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

Small-molecule STAT3 inhibitors face numerous challenges in clinical translation, including poor water solubility, rapid systemic clearance, low bioavailability, poor selectivity, and high cytotoxicity. To address these limitations, we conjugated the potent STAT3 inhibitor-LLL12 to generate six (G6) hydroxyl-terminated (poly(amidoamine)) PAMAM dendrimers using pH-sensitive linkers: sulfonyl carbamate (carbamate), sulfonyl carbamoyl (amide), and hydrazone for intracellular drug delivery. Conjugation greatly enhanced LLL12 solubility (up to 10 mg/mL) and reduced cytotoxicity without altering dendrimer size or surface charge. All three G6-LLL12 conjugates remained stable under neutral pH but exhibited sustained, pH-dependent drug release correlating with <i>in vitro</i> potency and cytotoxicity. Notably, hydrazone-linked conjugate showed an IC₅₀ = 0.42 ± 0.035 μg/mL, comparable to free LLL12 (IC₅₀ = 0.31 ± 0.05 μg/mL) and superior to amide- and carbamate-linked conjugates. In bone marrow-derived immune suppressive myeloid cells, hydrazone-based G6-LLL12 effectively reduciii-derrive, hydrazone-based G6-LLL12 effectively reduced monocytic myeloid-derived suppressor cell expansion and promoted antigen-presenting cell maturation, highlighting a promising pH-responsive delivery system that enhances solubility and safety while retaining potency.