Self-assembly of multifunctional integrated nanoparticles loaded with a methotrexate-phospholipid complex: combining simplicity and efficacy in both targeting and anticancer effects

Recently, the global trend in the field of nanomedicine has been toward the design of highly sophisticated drug delivery systems with active targeting and therapeutic functions, as well as responsiveness to biological stimuli for improving therapeutic efficacy. But offering sophistication generally increases their complexity that might be disadvantageous in pharmaceutical development. In this paper, we hypothesize that using a clinical anticancer drug methotrexate (MTX) as both a targeting ligand and a therapeutic agent to interact with natural product phospholipid (PC) and thus self-assemble will lead to an efficient but simple and flexible, moreover, multifunctional integrated system. The methotrexate (MTX)-phospholipid (PC) complex is prepared by a co-solvent method and can be self-assembled into nanoparticles (MTX-PC NPs), which significantly increases the drug-loading ability and reduces the burst drug release compared with free MTX and MTX-loaded liposomes. The MTX-PC complex and its self-assembled MTX-PC NPs were evaluated by UV, TGA, DSC, XRD, FTIR, H-1-NMR, SEM, TEM, AFM, and in an in vitro drug release study. The MTX-PC NPs had a particle size of 152.5 +/- 3.2 nm, a narrow size distribution, a high drug-loading efficiency of 20.7 +/- 2.4%, and a controlled and sustained release behavior. The in vitro cellular uptake results showed that a vital advantage of this system is that MTX-PC NPs with pH-triggered drug release can exert an early-phase good active targeting efficiency (attributed to the surface-absorbed MTX) cooperating with a late-phase excellent anticancer efficiency (was attributed to the core-dispersed MTX). The concept of the self-targeted anticancer effect based on drug-lipid hybrid systems might be a promising candidate for cancer therapy compared with traditional drug delivery systems.