Supramolecular Complexation of Niclosamide and Nafamostat: Improved Physicochemical Profile and Enhanced Anticancer Effect.

Background/

Objective

Niclosamide exhibits considerable potential for the treatment of drug-resistant cancers. However, its poor aqueous solubility substantially limits its oral bioavailability and therapeutic efficacy. To overcome this limitation, we developed a novel pharmaceutical supramolecular crystalline phase comprising niclosamide and nafamostat.

Methods

In this study, we developed a niclosamide-nafamostat pharmaceutical supramolecular crystalline phase using a conventional solvent evaporation technique. Comprehensive solid-state characterization was carried out using X-ray powder diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). In vitro drug transport kinetics and barrier transport efficiency were evaluated across artificial transpermeable membranes using a diffusion cell setup. In vitro anticancer efficacy was systematically screened against human lung, breast, and pancreatic cancer cell lines. Finally, in vivo translation was established using female NOD/SCID mice tumor-bearing animal models; therapeutic efficacy and total tumor burden were evaluated.

Results

Niclosamide-nafamostat cocrystal (NNC) was found to form a distinct crystalline phase, with characterization results supporting a unique crystal lattice stabilized through strong intermolecular hydrogen-bonding interactions and exhibiting high thermal purity. Crucially, the supramolecular crystalline phase considerably enhances membrane transport, yielding superior cumulative permeation and enhanced apparent permeability (Papp) values compared to those of pure niclosamide. In vitro evaluation across multiple cancer cell lines demonstrated a tenfold increase in antiproliferative potency compared to the parent compounds. Furthermore, in vivo studies revealed a twofold increase in tumor growth inhibition and a tenfold reduction in total tumor burden (p < 0.05).

Conclusions

These findings demonstrate that the NNC supramolecular crystalline phase platform successfully optimizes membrane permeability and antitumor efficacy, highlighting its potential for treating advanced cancers.