Albumin Nanocages with Methotrexate and Chondroitin Sulfate as a Dual pH/GSH-Responsive Tumor Targeting Nanomedicine for Synergistic Cancer Therapy

Cancer is a devastating disease, and its pathogenesis is highly associated with malnutrition and poor lifestyle. Chemotherapy continuously causes inadequate therapeutic efficacy and induces off-target toxicities. Hence, targeted co-administration of chemotherapy and dietary supplement producing anticancer effect at low doses with minimized toxicities would be a promising strategy for cancer treatment. In this study, we constructed chondroitin sulfate (CS) and methotrexate (MTX) carried serum albumin nanocages (C/M@Alb NCs) by albumin nanoreactor strategy. During fabrication, we achieved the precipitation of MTX and CS inside the albumin nanocore under mild reaction condition to prepare C/M@Alb NCs. The enhanced anticancer efficacy of C/M@Alb NCs was comprehensively assessed by in vitro and in vivo experiments. Biodistribution, pharmacokinetic profile, and in vivo therapeutic efficacy of C/M@Alb NCs were investigated in human colorectal adenocarcinoma (HT-29), murine breast cancer (E0071), and patient-derived (PDX) lung cancer models. The as-prepared C/M@Alb NCs facilitated higher MTX and CS encapsulation, exhibiting small particle size, improved colloidal stability, dual stimuli (pH/GSH)-responsive drug release profile, an enhanced cellular uptake, cooperative synergistic cytotoxicity, extended blood residence time, improved lymph node and tumor targeting, and in vivo therapeutic efficacy against various cancers such as human colorectal adenocarcinoma, murine breast cancer, and patient-derived (PDX) lung cancer. Altogether, C/M@Alb NCs exhibited enhanced cellular uptake, extended blood residence time, and favorable tumor accumulation and lymph node extravasation, finally leading to the potent antitumor efficacy against various cancers. This nanoplatform offers a new strategy for designing lymph node- and cancer-targeted albumin-based nanomedicine for clinical applications.