Fine-tuning formulation and biological interaction of doxorubicin-loaded polymeric nanoparticles via electrolyte concentration modulation

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Doxorubicin (DOX) is amongst the most widely used chemotherapeutic drugs against various cancers. However, its controlled biodistribution to the tumor site at the required pharmacokinetics profile remains challenging. In this work, a vast study of formulation parameters has been performed to control doxorubicin loading into polymeric nanoparticles in physiological conditions. Water-in-oil-in-water (W 1/O/W 2) template emulsions have been formulated, including doxorubicin in the internal water phase. Specifically, the system [Doxorubicin in aqueous solution (W 1) / Pluronic F-127 (S) and PLGA in ethyl acetate (O)], [Polysorbate 80 (S) in water solution], using phosphate buffer on both aqueous phases at different electrolyte concentrations has been established. The first W 1/O nano-emulsion was formed by high-speed homogenization, and the second O/W 2 nano-emulsion was formed by the phase inversion composition method, a low-energy emulsification appropriated for pharmaceutical compounds. Although many previous studies had already used double emulsions for DOX encapsulation in nanofluids, here, for the first time, the salt concentration of the water phases has been varied to control the resulting doxorubicin and nanoparticle properties. The addition of high concentrations of electrolytes in both aqueous phases decreases the solubility and dissolution rates of the drug, leading to a high degree of DOX dimerization. This phenomenon significantly impacts the internalization and subcellular localization. Facilitating drug nuclear accumulation is of vital interest, and this is primarily achieved when doxorubicin is incorporated into nanoparticles formulated with PBS at low electrolyte concentrations (2.5 mM), which exhibit exceptional internalization properties. Thus, it has been demonstrated that doxorubicin loading in polymeric nanoparticles can be tuned by only varying salt concentrations of template W 1/O/W 2 emulsions. Consequently, our results show the adequacy of the double nano-emulsion templating for the generation of non-toxic DOX-loaded polymeric nanoparticles with different physicochemical properties and interaction with the cell surface that would allow their use for various anticancer therapies.

Original languageEnglish
Article number122986
Number of pages12
JournalJournal of Molecular Liquids
Publication statusPublished - 15 Nov 2023


  • Antitumor therapies
  • Double emulsions
  • Doxorubicin encapsulation
  • Nano-emulsions
  • Polymeric nanoparticles
  • Water-in-oil-in-water emulsions


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