Abstract
Metastatic breast cancer is a major cause of cancer-related female mortality worldwide. The signal transducer and activator of transcription 3 (STAT3) and the chemokine receptor CXCR4 are involved in the metastatic spread of breast cancer. The goal of this study was to develop nanomedicine treatment based on combined inhibition of STAT3 and CXCR4. We synthesized a library of CXCR4-inhibiting polymers with a combination of beneficial features that included PEGylation, fluorination, and bioreducibility to achieve systemic delivery of siRNA to silence STAT3 expression in the tumors. An in vivo structure-activity relationship study in an experimental lung metastasis model revealed superior antimetastatic activity of bioreducible fluorinated polyplexes when compared with nonreducible controls despite similar CXCR4 antagonism and the ability to inhibit in vitro cancer cell invasion. When compared with nonreducible and nonfluorinated polyplexes, improved siRNA delivery was observed with the bioreducible fluorinated polyplexes. The improvement was ascribed to a combination of enhanced physical stability, decreased serum destabilization, and improved intracellular trafficking. Pharmacokinetic analysis showed that fluorination decreased the rate of renal clearance of the polyplexes and contributed to enhanced accumulation in the tumors. Therapeutic efficacy of the polyplexes with STAT3 siRNA was assessed in early stage breast cancer and late-stage metastatic breast cancer with primary tumor resection. Strong inhibition of the primary tumor growth and pronounced antimetastatic effects were observed in both models of metastatic breast cancer. Mechanistic studies revealed multifaceted mechanism of action of the combined STAT3 and CXCR4 inhibition by the developed polyplexes relying both on local and systemic effects.
Published Version
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