Sequential nanotheranostics based on hollow mesoporous silica loaded doxorubicin and seed kernel extract from Mangifera indica L. as adjuvant therapy against hepatocellular carcinoma.

Mango seed kernel extract (MSKE) and its phytochemical compositions were investigated for their anticancer activities and synergistic effects with doxorubicin (DOX) against hepatocellular carcinoma (HCC) in both 2D and 3D culture models. Molecular docking studies were conducted to elucidate the mechanisms of DOX, MSKE, and major phytochemical components against overexpressed HCC-related proteins. Co-delivery of DOX and MSKE demonstrated significant synergistic anticancer activity in both models. A sequential nanotheranostic platform (SNP), consisting of MSKE encapsulated aminated hollow mesoporous silica nanoparticles capped with graphene quantum dots (GQD-MSKE-NH(2)HMSNs) and DOX encapsulated HMSNs (DOX-HMSNs), was synthesized for HCC treatment. GQD conjugation allowed real-time cellular tracking and photothermal therapy (PTT). The SNP exhibited particle sizes of 96.12 ± 5.12 nm for GQD-MSKE-NH(2)HMSNs and 94.99 ± 6.30 nm for DOX-HMSNs, both with positive surface charges. Encapsulation efficiency (%EE) and loading capacity (%LC) of GQD-MSKE-NH(2)HMSNs were 95.50 ± 0.20% and 46.72 ± 1.14%, respectively, while DOX-HMSNs achieved 96.42 ± 2.48 %EE and 29.0 ± 0.70 %LC. GQD-MSKE-NH(2)HMSNs provided PTT and disrupted the tumor microenvironment, collagen type 1, thereby enhancing the penetration of GQD-MSKE-NH(2)HMSNs in 3D-HCC spheroids. In parallel, DOX-HMSNs exhibited a pH-responsive drug release behavior, allowing controlled DOX delivery in the acidic tumor area. Therefore, the SNP demonstrated significantly higher anticancer efficacy than the combination of MSKE and DOX at equivalent concentrations and provided the synergistic effect of the triple combination therapy (herbal adjuvant, PTT and chemotherapy) against HCC.