Dexamethasone Pretreatment Potentiates a Folic Acid-Functionalized Delivery System for Enhanced Lung Cancer Therapy

Folic acid (FA) has been widely engineered to promote the targeted delivery of FA-modified nanoparticles (NPs) by recognizing the folate receptor alpha (FR alpha). However, the efficacy of FA-targeted therapy significantly varied with the abundance of FR alpha and natural immunoglobulin levels in different tumors. Therefore, a sequential therapy of dexamethasone (Dex)-induced FR alpha amplification and immunosuppression combined with FA-functionalized doxorubicin (DOX) micelles to synergistically suppress tumor proliferation was proposed in this study. In brief, a pH/reduction-responsive FA-functionalized micelle (FCSD) was obtained by grafting FA, derivatization-modified cholesterol, and 2,3-dimethylmaleic anhydride onto a chitosan oligosaccharide. The obtained FCSD/DOX NPs can effectively deliver DOX in tumors, and their targeting efficiency can be further improved with Dex pretreatment to decrease the immunoglobulin M (IgM) content in serum and amplify FR alpha levels on the surface of M109 cells. After internalization, charge reversal and disulfide bond breakage of FCSD vectors under the stimulation of tumor extracellular pH (pHe) and intracellular glutathione (GSH) would contribute to the disintegration of vectors and the rapid release of DOX. The sequential therapy that combined Dex pretreatment and targeted chemotherapy by FCSD/DOX NPs demonstrated superior tumor suppression compared with monotherapy, which is expected to provide a potential strategy for FR alpha-positive lung cancer patients.