Beyond inclusion: Mechanistic insights into niclosamide dual solubilization by 2-hydroxypropyl-ß-cyclodextrin through experimental and theoretical approaches
Por:
Valdés-Negrín, HL, Rincon-Londono, N, Figueroa-Gerstenmaier, S, Guadarrama, P, Luviano, AS, Rojas-Aguirre, Y
Publicada:
15 mar 2026
Resumen:
The poor aqueous solubility of niclosamide (Nic), a drug with broad therapeutic potential beyond its original antiparasitic use, presents a major challenge for formulation development. Here, we elucidate the molecular basis of Nic solubilization by 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) through combined experimental and computational approaches. (HNMR)-H-1 spectroscopy indicated the coexistence of inclusion and non-inclusion complexes in HP beta CD/Nic systems. Non-biased molecular dynamics (MD) simulations further showed that both protonated and deprotonated forms of Nic can spontaneously enter the HP beta CD cavity-preferentially through the nitrophenyl moiety-in agreement with NMR observations. Additional MD simulations involving multiple Nic molecules revealed strong, concentration-dependent self-association driven by pi-pi stacking and cation-pi interactions, consistent with radial distribution function profiles. HP beta CD also self-associated, forming aggregates that disrupted Nic-Nic interactions. Nic-Nic hydrogen bonds decreased by more than half upon HP beta CD addition, while Nic-HP beta CD hydrogen bonds increased, accompanied by a rise in the solvent-accessible surface area of HP beta CD/Nic assemblies. Dynamic light scattering experiments supported this mechanism. Pure Nic formed large clusters of similar to 700 nm, whereas HP beta CD alone displayed mainly small species near 2 nm and a minor population around 300 nm. In the presence of HP beta CD, the similar to 700 nm Nic clusters disappeared, giving rise to mixed aggregates of roughly 300-400 nm across multiple stoichiometries. Although inclusion complexation is thermodynamically feasible, Nic predominantly associated with HP beta CD aggregates rather than forming classical host-guest complexes. Together, these findings establish a complementary solubilization mechanism-Cyclodextrin-Driven Drug Deaggregation (CD-DA)-in which HP beta CD enhances solubility by preventing or reversing drug self-association through peripheral non-covalent interactions and occasional inclusion events. This work advances the molecular understanding of HP beta CD/Nic systems and highlights CD-DA as a relevant mechanism for improving the solubility of self-association-prone drugs.
Filiaciones:
Valdés-Negrín, HL:
Univ Nacl Autonoma Mexico, Dept Polimeros, Inst Invest Mat, Circuito Exterior S-N,Ciudad Univ, Mexico City 04510, Mexico
Rincon-Londono, N:
Univ Guanajuato, Dept Ingn Fis, Div Ciencias Ingn, Campus Leon, Leon, Gto, Mexico
Figueroa-Gerstenmaier, S:
Univ Guanajuato, Dept Ingn Quim Elect & Biomed, Div Ciencias Ingn, Campus Leon, Leon, Gto, Mexico
Guadarrama, P:
Univ Nacl Autonoma Mexico, Dept Polimeros, Inst Invest Mat, Circuito Exterior S-N,Ciudad Univ, Mexico City 04510, Mexico
Luviano, AS:
Univ Guanajuato, Dept Ingn Quim Elect & Biomed, Div Ciencias Ingn, Campus Leon, Leon, Gto, Mexico
Rojas-Aguirre, Y:
Univ Nacl Autonoma Mexico, Dept Polimeros, Inst Invest Mat, Circuito Exterior S-N,Ciudad Univ, Mexico City 04510, Mexico
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