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

ABSTRACT: 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 in vitro potency and cytotoxici

SUBMITTER: Siva Sankara C 

PROVIDER: S-EPMC12820809 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature