Tumor-targeting
combination chemotherapy is an important way to improve the therapeutic index and reduce the side effects as compared to traditional
cancer treatments. However, one of the major challenges in surface functionalization of nanoparticle (NP) is accomplishing multiple purposes through one single
ligand. Upon such consideration,
methotrexate (MTX), an anticancer drug with a targeting moiety inspired by the similar structure of
folate, could be used to covalently link with
lipid-
polymer conjugate (
DSPE-PEG) via a pH-sensitive dynamic covalent
imine (CH═N) bond to synthesize the
acid-induced function "targeting-anticancer" switching
DSPE-PEG-CH═N-MTX. We hypothesize that using this kind of MTX
prodrug to functionalize NP's surface would be conductive to combine the early phase active targeting function and the late-phase anticancer function in one nanosystem. Herein, a nanococktail is programmed for codelivery of
epirubicin (EPI) and MTX by co-self-assembly of
acid-dissociated EPI-
phospholipid (PC) complex and
acid-cleavable
DSPE-PEG-CH═N-MTX conjugate. The obtained nanococktail (MTX-PEG-EPI-PC NPs) could not only actively target
folate receptors-overexpressing
tumor cells but also respond to acidic endo/lysosomes for triggering the on-demand release of pharmaceutically active EPI/MTX. The intracellular drug distribution also demonstrated that the system could codeliver two drugs to individual target sites of action, inducing the significant synergistic anticancer efficiency based on different anticancer mechanisms. More importantly, the in vivo
tumor accumulation and anticancer efficacy of MTX-PEG-EPI-PC NPs (via cleavable
imine bond) were significantly enhanced as compared to the individual free drug, both free drugs, PEG-EPI-PC NPs, and MTX-PEG-EPI-PC NPs (via the uncleavable
amide bond). This self-synergistic
tumor-targeting
therapy might represent a promising strategy for
cancer treatment.