Nanopartículas pH-responsivas de goma do cajueiro para terapia combinada contra o câncer

Abstract

Cancer is a serious public health problem worldwide, and chemotherapy is considered the first-line approach in treating this disease. However, therapeutic effectiveness is limited by adverse events and the low bioavailability associated with chemotherapeutic agents. Combining two or more therapeutic agents represents an important strategy to enhance anticancer effects through synergistic actions and simultaneous accumulation in the tumor microenvironment. Polysaccharide-based pH-responsive prodrug nanocarriers show promise as co-delivery systems in cancer therapy. To demonstrate this, in this study, carboxymethyl cashew gum (CMCG) was successfully conjugated with curcumin (CUR) to form an acid-sensitive prodrug (CMCG-CUR). Paclitaxel (PTX) and resiquimod (R848) were then encapsulated in CMCG-CUR nanoparticles (CMCG-CUR/PTX and CMCG-CUR/R848) through non-covalent interactions. These nanoparticles were designed to promote the co-delivery of drugs to the tumor microenvironment. The structures of the prodrugs were confirmed by infrared spectroscopy and hydrogen nuclear magnetic resonance. Self-assembly into nanoparticles was observed using fluorescence spectroscopy, dynamic light scattering, and atomic force microscopy, indicating good dispersion and diameters below 200 nm. The drug loading values for CUR in the CMCG-CUR, CMCG-CUR/PTX, and CMCG-CUR/R848 nanoparticles were 7.0%, 3.0%, and 2.0%, respectively. The nanoparticles protected CUR from degradation and exhibited a controlled pH-responsive release profile. Furthermore, the CMCG-CUR and CMCG-CUR/PTX nanoparticles showed in vitro activity against CT-26 cells (murine colorectal carcinoma) and reduced cytotoxicity in non-tumor cells (RAW 264.7, murine macrophages), with a greater effect observed in the co-administration of CUR/PTX than the free drug. On the other hand, the CMCG-CUR/R848 nanoparticle showed no cytotoxicity in CT-26 cells but induced a proliferative effect in RAW 264.7 immune cells. The cell uptake study confirmed that the nanoparticles with CUR/PTX were absorbed by CT-26 cells, while those containing CUR/R848 were absorbed by RAW 264.7 cells. pH-responsive polysaccharide-based nanoparticles have shown promise for the selective and controlled co-delivery of drugs to the tumor microenvironment, with potential application in combination cancer therapies.