Methotrexate Targeting Pro-drug Self-Assembling Nanoparticles for Combination Cancer Therapy

In order to achieve multi-chemotherapeutic drugs delivery and combination cancer therapy, the research team designed the acid-labile methotrexate (MTX) targeting pro-drug self-assembling nanoparticles loaded with curcumin (CUR) drug.

As an anticancer drug and also a tumor-targeting ligand, the dual-acting MTX was connected to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[aldehyde(polyethylene glycol)-2000] through Schiff’s base reaction. The synthesized pro-drug conjugate DSPE-PEG-Imine-MTX can be self-assembled into micellar nanoparticles MTX-Imine-M in aqueous solution, which encapsulated CUR into their core by hydrophobic interactions MTX-Imine-M-CUR.

The prepared MTX-Imine-M-CUR nanoparticles were composed of the inner hydrophobic DSPE/CUR core and the outer hydrophilic bishydroxyl polyethylene glycol (PEG) shell with a self-targeting MTX pro-drug corona. As a dynamic covalent bond, the imine linker between 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[aldehyde(polyethyleneglycol)-2000] and MTX was strong enough to remain integral in physiological pH, although it is rapidly cleaved in acidic pH. By the rapid intracellular CUR release and active form of MTX via the acidity of endosomes/lysosomes, the MTX and CUR can be co-delivered selectively and efficiently by the MTX-Imine-M-CUR into the cancer cells through folate receptor-mediated endocytosis.

Compared to pH-insensitive DSPE-PEGAmide-MTX assembling nanoparticles loaded with CUR (MTX-Amide-M-CUR), MTX unconjugated DSPE-PEG assembling micellar nanoparticles loaded with CUR (M-CUR), combination of both free drugs and individual free drugs, the MTX-Imine-M-CUR resulted in significantly higher in vitro and in vivo anticancer activity. Such nanosystem offered a simple and viable drug delivery strategy for targeted combination cancer therapy.

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