Macrocyclic histone deacetylase inhibitor-based near-infrared-responsive ionic nanomedicines for enhanced cancer...

The integration of epigenetic therapy with photothermal treatment offers a promising strategy to enhance anticancer efficacy while minimizing systemic toxicity. Herein, we report the design and development of a novel class of ionic nanomedicines (INMs) synthesized from macrocyclic histone deacetylase inhibitors (mac-HDACis) and Near-Infrared (NIR) dye for combination cancer therapy. The mac-HDACi components, incorporating an N-(2-aminophenyl)acylamide Zinc-Binding Group (ZBG), were first protonated using acetic acid to yield the cationic compounds of mac-para HDACi and mac-meta HDACi. Using ionic-liquid chemistry, the resulting cationic compounds were electrostatically integrated with the NIR cyanine dye IR820 anion to generate two ionic materials (IMs), which were then converted into the INMs. The INMs, [mac-para HDACi][IR820] and [mac-meta HDACi][IR820], comprise the mac-HDACis (chemotherapeutic agents) and the photothermal therapeutic dye IR820. Dynamic Light Scattering (DLS) studies showed that the INMs were well-dispersed in aqueous media, with stable particle sizes (93.1-141 nm), low polydispersity indexes (PDIs), and high negative Zeta potential (ζ) values. Photophysical studies of the INMs revealed high molar absorptivity, red-shifted absorption, and higher non-radiative rate constants (k_nr) than the parent NIR dye, indicating a more efficient release of absorbed photon energy through non-radiative pathways. Quantitative cellular uptake measurements in the human liver cancer cell line (Hep G2) confirmed that cells exposed to INMs exhibited significantly more drug uptake than those treated with the parent NIR compound. In vitroassays in Hep G2 and MCF-7 (breast cancer) cells demonstrated that INMs exert superior cytotoxicity over parent compounds under both dark and NIR-irradiated conditions. Combination Index (CI) values < 1confirmed a synergistic effect between the HDACi epigenetic regulation and the NIR-mediated phototherapy.In addition, flow cytometry results showed that the INMs promoted apoptosis in the dark and cell necrosis under NIR irradiation, indicating a light-dependent cell death mechanism. Molecular docking study also revealed that the binding affinity for both meta and para [mac-HDACi][IR820] IMs (-9.5 kcal/mol and -9.7 kcal/mol) significantly improved as compared to the parent meta and para mac-HDACi (-7.7 kcal/mol and -7.5 kcal/mol) for human HDAC1 (PDB ID: 4BKX), a validated Class I HDAC isoform. Overall, these results demonstrate the potential of HDACi-based INMs as combination agents for targeted cancer therapy.