Development of a new mannosylated curcumin-based prodrug for combination therapy with NSAID prodrugs: Enhancing anti-inflammatory and anticancer efficacy

Single-agent chemotherapy is often hindered by rapid systemic elimination, poor bioavailability, and multidrug resistance, reducing its therapeutic effectiveness. To overcome these challenges, this study presents a mannosefunctionalized nanocarrier designed to co-deliver two therapeutic agents with tumor-targeting capabilities. Unlike conventional monotherapy, this dual-drug delivery system enhances drug accumulation at tumor sites, optimizes pharmacokinetics, and facilitates controlled release within the tumor microenvironment. New mannosylated curcumin-based prodrug (Pro-Cur) was synthesized and co-formulated with previously reported NSAID-prodrugs, Ibu-TEG and DA-P, into a nanoparticle (NP) system. Structural confirmation of Pro-Cur was conducted via mass-spectrometry, 1H NMR, 13C NMR, and FTIR. Successful fabrication of NPs and their combination formulations was analyzed through FTIR, DLS, AFM, and SEM/EDX. Pro-Cur-NPs showed conjugated drug encapsulation efficiency and drug loading were 79.02 f 2.3 % and 32.0 f 1.5 %, respectively. The NPs exhibited monodisperse size distributions 128.9 f 1.68 nm (Pro-Cur-NPs), 283.5 f 5.36 nm (Pro-Cur-IbuTEGNPs), and 155.2 f 2.31 nm (Pro-Cur-DAP-NPs), with stable surface charges. TGA/DSC confirmed thermal stability. The formulations demonstrated pH-responsive enhanced Cur release in acidic environments due to the acid-labile Schiff base linkage. Anti-inflammatory activity assays showed significant inhibition of reactive oxygen species (ROS) and nitric oxide (NO) generation compared to Cur alone. In-vitro anticancer studies, MTT assays on HepG-2, NCI-H460, and cytotoxicity against IMR-90 cell lines, revealed efficient cellular uptake, improved anticancer activity, and non-cytotoxicity of these nanoformulations. Microscopic imaging further confirmed prominent cytotoxicity in treated cells as compared to free Cur. These results demonstrate that the Pro-Cur-NPs and its combination nanoformulations offer significant potential as an effective means for a dual-therapy drug delivery platform for treating cancer and inflammatory disorders.