Microfluidic engineering of triple-responsive cystine-crosslinked microgels for mild-redox-triggered chemotherapy

Area of Science:

• Biomaterials Science
• Nanotechnology
• Drug Delivery

Background:

• Stimuli-responsive microgels are promising for site-directed chemotherapy.
• Existing redox-sensitive carriers often use poorly soluble crosslinkers and require high intracellular glutathione (≥10 mM) for drug release.
• This limits their efficacy and applicability in tumor microenvironments.

Purpose of the Study:

• To develop novel redox-sensitive microgels using a water-soluble crosslinker for efficient in-process drug encapsulation.
• To investigate the stimuli-responsive properties and drug release kinetics of these microgels under tumor-relevant conditions.
• To evaluate the in vitro cytotoxicity and therapeutic potential of the microgels for localized chemotherapy.

Main Methods:

• Synthesis of poly(acrylamide) microgels crosslinked with N,N '-diacryloyl-L-cystine disodium salt (DACS) via microfluidics.
• In-process encapsulation of doxorubicin (DOX) into microgels of varying sizes (μG100 ≈ 412 μm, μG24 ≈ 82 μm).
• Assessment of microgel responsiveness to pH, ionic strength, and redox conditions (glutathione).
• In vitro cytotoxicity assays using cancer cells (MCF-7) and healthy cells (WJ).

Main Results:

• Achieved high encapsulation efficiencies (98% for μG100, 87% for μG24) in a single step.
• Demonstrated triple responsiveness: swelling with pH increase, shrinking with ionic strength increase, and degradation in redox conditions.
• Exhibited enhanced doxorubicin release at tumor-relevant pH 6.5 and low glutathione (100 μM), with complete network disintegration at 10 mM GSH.
• Showed selective cytotoxicity against cancer cells with reduced toxicity to healthy cells, with size modulating efficacy and safety.
• Particles remained stable for 90 days at pH 7.4.

Conclusions:

• DACS-crosslinked microgels offer a scalable, water-processable platform for stimuli-responsive drug delivery.
• The mild redox-triggered release mechanism and in-process encapsulation strategy are advantageous for chemotherapy.
• Size tuning of microgels allows for balancing therapeutic efficacy and healthy-cell sparing.
• These microgels represent a versatile system for localized chemotherapy and other biomedical applications.