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Novel dendritic monomers derived from cystamine (Cy) were firstly synthesized in this research. Then, these monomers were used as crosslinkers to prepare three series of thermosensitive hydrogels with 2-(2-methoxyethoxy) ethyl methacrylate (MEMA). The effects of these crosslinkers on the hydrogel’s properties such as swelling behavior, mechanical properties, decomposability and thermoreversibility were investigated and compared with the hydrogel crosslinked by N,N′-bisacrylyl cystamine. The results showed that the equilibrium swelling ratio (SReq) of the hydrogel was affected by the hydrophilic group on the structure of the crosslinker and branch distribution of dendrimer crosslinker. More hydrophilic groups led to higher SReq; however, more complex branch distribution occupied the storage space of water and thus reduced the SReq. The prepared hydrogels all showed apparent thermoreversibility, and the critical gel transition temperature (CGTT) of these hydrogels increased with an increase of hydrophilic group in the crosslinker. Their CGTT showed a range from 26 °C (pure polymer) to 45 °C. More importantly, disulfide bonds in the synthesized hydrogel could be decomposed in the presence of cysteine. This result was confirmed by the change of swelling ratio and mechanical properties before and after they were treated with cysteine. The hydrogels decomposed by cysteine showed higher swelling ratio than the pristine hydrogels. And for mechanical properties, the shear modulus, Young’s modulus and effective crosslinking density of the decomposed hydrogels are lower than the pristine hydrogels. In summary, a thermoresponsive and cysteine-responsive hydrogel has been developed.

Three crosslinkers, poly(ethylene glycol) diacrylate (PEGDA), glycerol ethoxylate triacrylate (GETA) and citric acid-(PEG acrylate)3 (CA-PEGTA) derived from poly(ethylene glycol) (PEG) were synthesized at first. The three series of poly (N-isopropylacrylamide) (PNIPAAm) hydrogels were prepared by photopolymerization with the crosslinkers and compared with a hydrogel based on commercial crosslinker, N,N′-methylene bis-acrylamide (NMBA). The influence of the crosslinker structures and contents on the swelling behaviour, mechanical properties, and drug release of the hydrogels was investigated. The results showed that the hydrogels based on PEGDA and NMBA exhibited the highest and the lowest swelling ratio, respectively. The content of crosslinker of all hydrogel series showed good thermosensitivity and thermo-reversibility. The critical gel transition temperature (CGTT) appeared at 32 °C for the hydrogel based on NMBA, but appeared at about 34 °C for other hydrogels due to higher hydrophilicity of the crosslinker. In the mechanical properties, three-arms crosslinker GETA and CA-PEGTA led to higher mechanical strength than a linear crosslinker PEGDA. A hydrogel based on GETA (NG6) showed the highest shear modulus of 656.9 kPa and Young’s modulus of 1655.0 kPa. The hydrogels containing higher content of crosslinker revealed lower swelling ratio and higher mechanical strength. In the drug release, the hydrogels with higher swelling ratios showed higher drug absorbed. The highest release percentage of caffeine and vitamin B12 for hydrogel based on PEGDA (NP6) could reach 68.3% and 75.4%, respectively. In addition, the bound water and toxicity of the hydrogels were also investigated.

Summary A novel degradable crosslinker, N, N′-bis(acryloyl) cystamine (BACy), was synthesized with cystamine dihydrochloride (Cy) and acryloyl chloride. Then three series of degradable thermosensitive hydrogels with different crosslinker contents were prepared from N-isopropyl acrylamide (NIPAAm), BACy (Bx-series) or N, N′-methylene-bis-acrylamide (NMBA)(Nx-series) or equimolar BACy and NMBA (BNx-series) as crosslinker, and diethoxyacetophenone (DEAP) as photoinitiator under UV-irradiation polymerization. The effect of crosslinker content on the properties of the hydrogels such as swelling behavior and mechanical properties was investigated. At the same time, their degradabilities were investigated by dissolving them into different concentrations of cysteine solution. The results show that the swelling ratios for the Bx-series hydrogels are lower than those for the Nx-series hydrogels. But, after degradation in the cysteine solution, the swelling ratios for the Bx-series hydrogels were greater than those for the Nx-series hydrogels. When the crosslinker content was increased, all values of shear stress (τ), shear modulus (G), and effective crosslinking density (ρX) increased. But, the ρX values for the reduced Bx series and BNx series hydrogels were lower than those for original hydrogels. Results also showed that the ρX values for the Nx series hydrogel were not affected by cysteine. The disulfide bonds of BACy in these novel hydrogels were decomposed (reduced) in the cysteine solution and converted into thiol group. These thiol groups could be used to absorb some metal ions such as silver ion. Hence, the absorption of silver ion for the hydrogel with thiol group was also investigated in this research.

Multifunctional nanoplatforms combined with photodynamic therapy (PDT) and anticancer drugs have shown great promising in cancer therapy. However, their efficacy is limited by the low specificity, low oxygen levels, and a tolerant tumor immune microenvironment. Herein, we developed a biocompatible theranostic nanoplatform (FM@VP) based on co-assembly of a nanocomplex formed by a functional polysaccharide fucoidan and a bioreducible polyamidoamine (PAMAM) dendrimer, a photosensitizer verteporfin (VP), and MnO2 nanoparticles (a tumor microenvironment responsive oxygen evolving nanomaterial) into a multifunctional nanoparticle cluster. The dendrimer-fucoidan polyionic nanocomplex (DFPN) specifically targeted P-selectin-overexpressed triple-negative breast cancer (TNBC) and the tumor-associated vasculature, and was sensitive to glutathione (GSH) in tumor. More importantly, this FM@VP nanocomplex simultaneously overcame tumor hypoxia, suppressed oncogenic signaling, and attenuated tumor-mediated immunosuppression, resulting in improving therapeutic efficacy of PDT while enhancing antitumor immunity and anti-metastasis. This discovery provides a powerful strategy for synergetic cancer targeting/photodynamic/immunotherapy and could serve as a safe clinical translational approach.

This study evaluates the sustained analgesic effect of ketorolac-eluting thermosensitive biodegradable hydrogel in the plantar incisional pain model of the rat hind-paw. A ketorolac-embedded 2, 2'-Bis (2-oxazolin) (BOX) linking methoxy-poly(ethylene glycol) and poly(lactide-co-glycolide) (mPEG-PLGA) diblock copolymer (BOX copolymer) was synthesized as keto-hydrogel based on optimal sol-gel phase transition and in vitro drug release profile. The effect of keto-hydrogel on postoperative pain (POP) was assessed using the established plantar incisional pain model in hind-paw of rats and compared to that of ketorolac solution. Pain and sensory threshold, as well as pain scoring, were evaluated with behavioral tests by means of anesthesiometer and incapacitance apparatus, respectively. Pro-inflammatory cytokine levels (TNF-α, IL-6, VEGF, and IL-1β) around incisional wounds were measured by ELISA. Tissue histology was assessed using hematoxylin and eosin and Masson’s trichrome staining. Ten mg/mL (25 wt%) keto-hydrogel showed a sol-gel transition at 26.4°C with a 10-day sustained drug release profile in vitro. Compared to ketorolac solution group, the concentration of ketorolac in tissue fluid was higher in the keto-hydrogel group during the first 18 h of application. Keto-hydrogel elevated pain and sensory threshold, increased weight-bearing capacity, and significantly reduced the levels of TNF-α, IL-6, and IL-1β while enhanced VEGF in tissue fluid. Histologic analysis reveals greater epithelialization and collagen deposition around wound treated with keto-hydrogel. In conclusion, our study suggests that keto-hydrogel is an ideal compound to treat POP with a secondary gain of improved incisional wound healing.

1-Acrylamidopyrene (AAP) was synthesized for the first time in this study. A series of thermosensitive copolymeric hydrogels were prepared by copolymerization of AAP and N-isopropyl acrylamide (NIPAAm) by UV irradiation. The effect of AAP content in the copolymeric hydrogels on the swelling ratio, mechanical properties, and drug release behavior of the hydrogels was investigated. The swelling ratios decreased from 6.5 to 4.9 (g/g) when the AAP content in the copolymeric hydrogels increased from 0.1 to 0.9 mol% owing to their increasing hydrophobicity. In addition, the thermosensitive behavior obviously diminished with increasing AAP content in the copolymeric hydrogels, but the mechanical properties and cross-linking densities of the hydrogels swollen in ethanol solution were enhanced with increasing AAP content. The swelling ratios of the hydrogels in different solvents were varied with increasing AAP content. The result of caffeine release in the hydrogels showed that when the content of AAP in the hydrogel increased, the caffeine-loading amount decreased; however, their fractional release increased. The corresponding copolymers of the NIPAAm/AAP copolymeric hydrogels were synthesized. The UV absorbance and photoluminescent (PL) behavior of AAP, NIPAAm/AAP copolymeric hydrogels, and their corresponding copolymers in some solvents with different polarities were investigated.

Bis[4-(phenyl-isopropyl)phenyl]-4-nitrophenylamine (BiPNPA) (iii) was firstly synthesized via nucleophilic substitution of 4-fluoronitrobenzene (ii) and bis-[4-(phenyl-isopropyl)phenyl]amine (BiPA) (i) in this study, and then compound (iii) was reduced to bis[4-(phenyl-isopropyl)phenyl]-4-aminophenylamine (BiPAmPA) (iv). At last, acrylation of BiPAmPA with acryloyl chloride was performed to obtain a novel bis[4-(phenyl-isopropyl)phenyl]-4-acrylamidophenylamine (BiPAcPA) compound (v). Then, a series of thermosensitive hydrogels were prepared by copolymerization of BiPAcPA and N-isopropyl acrylamide (NIPAAm) by UV irradiation. The effect of BiPAcPA content in the copolymeric hydrogels on the swelling ratio, mechanical properties, and drug release behaviors of the hydrogels was investigated. Results showed that the swelling ratios of the copolymeric hydrogels decreased from 8.2 (g/g) to 5.01 (g/g) when the monomer BiPAcPA content in the copolymeric hydrogel increased from 0.1 mol% to 0.9 mol%. In addition, the thermosensitive behavior obviously decreased with increasing of BiPAcPA content in the hydrogels, but the mechanical properties and crosslinking density of the hydrogel increased with increasing of BiPAcPA content; the caffeine release ratio from 46 % decreased to 29 %. The result of caffeine release also showed that the caffeine-loading amounts decreased with increasing content of BiPAcPA in the hydrogel, but their fractional release increased. In addition, the corresponding copolymers of the copolymeric hydrogels were prepared. Furthermore, the UV absorbance and photoluminescent (PL) behavior of the BiPAcPA, NIPAAm/BiPAcPA copolymeric hydrogels, and their corresponding copolymers in some solvents with different polarities were investigated. The results showed the PL intensity increased with increasing BiPAcPA amounts, especially the wavelength had obvious blue shift phenomenon in THF solvent. The wavelength of UV absorbance and PL emission of BiPAcPA all appeared in visible region. No matter what BiPAcPA monomer, NIPAAm/BiPAcPA hydrogels or NIPAAm/BiPAcPA copolymers, the wavelengths of UV absorbance and PL emission in DMSO solvent are all the same.

This study evaluates the sustained analgesic effect of ketorolac-eluting thermosensitive biodegradable hydrogel in the plantar incisional pain model of the rat hind-paw. A ketorolac-embedded 2, 2'-Bis (2-oxazolin) (BOX) linking methoxy-poly(ethylene glycol) and poly(lactide-co-glycolide) (mPEG-PLGA) diblock copolymer (BOX copolymer) was synthesized as keto-hydrogel based on optimal sol-gel phase transition and in vitro drug release profile. The effect of keto-hydrogel on postoperative pain (POP) was assessed using the established plantar incisional pain model in hind-paw of rats and compared to that of ketorolac solution. Pain and sensory threshold, as well as pain scoring, were evaluated with behavioral tests by means of anesthesiometer and incapacitance apparatus, respectively. Pro-inflammatory cytokine levels (TNF-α, IL-6, VEGF, and IL-1β) around incisional wounds were measured by ELISA. Tissue histology was assessed using hematoxylin and eosin and Masson's trichrome staining. Ten mg/mL (25 wt%) keto-hydrogel showed a sol-gel transition at 26.4°C with a 10-day sustained drug release profile in vitro. Compared to ketorolac solution group, the concentration of ketorolac in tissue fluid was higher in the keto-hydrogel group during the first 18 h of application. Keto-hydrogel elevated pain and sensory threshold, increased weight-bearing capacity, and significantly reduced the levels of TNF-α, IL-6, and IL-1β while enhanced VEGF in tissue fluid. Histologic analysis reveals greater epithelialization and collagen deposition around wound treated with keto-hydrogel. In conclusion, our study suggests that keto-hydrogel is an ideal compound to treat POP with a secondary gain of improved incisional wound healing.