ROS-Responsive Drug Delivery Systems

As another important redox-sensitive nanoDDS, ROS-responsive nanosystems are expected to stabilize the drug at the physiological condition and rapidly release the drug in response to ROS (Fig. 4.3). In order to achieve such goals, several ROS-responsive drug delivery strategies have been investigated. One approach is to introduce the functional groups, such as PPS, to nanomaterials as the "solubility switch." These groups undergo phase transition from hydrophobicity to hydrophilicity in the oxidative environment. Another approach is to use the "ROS-induced degradation" to control drug release. This can be done either by covalent attachment of drug molecules to the existing nanocarriers or by constructing new ROS-responsive nanocarriers for physical drug loading. In this part, both strategies will be discussed (Table 4.2).

Schematic of ROS-responsive drug release via the solubility switch or degradation

Figure 4.3 Schematic of ROS-responsive drug release via the solubility switch or degradation.

ROS-Responsive “Solubility Switch” Nanomedicines

Poly (propylene sulfide) containing nanomaterials

Polypropylene sulfide) is susceptible to ROS oxidation. This organic sulfide undergoes phase transition from the hydrophobic sulfide to hydrophilic sulfoxide or sulfone in oxidative environment [69].

Table 4.2 Representative ROS-responsive polymeric materials and their mechanisms

ROS-responsive

materials

Mechanisms

Ref.

ROS-induced solubility

Polypropylene

sulfide)

[70,71]

Selenium

[72, 73]

Tellurium

[74, 75]

ROS-induced degradation

Phenylboronic

acid

[76, 77]

Proline

oligomers

[78]

Polythioketal

[79,80]

This unique property makes it a promising candidate for the preparation of ROS-sensitive DDS [13]. In an early study, Hubbell et al. developed the oxidation-responsive polymeric vesicles based on the ABA block polymers of PEG and PPS [81]. The copolymer self-assembled into stable vesicles in aqueous solution at room temperature; however, after treating with H202, the most prevalent ROS in biological systems, the assembled vesicles underwent destabilization.

In a similar work, Dai and coworkers developed the ROS- sensitive polymeric micelles with an average diameter of 80 nm based on an amphiphilic polymer of polypropylene sulfide)- polyethylene glycol-serine-folic acid (PPS-mPEG-Ser-FA) [71], for co-loading of the photosensitizer, zinc phthalocyanine (ZNPC), and anticancer drug DOX. The endocytosed ZNPC could generate high concentration of ROS when exposed to laser irradiation to compensate the relatively low intracellular ROS concentration (50-100 mM) and disassemble the micelles (DOX release) via the ROS-induced hydrophobic to hydrophilic transition of the PPS core. Furthermore, high ROS concentration produced by ZNPC could efficiently kill tumor cells. Zhu laboratory conjugated the anticancer drug 7-ethyl-10-hydroxy-camptothecin (SN38) with hyperbranched polyglycerol (HPG) via a H202 responsive thioether bond to form HPG-2S-SN38 which could self-assemble into stable nanomicelles for encapsulating the cinnamaldehyde (CA). In this system, the thioether was easily oxidized in response to the oxidative condition, leading to the H202 dependent release of CA and SN38. Moreover, ROS production induced by the released CA not only facilitated the tumor cells apoptosis but also promoted the breakdown of micellar structure, thereby synergistically exerting an anti-tumor effect with SN38 [82].

Selenium containing nanomaterials

Another commonly used ROS responsive DDS is based on selenium containing compounds which are known for their oxidation and reduction dual sensitivity [72, 73]. Similar to the use of sulfide groups in the PPS to achieve the hydrophobic to hydrophilic transition, water-insoluble selenides are able to be oxidized to hydrophilic selenoxides and selenones. In addition, selenium- containing materials have a relatively higher sensitivity to oxidation due to weaker energy of the C-Se bond compared to that of the C-S bond [83].

A series of ROS-sensitive selenium-containing nanomedicines developed by Zhang's group could serve as good examples [84, 85]. In their works, the selenium-containing amphiphilic triblock copolymer (PEG-PUSe-PEG) was synthesized [84]. The copolymer could self-assemble into nanomicelles for loading of

DOX and be oxidized by ROS. 72% of DOX was released from the PEG-PUSe-PEG micelles in 10 h when exposed to 0.1% H202, while 41% of DOX was released from the PEG-PU micelles (nonsensitive micelles) in the same condition. In addition, a selenium-containing surfactant, phenylselenide-l-undecyl triethylammonium bromide (SeQTA) was prepared for fabrication of the polymeric superamphiphile via the electrostatic interaction between the surfactant and the hydrophilic polyethylene glycol)-b/oc/c-acrylic acid (PEG-b-PAA) copolymer [86]. Owing to the oxidation sensitivity of SeQTA, the micelles underwent the disassembly and released the cargos under mild oxidation (0.1% H202).

Additionally, Se-Se bonds could either be oxidized to seleninic acid in the presence of oxidants (0.01% ROS) or reduced to selenol in the reducing environment (0.01% GSH). Inspired by the unique dual responsive nature, Zhang et al. developed a diselenide-containing triblock copolymer (PEG-PUSeSe-PEG) containing PEG as a hydrophilic block and polyurethane- diselenide as a hydrophobic block. Collapse of the micelles was observed in the presence of either H202 or GSH, leading to the efficient cargo release [85].

Tellurium-containing nanomaterials

Although compared with aforementioned ROS responsive nanomaterials, tellurium-containing materials have been infrequently studied, they have gained increasing attention recently [87-90]. As an element of chalcogens, tellurium resembles selenium in terms of its oxidation-responsive properties. What is more, because of its lower electronegativity, telluride showed a higher ROS sensitivity than selenide. As shown in Table 4.2, divalent tellurium compounds are easy to be oxidized to the tetravalent and hexavalent states. Therefore, tellurium-containing nanomaterials are good choice for preparing the ROS-responsive drug delivery systems. Xu and coworkers synthesized an amphiphilic hyperbranched polymer containing tellurium and PEG [91]. In 1.0 x 10"4 M H202, the micelles formed by this polymer swelled resulting from the oxidation of tellurium to the tetravalent states, and transformed to irregular aggregates. The

ROS-responsiveness of the micelles could be adjusted by changing the cross-linking degree of the hyperbranched polymer. The ROS and radiation sensitivities made the nanomaterials a potential platform for chemo-radiation combination therapy. In another study, in order to improve the biocompatibility of tellurium- containing nanomaterials, Xu et al. developed ROS-responsive coassemblies by adding tellurium-containing molecules to biodegradable phospholipids (DPPE) which are the main component of the plasma membrane [92]. Owing to the reversible redox property of tellurium-containing molecules, the coassemblies could be oxidized and reduced by 2 equiv of H202 and ascorbic acid (Vc), respectively. The redox-sensitive properties were demonstrated by the fact that these coassemblies could respond to 100 pM H202, which is a biologically relevant ROS concentration.

Nanomedicines in Response to ROS-Induced Degradation

Boronic ester-containing nanomaterials

Boronic esters have been shown to undergo oxidation-induced degradation (Table 4.2) for decades. They can be oxidized under oxidizing condition then hydrolyzed in water. Recently, boronic esters have been used as ROS-degradable protecting groups for various applications [93]. The anticancer drugs, imaging agents and matrix metalloproteinase (MMP) inhibitors have been conjugated to boronic esters to realize the site-specific activation in the ROS-rich environment [94, 95]. Several boronic ester derivatives have been studied, among which aryl boronic esters with either ester or ether linkages showing superior degradation kinetics were used most frequently. As shown in Fig. 4.4, in the work of Lux et al., a ROS-sensitive boronic ester-containing polymer was synthesized (polymer 1) [77]. In order to improve the hydrolytic stability and cleavage kinetics, polymer 2 was developed through introducing an ether linkage between the aryl boronic ester groups and the backbone. The Nile red was used as a probe to evaluate the release of payloads from the polymer-assembled nanoparticles in oxidative environment.

Both nanoparticles had H202-dependant release kinetics, while polymer 2 nanoparticles were much more sensitive to H202 compared with polymer 1 nanoparticles. The release profiles of both nanoparticles in the absence H202 were comparable. When exposed to 1 mM H202, polymer 1 nanoparticles released only 50% of the dye in 26 h, while polymer 2 nanoparticles did so in 10 h. In addition, transmission electron microscopy (ТЕМ) revealed that more polymer 2 nanoparticles ripped and collapsed than polymer 1 nanoparticles when incubated at low concentrations of H202 (100 and 50 pM), while similar morphological changes of both nanoparticles were observed at relatively high concentrations of H202 (100 and 250 mM).

Moreover, Chen and coworkers developed a series of ROS- activated aromatic nitrogen mustard prodrugs in order to selectively kill chronic lymphocytic leukemia (CLL) cells [96]. These agents were composed of two separate domains joined by a linker: one is H202 responsive moiety (boronic eaters); the other is cell-damaging group (nitrogen mustard). These prodrugs showed strong DNA cross-linking abilities in the presence of H202, whereas little DNA cross-linking was detected without H202. The cytotoxicity data indicated that the prodrugs induced 40-80% apoptosis in CLL patient-derived leukemic lymphocytes but less than 25% apoptosis in normal lymphocytes obtained from healthy donors. More recently, Lee and coworkers fabricated a H202-activatable antioxidant prodrug (BRAP) [97] in response to high concentration of H202 in the ischemia/reperfusion (I/R) injury site. BRAP was synthesized through the simple conjugation of (4-(hydroxymethyl)phenyl)boronic acid to 2-(hydroxymethyl)- 2-methylpropane-l,3-diol at room temperature. In the prodrug, the p-hydroxybenzyl alcohol (HBA) served as an antioxidant moiety. BRAP containing boronic esters was anticipated to be oxidized by H202 to generate HBA. In addition, BRAP was added to H202- containing D20 and the signal changes of HBA were monitored by LC-MS/MS. The results showed that BRAP was oxidized and generated HBA in a H202-responsive manner. In addition, the Amplex Red assay indicated that BRAP could scavenge H202 in a cone entrati on- d ep end en t mann er.

Structures of Polymer 1 and Polymer 2

Figure 4.4 Structures of Polymer 1 and Polymer 2.

Proline oligomer-containing nanomaterials

The proteins or peptides containing aspartic acid, glutamic acid and proline residues are prone to be cleaved by ROS, causing protein fragmentation [98, 99]. Among the three residues, proline is mostly studied (Table 4.2), in developing the ROS-responsive nanoDDS [100]. Due to the superior biocompatibility to other ROS-responsive materials such as selenium, proline oligomers are more favorable for tissue engineering. Different from other ROS- responsive nanomaterials that usually show rapid ROS-induced degradation in a matter of hours or days, proline oligomers are degraded for few weeks. Thus, this type of nanomaterials is perfect for tissue engineering and controlled drug release in the chronic oxidative stress conditions, such as the inflammatory response to implants and atherosclerotic lesions. In a work by Sung group, poly(e-caprolactone) (PCL) and polyethylene glycol) (PEG) based polymeric scaffolds were fabricated using proline oligomers as cross-linkers [79]. Oligoproline peptides of varying lengths were conjugated to PEG and the proline oligomers were tested for degradability in 5 mM H202 and 50 pM Cu(II) at 37°C. After 6 days of incubation under this metal-catalyzed oxidation condition, all proline residues were degraded completely while PEG molecules were retained. In order to verify that the polyproline peptide as a cross-linker was responsible for the ROS degradability of the polymeric scaffolds, the authors synthesized PEG-P7-PEG- cross-linked scaffolds ("7” refers to the length of the oligo(proline) peptide) and PEG-dihydrazide-cross-linked scaffolds (as the control). The ROS-dependent degradation of the PEG-P7-PEG scaffolds was observed when exposed to the typical ROS generator SIN-1 which could produce peroxynitrite and hydroxyl radicals in situ. In addition, the activated murine macrophages were used to mimic an oxidative stress environment in vitro. Under this condition, the proline oligomer-containing scaffolds were degraded more effectively than the control scaffolds cross-linked with PEG-dihydrazide.

Polythioketal-containing nanomaterials

ROS can destabilize the thioketal bond in polymers, leading to chain scission and polymer breakdown with acetone as a byproduct (Table 4.2). In order to protect siRNA from degradation in the harsh environment of gastrointestinal tract and deliver siRNA to the inflamed intestinal tissue, Wilson et al. developed the thioketal-containing nanoparticles (TKNs) containing poly- (1,4-phenyleneacetone dimethylene thioketal) [19]. In in vitro studies, incubation of the CMFDA (dye)-loaded TKNs with the activated macrophages containing high level of ROS resulted in the intracelluar dye release seven-fold higher than that of incubation with the non-activated macrophages. In addition, the dye release could be mitigated by treating the activated macrophages with ROS scavenger, indicating that the dye release from the TKNs was triggered by ROS. The data was further confirmed by the in vivo biodistrubution data that the TKNs were accumulated in the inflamed intestinal tissues featured by a high level of ROS. Wang and co-workers used the ROS-sensitive thioketal (TK) as a linker between photodynamic nanoparticles and DOX. Singlet oxygen ^Ог), generated by photodynamic therapy (PDT) under the excitation of NIR light, was able to not only trigger the release of DOX but also damage cancer cells to compensate for the detrimental effects of chemotherapy [80].

In order to accelerate wound healing, Tang et al. tried to deliver the stromal cell-derived factor-1-alpha by the polythioketal- containing nanomaterial named (poly-(l,4-phenyleneacetone dimethylene thioketal (SDF-la-PPADT) [101]. Increased drug release was observed in the presence of ROS (60% of drugs released in 8 h) compared with that in PBS (23% of drugs released in 48 h). Upon administration of SDF-la-PPADT in the mice with the full-thickness skin defects, the SDF-la level increased significantly and stayed stable for 24 h in the wounds.

Silicon nanoparticles

It was reported that the inner pores of silicon (Si) particles could be the shelter for various drugs [102, 103]. It was also reported that the nanostructured porous silicon (PSi) could be degraded by ROS in the diseased environment [104]. However, simple adsorption of drug molecules to the Si surface usually results in the uncontrolled, rapid burst release of loaded drugs, compromising drug efficacy. To address this issue, Sailor group conjugated the fluorescent dye Alexa Fluor 488 or anticancer drug DOX with the Si particles through Si-C bonds [105]. Before the Alexa Fluor 488 or DOX attachment, the authors modified the surface of the Si particles to activate the carboxylic groups. The Si-C bonds were stable in aqueous media, but could be cleaved in ROS-rich environments. By this way, drug release could be controlled by the cleavage of the covalent bonds of Si matrix.

 
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