A pH-sensitive nanotherapeutic system based on a marine sulfated polysaccharide for the treatment of metastatic breast cancer through combining 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 PSS@DC 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. PSS@DC 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, PSS@DC nanoparticles notably inhibited the growth of mouse breast cancer 4T1 cells with an IC50 of about 0.82 μg/mL DOX, and meanwhile reduced cell migration, invasion and adhesion abilities more efficiently. In 4T1 tumor-bearing mice, PSS@DC nanoparticles exhibited good tumor-targeting ability and markedly inhibited tumor growth with an inhibition rate of approximately 73.3%, and furthermore suppressed tumor metastasis through anti-angiogenesis. In summary, this nanotherapeutic system shows a great potential for the treatment of metastatic breast cancer by combining chemotherapy and COX-2 inhibitor. Statement of Significance A pH-sensitive nanotherapeutic system (PSS@DC nanoparticles) containing both chemotherapeutic drug doxorubicin (DOX) and COX-2 specific inhibitor celecoxib was designed based on a marine sulfated polysaccharide that possesses anti-platelet aggregation activity and has been used as a heparinoid drug in China. PSS@DC nanoparticles had distinct pH-sensitivity and could accelerate the release of DOX at the acidic pH values of tumor microenvironment and endocytic-related organelles. Both in vitro and in vivo, PSS@DC nanoparticles showed synergistic effects on the suppression of breast tumor growth and metastasis by combining chemotherapy and COX-2 inhibition.