Recent advances in drug delivery applications of aqueous two-phase systems

Abstract

Aqueous two-phase systems (ATPSs) are liquid-liquid equilibria between two aqueous phases that usually contain over 70% water content each, which results in a nontoxic organic solvent-free environment for biological compounds and biomolecules. ATPSs have attracted significant interest in applications for formulating carriers (microparticles, nanoparticles, hydrogels, and polymersomes) which can be prepared using the spontaneous phase separation of ATPSs as a driving force, and loaded with a wide range of bioactive materials, including small molecule drugs, proteins, and cells, for delivery applications. This review provides a detailed analysis of various ATPSs, including strategies employed for particle formation, polymerization of droplets in ATPSs, phase-guided block copolymer assemblies, and stimulus-responsive carriers. Processes for loading various bioactive payloads are discussed, and applications of these systems for drug delivery are summarized and discussed.

Keywords: aqueous two-phase system; drug delivery; microparticle; nanoparticle; stimuli-responsive carrier.

Fig. 1.

Schematic representation of ATPS.

Fig. 2.

Schematic illustration of an ATPS, various particles made using ATPSs, their current application as carriers, and the stimuli used in these carriers.

Fig. 3.

The confocal microscopic images of the obtained microparticles in the Pluronic F127/ dextran ATPS in the presence of PLGA (0.0625% Cy5-PLGA, 2% fluorescein isothiocyanate (FITC)-pluronic/10% TRITC-dextran). A) TRITC-dextran, B) FITC-Pluronic F127, C) Cy5-PLGA, D) Pluronic F127-dextran core-shell morphology of particles, and E) PLGA backbone matrix. Scale bar 10 μm. Reproduced with permission from Ref. (95).

Scheme 1.

Schematic representation of crosslinking of acrylate functional groups (A), which can result in a crosslinked polymeric network (B).

Fig. 4.

A) GMA-gelatin microparticle preparation procedure. B) Optical microscopy image of the microparticle. Reproduced with permission from Ref. (94).

Scheme 2.

Ionic crosslinking using sodium alginate and calcium ion.

Scheme 3.

The mechanisms of thiol-ene and thiol-yne click reactions.

Fig. 5.

A) Schematic representation of microfluidic device for PEG/dextran microcapsule preparation using ATPS. B) Thiol-yne click reaction and photocrosslinking of dextran phase. Reproduced with permission from Ref. (113).

Fig. 6.

The Preparation of asymmetric polymersomes using ATPSs. Reproduced with permission from Ref. (105).

Fig. 7.

Doxorubicin release profile from surface-modified SiO₂ nanoparticles. Reproduced with permission from Ref. (100).

Fig. 8.

Confocal microscopic images of P. aeruginosa–loaded microcapsules with a polyelectrolyte-based shell, analyzed through live/dead assay. Cells were stained with SYTO 9 (all cells) and propidum iodide (dead cells). A) t = 0 h, B) t = 24 h. All scale bars = 100 μm. Reproduced with permission from Ref. (87).

Fig. 9.

Schematic representation and overlay images of HepG2-loaded multiaqueous core hydrogel capsules with/without HUVECs at day 0. Reproduced with permission from (109).