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.Keywords: albendazole; albumin nanoparticles; metastasis; Multidrug resistance; silver nanoparticles; trichosanthin;

To evaluate the effect of borneol on the brain targeting efficiency of aprotinin-conjugated poly (ethyleneglycol)–poly (L-lactic-co-glycolic acid) nanoparticles (Apr-NP) and the activity of huperzine A (Hup A) loaded nanoparticles to AD rats .Apr-NP was prepared by emulsion and solvent evaporation method. The uptake of Apr-NP alone or combined with borneol by brain capillary endothelial cells (BCECs) was evaluated by incorporating coumarin-6 as a tracer. In vivo imaging and the distribution of Hup A in the brain were measured to investigate the brain delivery of Apr-NP in rats, with or without the oral administration of borneol. Morris water maze was used to evaluate the memory improvement effect of Hup A loaded nanoparticles (Apr-NP-Hup).Co-incubation with borneol could increase the uptake of nanoparticles by BCECs. Nanoparticles delivered into the rat brain were enhanced significantly by the co-administration of borneol. The pharmacological effects of Hup A loaded nanoparticles on improving the memory impairment of AD rats were greatly improved when combined with borneol.Borneol is a promising enhancer for brain-targeting delivery systems. When co-administered with aprotinin-modified nanoparticles, borneol could improve the brain targeting efficiency of nanoparticles significantly.

Effective targeting drug delivery for cancer therapy still remains a formidable challenge due to the complication and heterogeneity of malignant tumors. Herein, a multifunctional targeting strategy was proposed, in which a novel pH-sensitive polymethacrylates (PMA)-grafted poly(amidoamine) (PAMAM) nano delivery system was designed to be responsive to the acidic tumor microenvironment, and thereby trigger drug release in the intra-tumoral space. In addition, folate-PEGylation was applied to modify the surface of PMA-PAMAM nanoparticles in order to enhance tumor selectivity via both active and passive targeting mechanisms: folate receptor targeting, long circulation and EPR effect. The utility and efficacy of such system was demonstrated both in vitro and in vivo. Tumor drug accumulation was significantly enhanced by folate-PEGylated PMA-PAMAM nanoparticles, and such observation corresponded to their strong inhibition of tumor growth in tumor-bearing mice, demonstrating the success of the multifunctional targeting delivery. This multifunctional targeting strategy provides a promising solution to improve targeting drug delivery for combating the complex cancer diseases.