG-NPs particularly efficacious. CONCLUSIONS. Surface-modified NPs achieved enhanced association and efficacy in retinoblastoma cells relative to unmodified NPs, with MPG and surface-modified NPs exhibiting the strongest efficacy relative to other NP groups. In future work we seek to assess the ability of these NPs to improve transport in the vitreous, where we expect a more dramatic impact on efficacy as a function of surface modification.

Phosphatidylinositol Stabilizes Fluid-Phase Liposomes Loaded with a Melphalan Lipophilic Prodrug

“…Encapsulation of melphalan in a nanocarrier can improve its pharmacological characteristics. Several studies on successful incorporation of melphalan as an active pharmaceutical ingredient in polymeric [16,17] or solid lipid PEG-coated nanoparticles [18,19] have been reported recently. As for nanosized liposomes, passive encapsulation of even highly water-soluble drugs is inefficient.…”

Advances in biomaterials for the treatment of retinoblastoma

“…In another study published in 2019, 288 the use of surface-modified PNPs for the management of retinoblastoma was also reported (Fig. 7B).…”

“…These two examples 282,288 provide a source of innovation and inspiration in the field of polyester-based drug nanocarriers for targeting and treating retinoblastoma. In fact, PNPs are effective tools that can enhance drug bioavailability and targeted delivery.…”

Next-generation nanomaterials: advancing ocular anti-inflammatory drug therapy

“…This figure is reproduced from Ref. [ 345 ] with permission from the Association for Research in Vision and Ophthalmology Inc …”