Combination of nitric oxide and drug delivery systems: tools for overcoming drug resistance in chemotherapy

Abstract

Chemotherapeutic drugs have made significant contributions to anticancer therapy, along with other therapeutic methods including surgery and radiotherapy over the past century. However, multidrug resistance (MDR) of cancer cells has remained as a significant obstacle in the achievement of efficient chemotherapy. Recently, there has been increasing evidence for the potential function of nitric oxide (NO) to overcome MDR. NO is an endogenous and biocompatible molecule, contrasting with other potentially toxic chemosensitizing agents that reverse MDR effects, which has raised expectations in the development of efficient therapeutics with low side effects. In particular, nanoparticle-based drug delivery systems not only facilitate the delivery of multiple therapeutic agents, but also help bypass MDR pathways, which are conducive for the efficient delivery of NO and anticancer drugs, simultaneously. Therefore, this review will discuss the mechanism of NO in overcoming MDR and recent progress of combined NO and drug delivery systems.

Keywords: Cancer; Chemosensitization; Multidrug resistance (MDR); Nanoparticle; Nitric oxide (NO) donor.

Figure 1

Schematic summarizes the potential mechanisms of NO in overcoming MDR.

Figure 2

Schematic illustration of the development of NO-releasing mineralized nanoparticles. The pretreatment of this NO delivery system enhances the chemotherapy efficacy. Reprinted with permission from [62]. Copyright 2016, Elsevier.

Figure 3

Combined NO and drug delivery system that was first evaluated in vivo. DOX is loaded into the micelles comprised of D-α-tocopheryl polyethylene glycol succinate (TPGS) with the NO-releasing nitrate (-ONO₂). The nanoparticles showed enhanced anticancer effects in vivo compared to the control groups. Reprinted with permission from [66]. Copyright 2014, American Chemical Society.

Figure 4

Schematic illustration of the synthesis of combined NO and drug delivery system utilizing cisplatin and diazeniumdiolate-modified MSN. Reprinted with permission from [68]. Copyright 2015, Elsevier.

Figure 5

The composition of microparticles for combined NO and drug delivery and its therapeutic mechanism. The PLGA shell of the microparticle contains CPT-11 and DETA-NONOate. The tumor’s acidic pH induces the release of NO that forms defects on the shell of the microparticle to allow for drug release. In addition, the NO inhibits the expression of Pgp, which reverses the MDR effects. Reprinted with permission from [69]. Copyright 2015, WILEY-VCH Verlag GmbH & Co. KGaA.

Figure 6

Schematic diagram of mPEG-PLGA-BNN6-DOX and its mechanism of drug release. The UV irradiation not only elicits NO release, but also induces defects in the nanoparticle. The NO inhibits the ABC transporter that effluxes anticancer drugs, which potentiates the effects of chemotherapy. Reprinted with permission from [70]. Copyright 2016, American Chemical Society.