Combination therapy has emerged as a promising strategy in cancer treatment, aiming to enhance therapeutic efficacy and overcome drug resistance. In this study, ina collaboration of researchers from Spain, Italy, Argentina and Thiland,. cyclodextrin-based nanosponges (EpCNs) were engineered for the co-delivery of doxorubicin (DX), a hydrophilic chemotherapeutic, and N,N-bis(5-ethyl-2-hydroxybenzyl)methylamine (EMD), a hydrophobic c-Myc inhibitor. EpCNs were synthesized by crosslinking β-cyclodextrin with epichlorohydrin, followed by single or dual drug loading. Comprehensive characterization using Dynamic Light Scattering (DLS), Atomic Force Microscopy (AFM), Scanning Electron Microscopy (SEM), and Nuclear Magnetic Resonance (NMR) confirmed their physicochemical properties. Dual-loaded EpCNs (DX/EMD-EpCNs) exhibited uniform particle sizes (30 ± 13 nm), high encapsulation efficiency (>98%), a positive surface charge (+23 ± 4 mV), and pH-responsive release with accelerated drug release under acidic, tumor-like conditions.
In vitro assays on cancerous (A549 and MCF-7) and non-cancerous (WI-38) cells revealed that DX/EMD-EpCNs significantly decreased cancer cell viability compared to free drugs or single-drug-loaded nanosponges. Combination therapy within EpCNs showed strong synergism (combination index <0.6), reduced the effective dose, and improved selective drug uptake in cancer cells while sparing normal cells. Cell cycle analysis demonstrated that DX/EMD-EpCNs induced multi-phase arrest at G0/G1 and G2/M, leading to enhanced apoptosis, as confirmed by annexin V/Zombie UV staining. Western blotting further revealed marked downregulation of c-Myc and Bcl-2, alongside increased cleaved-PARP expression, indicating caspase-dependent apoptosis. In contrast, single-drug-loaded EpCNs altered cell cycle progression but failed to induce substantial apoptosis.
Overall, the co-delivery of DX and EMD via EpCNs enhanced therapeutic efficacy through multiple mechanisms. These results highlight cyclodextrin-based nanosponges as a versatile drug delivery platform capable of simultaneously encapsulating hydrophilic and hydrophobic drugs, thereby offering a powerful approach for combination chemotherapy.
Sunisa Thongsom, Paolo Di Gianvincenzo,a Giulia Ciattaglia,b Ahmed Subrati, Desiré DiSilvio,a Ariadna M. Birocco, Marco D’Abramo, Chanchai Boonla, Pithi Chanvorachoteef and Sergio E. Moya (2025) Cyclodextrin-based nanosponge co-delivery of doxorubicin and EMD: synergistic anticancer activity with improved selectivity toward cancer cells. RSC Pharm., 2025, Advance Article. DOI
https://doi.org/10.1039/D5PM00183H