1 research outputs found
Programmed Nanococktail Based on pH-Responsive Function Switch for Self-Synergistic Tumor-Targeting Therapy
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 (CHî—»N)
bond to synthesize the acid-induced function “targeting-anticancer”
switching DSPE-PEG-CHî—»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-CHî—»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