Drug resistance is a major barrier to an effective treatment against non-small cell lung cancer (NSCLC); it often leads to treatment failure and poor survival outcomes. Many genetic factors play a role in developing drug resistance, for instance, overexpression of the Enhancer of Zeste Homolog 2 (EZH2) gene. This event has been implicated in developing drug resistance in NSCLC against tyrosine kinase inhibitors (TKIs) such as Gefitinib (Gef). In this study, the use of GSK-126 in combating drug resistance against TKIs was evaluated. Initially, mechanistic studies on the effect of GSK-126 against EZH2 and its mediator H3K27me3 (trimethylation of lysine 27 on histone H3 protein) were derived. It was noted that GSK-126 exhibits an indirect effect against EZH2 expression by downregulating the expression of H3K27me3 in time and dose-dependent manner. The pretreatment with GSK-126 sensitized the A549 cells to Gef, enabling an improved cytotoxic effect at lower concentrations. However, due to the poor pharmacokinetic and physicochemical profiles, a suitable delivery system is needed to address the drawbacks and modify their release characteristics for improved therapeutic potency. In this regard, a delivery platform, i.e., mesoporous silica nanoparticles (MSN), was used to deliver GSK-126. Early results demonstrate MSN’s successful synthesis, size characterization by DLS and TEM, cellular internalization, and loading of GSK-126. However, release kinetic exhibited a burst release. Hence, additional modifications were made to coordinate and optimize the responsiveness to pH and temperature in the co-delivery of GSK-126 and Gef for an improved therapeutic outcome. MSN was coated with polydopamine and was found to be biocompatible and controlled the release of GSK 126 in different pH (5.0, 6.0, and 7.4). Ongoing studies will further elucidate this innovative platform for dual hydrophobic drug delivery by assessing the following: dual drug loading and internalization, establishing controlled delivery of the payloads from the nanocarrier system and assessing their synergistic effects.

Temperature and pH-responsive drug delivery using modified mesoporous silica nanoparticles to combat EZH2 induced gefitinib-resistant lung cancer

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