PEGylated Polymer Micelle-based Nitric Oxide (NO) Photodonor with NO-mediated Antitumor Activity

Abstract

PEGylated polymer micelles containing 4-nitro-3-trifluoromethylphenyl units within the core moiety were prepared, and their phototriggered nitric oxide (NO)-generating ability was confirmed by electron spin resonance (ESR) spin-trapping and the Griess method. These micelles were found to be capable of delivering exogenous NO into tumor cells in a photocontrolled manner and showed an NO-mediated antitumor effect, indicating the usability of this molecular system in NO-based tumor therapy.Nitric oxide (NO) is a free radical endogenously synthesized in the body and plays multiple physiological roles, including vasodilation, angiogenesis, neurotransmission, and immune response. Depending on its concentration and localization, NO has diverse biological functions.2 For example, NO can both promote and inhibit tumor progression depending on its local concentration. Relatively high concentrations of NO have been shown to inhibit tumor progression by promoting apoptosis.2 This means that a molecular system capable of site-specific delivery of a high amount of NO should be useful in antitumor treatment. Due to the poor bioavailability of NO, great efforts have been made to develop a methodology for the controlled delivery of exogenous NO in living systems.3 One promising approach is the exploitation of a photochemical process which can be spatiotemporally controlled by manipulating the incident light. Until now, various NO-photogenerative compounds (NO photodonors) have been developed and applied for the examination of photocontrolled NO delivery. 4,5 However, the development of NO photodonors with excellent water solubility, biocompatibility, and tumor specificity is still challenging. In this regard, we newly designed a PEGylated polymer micelle-based NO photodonor which contains NO photogenerative units in the core moiety. It is well recognized that PEGylated polymer micelles several tens of nanometers in size are potent carriers of various therapeutics agents.6 They show high colloidal stability under physiological conditions and preferentially accumulate in solid tumors by the enhanced permeation and retention (EPR) effect.7 Here, we wish to communicate the preparation of a PEGylated polymer micelle-based NO photodonor and its potential for NO-based therapeutic application.The PEG-based amphiphilic block copolymer used in this study [PEG-b-PNTP (PEG: 5000 g mol ¹1, PNTP: 3600 g mol ¹1 , DP PNTP (n) = 11] in Figure 1) was synthesized via conjugation between PEG-b-poly(4-chloromethylstyrene) 8 and 4-nitro-3-trifluoromethylphenol (NTP) in the presence of potassium carbonate. 9Nitrobenzene derivatives having bulky substituents at the orthoposition are known to generate NO upon appropriate light irradiation though a nitro-to-nitrite photorearrangement followed by the rupture of the ONO bond (Figure 1). 5 Micellization of PEGb-PNTP was carried out by dialysis. The hydrodynamic diameter and polydispersity index (PDI) of the resulting micelles (ND micelles) were determined by dynamic light scattering to be 42.3 nm and 0....

Nitric oxide and cancer: a review

“…Kanayama et al [115] reported that PEGylated polymer micelles may be capable of delivering exogenous NO to tumor cells in a photocontrolled manner, resulting in an NO-mediated antitumor effect, which indicates the promise of this polymeric system in NO-based tumor therapy. Friedman et al reported that therapeutic levels of NO, in controlled and sustained manner, can be achieved by using combination of glassy matrices and hydrogels [116].…”

Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO)

“…To improve the NO payload and stability, achieve targeted NO delivery through multi-functionalization and elongate NO releasing lifetime, many different scaffolds have been used as NO-releasing or NO-generating vehicles. These include micelles, 138,190,191 microbubbles, 192 proteins, 193–197 liposomes, 126,198 inorganic nanoparticles (such as silica, 70,199–203 gold, 204,205 microparticles, 198,206 zeolites, 207,208 ), metal-organic frameworks (MOFs), 209–212 dendrimers, 71,213,214 xerogels, 215–217 electrospun fibers, 88,100,218 natural polymers (chitosan, 85–87,219–221 gelatin, 222 etc. ), and other organic polymers (polymethacrylate, 223 polyester, 224,225 polydimethylsiloxane (PDMS), 226 polysaccharides, 227,228 hydrogel, 178,179,229,230 PVA, 49,231,232 polyurethanes, 161,162,233,234 and PVC 154 ).…”

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

“…NO is considered to be a promising ideal drug that not only exerts therapeutic effects, but also minimizes side effects because of its endogenous presence in vivo and rapid transformation into innocuous ions within six seconds or less after its action, as contrasted with other chemotherapeutics and nucleotide drugs [27–34]. Accordingly, numerous NO-donors defined as NO-releasing functional moieties or small molecule drugs have been developed and applied to biomaterials for evaluation as therapeutic modalities [29–38]. As the complicated functions of NO are highly dependent on its concentration and duration [28], NO delivery systems that can deliver NO donors to the target sites and control the NO release are prerequisite to realize the full potential of NO [34].…”

“…Direct killing of cancer cells can be achieved with high concentration of NO (µM-mM) [35–38], however, its practical applications are limited due to the poor bioavailability of NO-donors with low NO capacity and instability during storage and systemic circulation. On the other hand, broad ranges of NO concentrations have shown chemosensitizing effect to reverse MDR, which has recently inspired researchers to develop combined NO and drug delivery systems.…”