Hyaluronic acid (HA)-coated naproxen-nanoparticles selectively target breast cancer stem cells through COX-independent pathways

• Published in: Materials Science & Engineering C Vol. 124; p. 112024
• Main Authors: Espinosa-Cano, Eva, Huerta-Madroñal, Miguel, Cámara-Sánchez, Patricia, Seras-Franzoso, Joaquin, Schwartz, Simo, Abasolo, Ibane, San Román, Julio, Aguilar, Maria Rosa
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2021; Elsevier BV
• Subjects: Anti-inflammatory agents; Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Breast cancer; Breast Neoplasms - drug therapy; Cancer stem cells; Carcinogenesis; Carcinogens; Cationic polymerization; CD44; Cell Line, Tumor; Cell viability; Chemotherapy; Coatings; Cytotoxicity; Electrostatic properties; Endothelial Cells; Glycogen Synthase Kinase 3 beta; Humans; Hyaluronan Receptors; Hyaluronic Acid; Inflammation; Ionic strength; Leukocyte migration; Macrophages; Materials science; Metastases; Metastasis; Nanoparticle; Nanoparticles; Naproxen; Naproxen - pharmacology; Neoplastic Stem Cells; Nonsteroidal anti-inflammatory drugs; Self-assembly; Stem cells; Wounds; Breast cancer; Cancer stem cells; Hyaluronic acid; Nanoparticle; Naproxen; CD44
• ISSN: 0928-4931; 1873-0191
• DOI: 10.1016/j.msec.2021.112024

Cytotoxic chemotherapy continues to be the main therapeutic option for patients with metastatic breast cancer. Several studies have reported a significant association between chronic inflammation, carcinogenesis and the presence of cancer stem cells (CSC). We hypothesized that the use of non-steroidal anti-inflammatory drugs targeted to the CSC population could help reducing tumor progression and dissemination in otherwise hard to treat metastatic breast cancer. Within this study cationic naproxen (NAP)-bearing polymeric nanoparticles (NPs) were obtained by self-assembly and they were coated with hyaluronic acid (HA) via electrostatic interaction. HA-coated and uncoated NAP-bearing NPs with different sizes were produced by changing the ionic strength of the aqueous preparation solutions (i.e. 300 and 350 nm or 100 and 130 nm in diameter, respectively). HA-NPs were fully characterized in terms of physicochemical parameters and biological response in cancer cells, macrophages and endothelial cells. Our results revealed that HA-coating of NPs provided a better control in NAP release and improved their hemocompatibility, while ensuring a strong CSC-targeting in MCF-7 breast cancer cells. Furthermore, the best polymeric NPs formulation significantly (p < 0.001) reduced MCF-7 cells viability when compared to free drug (i.e. 45 ± 6% for S-HA-NPs and 87 ± 10% for free NAP) by p53-dependent induction of apoptosis; and the migration of these cell line was also significantly (p < 0.01) reduced by the nano-formulated NAP (i.e. 76.4% of open wound for S-HA-NPs and 61.6% of open wound for NAP). This increased anti-cancer activity of HA-NAP-NPs might be related to the induction of apoptosis through alterations of the GSK-3β-related COX-independent pathway. Overall, these findings suggest that the HA-NAP-NPs have the potential to improve the treatment of advanced breast cancer by increasing the anti-proliferative effect of NAP within the CSC subpopulation. •HA-coated nanoparticles bearing naproxen were synthesized.•HA-coated nanoparticles presented higher stability and improved hemocompatibility.•HA-coated nanoparticles demonstrated selective targeting towards CD44-overexpressing cells.•HA-coated nanoparticles demonstrated pro-apoptotic and anti-migratory activity.•Anti-cancer activity could be due to the induction of apoptosis through COX-independent pathways.