PH-Sensitive Nanotherapeutic System Based on a Marine Sulfated Polysaccharide for Treatment of Metastatic Breast Cancer Through Combing Chemotherapy and COX-2 Inhibition

Abstract

Metastasis and chemotherapy resistance are the leading causes of breast cancer mortality. Celecoxib (CXB), a selective cyclooxygenase-2 (COX-2) inhibitor, has antiangiogenetic activity and inhibitory effect on tumor metastasis, and can also enhance the sensitivity of chemotherapeutic drug doxorubicin (DOX) in breast cancer. To combine anticancer effects of DOX and CXB more efficiently, we designed a pH-sensitive nanotherapeutic system based on propylene glycol alginate sodium sulfate (PSS), a marine sulfated polysaccharide that possesses anti-platelet aggregation activity and has been used as a heparinoid drug in China. A facile one-pot nanoprecipitation method was used to prepare this nanotherapeutic system named as PDC nanoparticles, in which DOX and CXB were complexed to form hydrophobic nanocores and PPS coated these nanocores through conjugation with DOX via a highly acid-labile benzoic-imine linker. PDC nanoparticles showed distinct pH-sensitivity and significantly accelerated the release of DOX at the acidic pH mimicking the tumor microenvironment and endocytic-related organelles. Compared to single- and mixed-drug treatments, PDC nanoparticles notably inhibited the growth of mouse breast cancer 4T1 cells and reduced cell migration, invasion and adhesion abilities. In 4T1 tumor-bearing mice, PDC nanoparticles exhibited good tumor-targeting ability and markedly suppressed the tumor growth and metastasis. In summary, this nanotherapeutic system shows a great potential for clinical treatment of metastatic breast cancer by combining chemotherapy and COX-2 inhibitor.