Design of pH-sensitive methotrexate prodrug-targeted curcumin nanoparticles for efficient dual-drug delivery and combination cancer therapy

Design of pH-sensitive methotrexate prodrug-targeted curcumin nanoparticles for efficient dual-drug delivery and combination cancer therapy Jiajiang Xie,1,2,* Zhongxiong Fan,2,* Yang Li,2,* Yinying Zhang,2 Fei Yu,3 Guanghao Su,4 Liya Xie,5 Zhenqing Hou2 1Xiamen Xianyue Hospital, Xiamen, China; 2Research Center of Biomedical Engineering of Xiamen, Key Laboratory of Biomedical Engineering of Fujian Province, Fujian Provincial Key Laboratory for Soft Functional Materials Research, Department of Biomaterials, College of Materials, Xiamen University, Xiamen, China; 3College of Medicals, Xiamen University, Xiamen, China; 4Children's Hospital of Soochow University, Suzhou, China; 5The First Affiliated Hospital of Xiamen University, Xiamen, China *These authors contributed equally to this work Aim: We designed acid-labile methotrexate (MTX) targeting prodrug self-assembling nanoparticles loaded with curcumin (CUR) drug for simultaneous delivery of multi-chemotherapeutic drugs and combination cancer therapy. Methods: A dual-acting MTX, acting as both an anticancer drug and as a tumor-targeting ligand, was coupled to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[aldehyde(polyethylene glycol)-2000] via Schiff's base reaction. The synthesized prodrug conjugate (DSPE-PEG-Imine-MTX) could 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). Results: The prepared MTX-Imine-M-CUR nanoparticles were composed of an inner hydrophobic DSPE/CUR core and an outside hydrophilic bishydroxyl poly (ethyleneglycol) (PEG) shell with a self-targeting MTX prodrug corona. The imine linker between 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[aldehyde(polyethyleneglycol)-2000] and MTX, as a dynamic covalent bond, was strong enough to remain intact in physiological pH, even though it is rapidly cleaved in acidic pH. The MTX-Imine-M-CUR could codeliver MTX and CUR selectively and efficiently into the cancer cells via folate receptor-mediated endocytosis followed by the rapid intracellular release of CUR and the active form of MTX via the acidity of endosomes/lysosomes. Moreover, the MTX-Imine-M-CUR resulted in significantly higher in vitro and in vivo anticancer activity than 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. Conclusion: The smart system provided a simple, yet feasible, drug delivery strategy for targeted combination chemotherapy. Keywords: pH-sensitive prodrug, self-assembly, targeting, combination therapy, nanoparticles