Engineering pH-Responsive Dendrimer-STAT3 Inhibitor Conjugates for Intracellular Delivery

Area of Science:

• Bioconjugation Chemistry
• Nanomedicine
• Immunology

Background:

• Small-molecule STAT3 inhibitors face clinical translation challenges like poor solubility and high toxicity.
• Developing effective drug delivery systems is crucial for enhancing therapeutic outcomes.

Purpose of the Study:

• To create pH-responsive poly(amidoamine) dendrimer conjugates of the STAT3 inhibitor LLL12.
• To improve LLL12 solubility, reduce cytotoxicity, and enable controlled intracellular drug release.

Main Methods:

• Conjugation of LLL12 to G6 PAMAM dendrimers via pH-sensitive sulfonyl carbamate, sulfonyl carbamoyl, and hydrazone linkers.
• Assessment of drug solubility, cytotoxicity, stability, pH-dependent release, and *in vitro* potency.
• Evaluation of conjugate efficacy in suppressing myeloid-derived suppressor cells and promoting antigen-presenting cell maturation.

Main Results:

• Conjugation significantly increased LLL12 solubility to 10 mg/mL and decreased cytotoxicity.
• All conjugates showed pH-dependent drug release, with hydrazone-linked G6-LLL12 exhibiting potency comparable to free LLL12.
• Hydrazone-based G6-LLL12 effectively reduced immune suppressive myeloid cells and enhanced antigen-presenting cell maturation.

Conclusions:

• pH-responsive dendrimer conjugates offer a promising strategy to overcome limitations of small-molecule STAT3 inhibitors.
• The hydrazone-linked G6-LLL12 conjugate demonstrates enhanced safety and retained potency for potential immunomodulatory cancer therapy.