Co-Delivery of Trichosanthin and Albendazole by Nano-Self-Assembly for Overcoming Tumor Multidrug-Resistance and Metastasis.

Abstract

Multidrug resistance (MDR) and metastasis are the major obstacles in cancer chemotherapy. Nanotechnology-based combination therapy is a useful strategy. Recently, the combination of biologics and small drugs has attracted much attention in cancer therapy. Yet, the treatment outcomes are often compromised by the different pharmacokinetic profiles of the co-administered drugs thus leading to inconsistent drug uptake and suboptimal drug combination at the tumor sites. Nanotechnology-based co-delivery offers a promising method to address this problem, which is well demonstrated in the use of small drug combinations. However, co-delivery of the drugs bearing different physicochemical properties (e.g., proteins and small drugs) remains a formidable challenge. Herein, we developed a self-assembled nanosystem for co-delivery of trichosanthin (TCS) protein and albendazole (ABZ) as a combination therapy for overcoming MDR and metastasis. TCS is a ribosome-inactivating protein with high antitumor activity. However, the druggability of TCS is poor due to its short half-life, lack of tumor-specific action, and low cell uptake. ABZ is a clinically used antihelmintic drug, which can also inhibit tubulin polymerization and thus serve as a potential antitumor drug. In our work, ABZ was encapsulated in the albumin-coated silver nanoparticles (termed ABZ@BSA/Ag NP). The thus-formed NPs were negatively charged and could tightly bind with the cationic TCS that was modified with a cell-penetrating peptide (CPP) low-molecular-weight protamine (termed rTL). Via the stable charge interaction, the nanosystem (rTL/ABZ@BSA/Ag NP) was self-assembled, and featured by the TCS corona. The co-delivery system efficiently inhibited the proliferation of the drug-resistant tumor cells (A549/T and HCT8/ADR) by impairing the cytoskeleton, arresting the cell cycle, and enhancing apoptosis. In addition, the migration and invasion of tumor cells were inhibited presumably due to the impeded cytoskeleton functions. The anti-MDR effect was further confirmed by the in vivo studies with the subcutaneous A549/T tumor mouse model. More importantly, the co-delivery system was demonstrated to be able to inhibit metastasis. The co-delivery system of TCS/ABZ provided a potential strategy for both overcoming drug resistance and inhibiting tumor metastasis.