Programmed Nanococktail Based on pH-Responsive Function Switch for Self-Synergistic Tumor-Targeting Therapy

Abstract

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.

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

“…To endow the tumor-selective targeting capacity of small molecular anticancer drug MTX and seek its biomedical applications, an amphiphilic conjugate of DSPE-PEG-Imine-MTX was synthesized via the reductive amination reaction of Schiff's base between the aromatic amino group of MTX molecule and the aldehyde group of DSPE-PEG-CHO polymer. 39 The synthetic route of DSPE-PEG-Imine-MTX amphiphilic polymer prodrug is shown in Figure 1A. The chemical structure of DSPE-PEG-Imine-MTX was characterized by 1 H NMR spectroscopy, UV-vis spectrophotometer, X-ray diffractometer (XRD), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), and gel permeation chromatography (GPC), as shown in Figure S1.…”

“…47 Finally, DSPE-PEG-Imine-MTX was synthesized starting from DSPE-PEG-CHO lipopolymer and MTX molecule by reductive amination via Schiff's base formation. 39 DSPE-PEG-CHO (56.2 mg, 20 µmol) and MTX (13.6 mg, 30 µmol) were dissolved in 20 mL of DMSO/ chloroform in a round-bottom flask, and then a few drops of acetic acid were added to the flask with molecular sieves. The mixture was degassed through three freeze-pump-thaw procedures and made to react at 40°C for 48 h. The resultant product was evaporated and precipitated into excess dry, ice-cold ethyl ether and acetone (10:1) mixture.…”

Tetrac-decorated chitosan-coated PLGA nanoparticles as a new platform for targeted delivery of SN38

“…One of the attractive approaches to minimize the accumulation of chemotherapeutics in non-target organs is to benefit from targeted delivery systems using homing agents such as folic acid [2,3], transferrin [4], small chemical molecules [5], aptamers [6] and peptides [7]. Despite many promising findings reporting the efficient uptake and activity of simple targeted delivery systems, the extravasation of targeted agents from tumour vasculature to the parenchyma is still the ratelimiting stage for specific drug delivery [8].…”

Development of dual-drug-loaded stealth nanocarriers for targeted and synergistic anti-lung cancer efficacy

“…Many targeted approaches for MTX have been exploited to reduce adverse effects, improve bioavailability and maximize treatment effect (Jain et al, 2015 ; Farjadian et al, 2016 ; Guo et al, 2018 ; Liu et al, 2017 ). Earlier paper demonstrated that MTX-mediated nanoparticle drug delivery system would be a predominant targeted anticancer chemotherapeutic formulation (Chen et al, 2014 ; Li et al, 2017a , 2017b ; Singh & Subudhi, 2016 ).…”