Nanodrug Formed by Coassembly of Dual Anticancer Drugs to Inhibit Cancer Cell Drug Resistance

Abstract

Carrier-free pure nanodrugs (PNDs) that are composed entirely of pharmaceutically active molecules are regarded as promising candidates to be the next generation of drug formulations and are mainly formulated from supramolecular self-assembly of drug molecules. It benefits from the efficient use of drug compounds with poor aqueous solubility and takes advantage of nanoscale drug delivery systems. Here, a type of all-in-one nanoparticle consisting of multiple drugs with enhanced synergistic antiproliferation efficiency against drug-resistant cancer cells has been created. To nanoparticulate the anticancer drugs, 10-hydroxycamptothecin (HCPT) and doxorubicin (DOX) were chosen as a typical model. The resulting HD nanoparticles (HD NPs) were formulated by a “green” and convenient self-assembling method, and the water-solubility of 10-hydroxycamptothecin (HCPT) was improved 50-fold after nanosizing by coassembly with DOX. The formation process was studied by observing the morphological changes at various reaction times and molar ratios of DOX to HCPT. Molecular dynamics (MD) simulations showed that DOX molecules tend to assemble around HCPT molecules through intermolecular forces. With the advantage of nanosizing, HD NPs could improve the intracellular drug retention of DOX to as much as 2-fold in drug-resistant cancer cells (MCF-7R). As a dual-drug-loaded nanoformulation, HD NPs effectively enhanced drug cytotoxicity to drug-resistant cancer cells. The combination of HCPT and DOX exhibited a synergistic effect as the nanosized HD NPs improved drug retention in drug-resistant cancer cells against P-gp efflux in MCF-7R cells. Furthermore, colony forming assays were applied to evaluate long-term inhibition of cancer cell proliferation, and these assays confirmed the greatly improved cytotoxicity of HD NPs in drug-resistant cells compared to free drugs.

Nanoformulations for combination or cascade anticancer therapy

“…The combinatory drugs are mainly formulated from supramolecular self-assembly of drug molecules [105]. For example, DOX has the characteristic structure of a surfactant with the unsaturated anthracycline rings acting as the hydrophobic part and the saturated end of the ring system as a hydrophilic part.…”

“…HCPT molecules are also hydrophobic; therefore, Zhao et al have shown that DOX could potentially be used for solubilizing and nanosizing HCPT through hydrophobic-hydrophobic interaction. Indeed, the water-solubility of HCPT was improved 50-fold after co-assembly with DOX [105]. The intermolecular forces or hydrophobic interaction between combinatory drug moieties were not only observed in these carrier-free pure nanodrugs but also when loading simultaneously in one polymeric micelles or particles (formulations described in section 3.1) [9, 106].…”

A green approach to dual-drug nanoformulations with targeting and synergistic effects for cancer therapy

“…Its nanocrystalline form, protected by surfactants or polymers, was obtainable in an anti-solvent precipitation process with water as an anti-solvent in previous studies Yang et al, 2015;Zhao et al, 2015). For instance, our recent study showed that a membrane emulsifier-assisted anti-solvent precipitation could be employed for integration of HCPT nanoneedles with a polymer layer to achieve comet-shaped microparticles with the sustained release property (Yang et al, 2015).…”

A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy

“…SMND includes amphiphilic self-assembly nanodrug, [1][2][3] nanocrystallized or template-assisted nanodrug, [4][5][6][7] disulfide-induced self-assembled nanodrug, [8][9][10] and so on. It has attracted great interest as a desirable strategy, because of its unique properties in increased chemical stability and solubility, high drug loading, economical fabrication, relative "green" nanoformulation.…”