ArticleInternational journal of nanomedicine2026
Improved Physicochemical Stability and Retinoblastoma Anticancer Activity of Salt-Caged Acid-Base Neutralized Melphalan Loaded in L-Glutathione and pH Responsive Fattigated Nanoparticles.
Article in International journal of nanomedicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Purpose: The clinical uses of melphalan (MEL) for ocular retinoblastoma (RB) delivery are limited by its poor aqueous stability and insufficient ocular bioavailability. Intravitreal injection of MEL is also invasive and less common for patients. A novel MEL-loaded formulation was developed to improve the stability and RB cellular uptake of MEL using the acid-base neutralization (ABN) and the enzyme-responsive hyaluronic acid (HA)-cystamine (CYS)-oleic acid (OA) nanoparticles (HON). Methods: An amphiphilic HA-CYS-OA conjugate (HOC) with an L-glutathione (GSH)-responsive CYS linker was synthesized via a two-step coupling method and subsequently self-assembled to form HON. Neutralized MEL (NM) was prepared using ABN, loaded into HA (NM-HA) and HON (NM-HON), and lyophilized to obtain solid-state powders. Results: ABN reduced the hydrolysis of MEL by forming salt-induced cage nanoaggregates. The ionic complexation of NM with HA further improved the stability of the solution. The NM-HON exhibited improved chemical and solid-state stabilities through synergistic ionic complexation and hydrophobic encapsulation. HONs demonstrated nanoscale size, negative zeta potential, and high entrapment efficiency based on dynamic light scattering (DLS), field-emission scanning electron microscopy (FE-SEM), and field-emission transmission electron microscopy (FE-TEM), whereas fourier-transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and high-power X-ray diffraction (HP-XRD) indicated amorphization and strong drug-polymer interactions. NM-HON and NM-HA exhibited enhanced in vitro permeability compared to free MEL and NM. Most importantly, NM-HON exhibited controlled drug release, pH sensitization, and GSH responsiveness via CYS linker. NM-HON exerted improved anticancer activity and the lowest inhibitory concentration (10.52 ± 2.24) in RB cells (WERI-Rb-1) with statistical significance as compared with free MEL (7.53 ± 0.35 µg/mL) while preserving low toxicity in normal cells (ARPE-19). Conclusion: The synergistic strategy of ABN to prepare salt-caged NM and fattigated HOC to form self-assembled nanoparticles offers a promising way to simultaneously improve the stability, permeability, and pH- and GSH-responsive controlled release of MEL for ocular chemotherapy.
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