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ਅਪ੍ਰੈਲ . 09, 2024 16:13 Back to list

PASP Hydrogel Particles (i.e., Nanogels and Microgels)

Hydrogel nanoparticles (i.e., nanogels) can find much more applications compared to their own bulk counterpart especially as a carrier for delivery of bioactive agents (Cuggino et al., 2019; Molaei et al., 2019). Preparation of such structures is generally carried out via inverse type emulsion techniques where aqueous phase containing hydrophilic polymer is dispersed in an organic solvent (typically hydrocarbons such as hexane) containing emulsifier (e.g., span-80; Krisch et al., 2017). Formation of small droplets/particles requires high shear stress which can be applied through high speed homogenizer or sonication. Schematic representation of typical emulsification is drawn in Figure 4A. Network formation should be conducted after particle formation as premature crosslinking leads to bulk gelation and does not allow emulsification. For example, Krisch et al. (2016) prepared nanogels of thiolated PASP by inverse miniemulsion (water in n-hexane). After particle formation, the thiolated groups of PASP were oxidized by sodium bromate NaBrO3, giving rise to gel formation. To maintain structural integrity of nanogels in reducing media, the same group utilized poly(ethylene glycol) diglycidyl ether for crosslinking of a part of S-H groups. The nanogels diameter increased in reducing media due to disulfide bond breakage and thus swelling while maintaining nanogel integrity (Figure 4B; Krisch et al., 2018).

Inverse emulsion method, though effective in preparation of small size and uniform particles, is accompanied with several problems such as using toxic organic solvent, relatively high amount of emulsifier, and the need for medium substitution to water. Therefore, alternative methods need to be adopted. Since PSI is hydrophobic, its particles can be formed in aqueous media (Hill et al., 2015). PASP-g-PEG hydrogel nanoparticles were fabricated via self-association of hydrophobic PSI units in water (i.e., micelle formation), followed by their hydrolysis (Park et al., 2017). The particles were crosslinked with HMDA or cystamine. PASP particles can also be formed via self-assembly with cationic polymers such as chitosan, as it is an anionic polyelectrolyte. Such an electrostatic self-assembly (also referred to as ionic gelatification) can yield composite nanoparticles in water through polyelectrolyte complexation (i.e., electrostatic charge attraction of the two polymer; Zheng et al., 2007; Zhang et al., 2008; Wei Wang et al., 2009). PASP/chitosan particles were prepared by drop-wise addition of chitosan to PASP solution. When chitosan/PASP ratio increased from 0.75 to 2.5, the size increased from 84 to 1,364 nm (Hong et al., 2014).

PASP Hydrogel Nanofibers

Regarding the fiber formation, since gels cannot flow, network formation should be conducted after fiber formation similar to the emulsification mentioned above. A typical PASP-based fiber preparation is exhibited in Figure 4C. In this method, PSI is dissolved in its solvent (commonly DMF or DMSO) and electrospun into nanofibers. The resulting PSI nanofibers are cross-linked in this step, employing a suitable agent (e.g., ethylenediamine) and converted to PASP by alkali hydrolysis (Zhang et al., 2015; Zhang C. et al., 2017). Interestingly, Zhang C. et al. (2017) found that inter-fiber crosslinking can also occur, resulting in hydrogels with interconnected microporous structure. This causes higher deformation, swelling kinetic, and swelling ratio compared to hydrogel films. Another study revealed that crosslinking can also be carried out during electrospinning for cysteamine-grafted PASP (diameter 80–500 nm; Molnar et al., 2014). However, relatively lower polymer concentration (15 wt.%) compared to conventional electrospinning process should be used to avoid premature gelation.

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Interpenetrating Polymer Network (IPN) Based on PASP

Interpenetrating polymer networks (IPN) are a class of materials composed of two chemically distinct, but highly compatible polymers that are uniformly mixed in each other in microscopic scales without any phase separation. IPNs are divided into semi-IPNs and full IPNs, in which one or both components are cross-linked, respectively (Roland, 2015). IPNs are generally fabricated to take advantage of the features of both components.

For instance, poly(N-isopropylacrylamide) [poly(NIPAAm)] which is a well-known polymer with LCST at around physiological temperature, can be introduced for providing the IPN with temperature sensitivity. Liu et al. (2012) prepared NIPAAm/PASP IPN hydrogels that show response both to pH and temperature. They first cross-linked PSI with a diamine, followed by its hydrolysis to PASP hydrogel. The hydrogel was then swelled with NIPAAm monomer/N,N′-methylene bisacrylamide (MBA) crosslinker followed by their polymerization. Némethy et al. (2013) synthesized NIPAAm/PASP co-network hydrogels by grafting allyl amine monomer onto PSI backbone followed by its radical polymerization with NIPAAm, and PSI hydrolysis. Nistor et al. (2013) evaluated swelling degree of PASP/PNIPAAm semi-IPN as a function of pH, temperature and NIPAAm content (Figures 5A,B). Other polymers including poly(vinyl alcohol), poly(acrylic acid), and poly(acrylamide) have also been employed for PASP-based IPN preparation as summarized in Table 1. Zhao et al. (2006) introduced PAA to PASP-based semi-IPN hydrogels by polymerization of acrylic acid and MBA as a cross-linker in the PASP solution. It was found that the swelling ratio increases with increasing PASP content as well as temperature (range of 40–60°C). The incorporation of high Mw PASP also inhibited gel formation due to steric hindrance. Jv et al. (2019) indicated that semi-IPNs based on PASP/PAA possess excellent ability for removal of methylene blue and neutral red with maximum adsorption of 357.14 and 370.37 mg/g, respectively (Figure 5C). Magnetic nanoparticles of Fe3O4, were incorporated into the hydrogels for facile separation of the dye-containing solid. Lee et al. (2018) exhibited that PASP improves mechanical properties of brittle PAAm significantly. They suggested that the addition of multivalent cations such as Fe3+, Al3+, Pb2+, Cu2+ results in ionic coordination, and thus creation of second network. Iron cation (Fe3+) had the highest impact on improving mechanical properties (Figure 5D).

Inverse emulsion method, though effective in preparation of small size and uniform particles, is accompanied with several problems such as using toxic organic solvent, relatively high amount of emulsifier, and the need for medium substitution to water. Therefore, alternative methods need to be adopted. Since PSI is hydrophobic, its particles can be formed in aqueous media (Hill et al., 2015). PASP-g-PEG hydrogel nanoparticles were fabricated via self-association of hydrophobic PSI units in water (i.e., micelle formation), followed by their hydrolysis (Park et al., 2017). The particles were crosslinked with HMDA or cystamine. PASP particles can also be formed via self-assembly with cationic polymers such as chitosan, as it is an anionic polyelectrolyte. Such an electrostatic self-assembly (also referred to as ionic gelatification) can yield composite nanoparticles in water through polyelectrolyte complexation (i.e., electrostatic charge attraction of the two polymer; Zheng et al., 2007; Zhang et al., 2008; Wei Wang et al., 2009). PASP/chitosan particles were prepared by drop-wise addition of chitosan to PASP solution. When chitosan/PASP ratio increased from 0.75 to 2.5, the size increased from 84 to 1,364 nm (Hong et al., 2014).

PASP Hydrogel Nanofibers

Regarding the fiber formation, since gels cannot flow, network formation should be conducted after fiber formation similar to the emulsification mentioned above. A typical PASP-based fiber preparation is exhibited in Figure 4C. In this method, PSI is dissolved in its solvent (commonly DMF or DMSO) and electrospun into nanofibers. The resulting PSI nanofibers are cross-linked in this step, employing a suitable agent (e.g., ethylenediamine) and converted to PASP by alkali hydrolysis (Zhang et al., 2015; Zhang C. et al., 2017). Interestingly, Zhang C. et al. (2017) found that inter-fiber crosslinking can also occur, resulting in hydrogels with interconnected microporous structure. This causes higher deformation, swelling kinetic, and swelling ratio compared to hydrogel films. Another study revealed that crosslinking can also be carried out during electrospinning for cysteamine-grafted PASP (diameter 80–500 nm; Molnar et al., 2014). However, relatively lower polymer concentration (15 wt.%) compared to conventional electrospinning process should be used to avoid premature gelation.

Go to:

Interpenetrating Polymer Network (IPN) Based on PASP

Interpenetrating polymer networks (IPN) are a class of materials composed of two chemically distinct, but highly compatible polymers that are uniformly mixed in each other in microscopic scales without any phase separation. IPNs are divided into semi-IPNs and full IPNs, in which one or both components are cross-linked, respectively (Roland, 2015). IPNs are generally fabricated to take advantage of the features of both components.

For instance, poly(N-isopropylacrylamide) [poly(NIPAAm)] which is a well-known polymer with LCST at around physiological temperature, can be introduced for providing the IPN with temperature sensitivity. Liu et al. (2012) prepared NIPAAm/PASP IPN hydrogels that show response both to pH and temperature. They first cross-linked PSI with a diamine, followed by its hydrolysis to PASP hydrogel. The hydrogel was then swelled with NIPAAm monomer/N,N′-methylene bisacrylamide (MBA) crosslinker followed by their polymerization. Némethy et al. (2013) synthesized NIPAAm/PASP co-network hydrogels by grafting allyl amine monomer onto PSI backbone followed by its radical polymerization with NIPAAm, and PSI hydrolysis. Nistor et al. (2013) evaluated swelling degree of PASP/PNIPAAm semi-IPN as a function of pH, temperature and NIPAAm content (Figures 5A,B). Other polymers including poly(vinyl alcohol), poly(acrylic acid), and poly(acrylamide) have also been employed for PASP-based IPN preparation as summarized in Table 1. Zhao et al. (2006) introduced PAA to PASP-based semi-IPN hydrogels by polymerization of acrylic acid and MBA as a cross-linker in the PASP solution. It was found that the swelling ratio increases with increasing PASP content as well as temperature (range of 40–60°C). The incorporation of high Mw PASP also inhibited gel formation due to steric hindrance. Jv et al. (2019) indicated that semi-IPNs based on PASP/PAA possess excellent ability for removal of methylene blue and neutral red with maximum adsorption of 357.14 and 370.37 mg/g, respectively (Figure 5C). Magnetic nanoparticles of Fe3O4, were incorporated into the hydrogels for facile separation of the dye-containing solid. Lee et al. (2018) exhibited that PASP improves mechanical properties of brittle PAAm significantly. They suggested that the addition of multivalent cations such as Fe3+, Al3+, Pb2+, Cu2+ results in ionic coordination, and thus creation of second network. Iron cation (Fe3+) had the highest impact on improving mechanical properties (Figure 5D).

Apart from conventional and common applications of hydrogels such as hygiene, and agricultural products, PASP hydrogels can be utilized in a wide variety of biomedical engineering areas such as development of scaffolds for tissue engineering, and carriers for sustained or targeted drug delivery systems (DDS). This is mainly due to its biocompatibility, biodegradability, as well as stimuli-responsive characteristic. Regarding the latter, in particular pH- and redox/oxidation-sensitivity of PASP has been exploited for DDS (Horvát et al., 2015; Sim et al., 2018). In this section, some recent studies in these regards are presented.

PASP/PNIPAAm co-network hydrogels loaded with sodium diclofenac (DFS) showed pH sensitivity such that the release of DFS increased when the gel is delivered from stomach (pH 1.2) into the bowels (pH 7.6) (Némethy et al., 2013). Such a conventional pH sensitivity feature can protect both the stomach from the side effects of DFS and the drug itself from acidity of stomach. However, in another study, unusual pH-response was observed in PASP hydrogels cross-linked with hydrazine and aldehyde (Lu et al., 2014). The release rate of DOX was accelerated by decreasing pH from 7 to a weak acidic condition (ca. pH 5). This behavior was attributed to instability of the hydrazone bond in acidic media, resulting in loosening of gel network. DFS was also employed as an ocular drugs and loaded in in-situ gelling thiolated PASP for its sustainable delivery (Horvát et al., 2015). The polymer due to its negative charge showed strong mucoadhesion, as well as high resistance against lachrymation of the eye. This is attributed to mucin glycoproteins role for crosslinking (i.e., disulfide linkage). The drug release showed a burst-like profile in the first hour followed by sustained release up to 24 h. In another work, fluorescent dextran (FTIC-Dx) was loaded into thiolated PASP nanogels prepared by inverse emulsion (Krisch et al., 2016). Disulfide bonds were cleaved by a reducing agent for gel disintegration, and release of the loaded drug. As seen in Figure 6A, the release profile dramatically increased by the addition of DTT as a reducing agent. The same redox-response and DOX release was seen in thiolated PASP-g-PEG nanogels (Park et al., 2017). Under reductive intracellular conditions, the prepared nanogels were shown to have the ability to release DOX and efficiently translocated to the nucleus of cancer cells (Figure 6B). Epigallocatechin Gallate (EGCG) which is the main bioactive element of green tea and is unstable in vitro was encapsulated in PASP/chitosan particles (Hong et al., 2014). The release of EGCG was investigated by simulation of food ingestion pH condition. It was demonstrated that EGCG is much more effective against rabbit atherosclerosis when encapsulated into PASP/chitosan.

Jang and Cha (2018) incorporated RGD peptide to PSI for improving 3T3 fibroblast cell adhesion. PSI was further modified with hydrazide, and subsequently reacted with oxidized alginate, bearing aldehyde groups. The Schiff reaction (i.e., aldehyde-hydrazide, yielding hydrazone bond) leads to in-situ gelation of poly(aspartamide)/alginate. As shown in Figure 6C, RGD-modified hydrogels possessed much better cell viability, adhesion and proliferation compared to un-modified hydrogels. Juriga et al. (2016) also modified thiolated PASP hydrogels with RGD and utilized them as scaffolds for MG-63 osteoblast-like cells. It was shown that RGD introduction leads to compacted cluster formation of the cells. The prepared scaffolds provided the osteoblast-like cells with excellent condition for adhesion, viability, and proliferation.

Zakharchenko et al. (2011) fabricated polymer tubes and encapsulated yeast cells within them. The tubes composed of bilayer cross-linked films of PSI/polycaprolactone. Upon the hydrolysis of PSI in physiological buffer environment, and conversion into PASP gels, the films self-rolled due to the produced internal stress as a result of swelling of the lower layer, i.e., PASP (Figure 6D). Such a self-rolling was exploited for cell encapsulation. Hydrolysis of PSI was shown to be step like process and initiates after nearly 8 h in PBS buffer.

PASP due to its negative charge can endow electrostatic stability to colloidal systems. For example, iron oxide (Fe3O4) nanoparticles coated with a thin layer of PASP hydrogels had improved colloidal stability (Vega-Chacón et al., 2017). The composite magnetic particles did not show any adverse effect on cell viability of L929 fibroblast. Also, particles exhibited response to pH, presenting them as promising candidate for magnetic drug delivery. Iron oxide nanoparticles as negative contrast agents for magnetic resonance imaging (MRI) have been employed widely for detection of diseases (Ta et al., 2011, 2017a,b, 2018; Gaston et al., 2018; Wu et al., 2018; Yusof et al., 2019; Zhang et al., 2019). Multifunctional PASP nanoparticles containing iron oxide nanocrystals and doxorubicin was also developed for simultaneous diagnosis and treatment of cancer by Yang et al. (2011). Iron oxide nanocrystals were loaded in PASP nanoparticles through an emulsion method using octadecyl grafted PASP, then doxorubicin (DOX), was incorporated in the magnetic PASP nanoparticles. It was shown that the DOX loaded nanoparticles exhibited high T2 relaxivity and strong cytotoxicity for cancer cells.

Due to its strong ability for chelation, PAPS nanofiber hydrogels were utilized as chemosensor for Cu2+ ions detection (Zhang et al., 2015). The hydrogels showed high sensitivity and selectivity to Cu2+ ions compared with other ions such as Ag+, and Ca2+ where no color change was observed (Figures 6E,F). The detection limit of as low as 0.01 mg/L was reported.

Because of its bio-degradation and water uptake, PASP hydrogels could be regarded as a promising candidate for ecological restoration and plant survival especially in arid area. Wei et al. (2016) employed PASP hydrogel to transplant Xanthoceras sorbifolia seedlings. The survival rate and the leaf water content were improved in soils containing PASP hydrogels.

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Conclusion and Prospects

Although synthesis of PASP-based hydrogels is relatively more complex than other anionic-based hydrogels such as PAA-based ones, its biocompatibility and biodegradability make it attractive particularly in biomedical applications. Though pH-responsive, PASP is further modified with other moieties to provide sensitivity to the desired stimuli as well including temperature and reducing/oxidizing media. Incorporation of other water-soluble polymers into the PASP network may also provide the final hydrogel with superior properties. Scrutinizing the literature, it is found that PASP hydrogels has not yet been employed for inhibition of scale formation in which PASP solution has exhibited promising results (Hasson et al., 2011). Moreover, PASP hydrogel fibers may potentially be a good candidate as scaffold for cell culture as well as tissue engineering. Additionally, due to its anionic nature, PASP-based hydrogels can be used for preparation of electrically-responsive materials (Murdan, 2003).

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Author Contributions

HA wrote and revised the manuscript. IB and PL supervised the work. HT supervised and revised the manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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