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

• Published in: International journal of nanomedicine Vol. 13; pp. 1381 - 1398
• Main Authors: Xie, Jiajiang, Fan, Zhongxiong, Li, Yang, Zhang, Yinying, Yu, Fei, Su, Guanghao, Xie, Liya, Hou, Zhenqing
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2018; Taylor & Francis Ltd; Dove Medical Press
• Subjects: Acids; Aldehydes; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomedical engineering; Bonds (Securities); Cancer; Cancer cells; Cancer therapies; Cell cycle; Cell Death - drug effects; Chemotherapy; Colloids; Combination drug therapy; combination therapy; Curcumin - chemistry; Curcumin - pharmacology; Curcumin - therapeutic use; Dihydrofolate reductase; Drug Carriers - chemistry; Drug delivery systems; Drug Delivery Systems - methods; Drug Liberation; Drug therapy; Drugs; Endocytosis - drug effects; Folic acid; Glycols (Class of compounds); Health aspects; HeLa Cells; Humans; Hydrodynamics; Hydrogen-Ion Concentration; Laboratories; Lipids; MCF-7 Cells; Methotrexate; Methotrexate - pharmacology; Methotrexate - therapeutic use; Mice, Inbred BALB C; Mice, Nude; Micelles; Nanoparticles; Nanoparticles - chemistry; Neoplasms - drug therapy; Neoplasms - pathology; Original Research; Particle Size; Permeability; pH-sensitive prodrug; Phosphatidylethanolamines - chemical synthesis; Phosphatidylethanolamines - chemistry; Physiological aspects; Physiology; Polyethylene glycol; Polyethylene Glycols - chemical synthesis; Polyethylene Glycols - chemistry; Polymers; Polyols; Prodrugs - pharmacology; Prodrugs - therapeutic use; self-assembly; targeting; Tumors; Vitamin B; United States > US; China; self-assembly; combination therapy; targeting; nanoparticles; pH-sensitive prodrug
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S152312

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. 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). 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. The smart system provided a simple, yet feasible, drug delivery strategy for targeted combination chemotherapy.