Injectable self-healing polysaccharide hydrogel loading CuS and pH-responsive DOX@ZIF-8 nanoparticles for synergistic photothermal-photodynamic-chemo therapy of cancer

doi:10.1016/j.jmst.2022.04.015

Abstract

Abstract:

The injectable self-healing polysaccharide hydrogel was prepared by the formation of Schiff base bonds between aldehyde-modified methylcellulose (MC—CHO) and carboxymethyl chitosan (CMC). The copper sulfide nanoparticles (CuS NPs) and pH-sensitive doxorubicin-loaded zeolitic imidazolate frameworks nanoparticles (DOX@ZIF-8 NPs) were prepared and could be well-dispersed into the hydrogel system. The presence of CuS NPs can achieve photothermal therapy (PTT) for tumors under the irradiation of the near-infrared (NIR) laser. Moreover, CuS NPs can generate photodynamic effects under NIR irradiation, converting oxygen into toxic reactive oxygen species (ROS) and presenting efficient photodynamic therapy (PDT). The DOX@ZIF-8 NPs can be decomposed under an intracellular acidic environment and realize the controlled release of DOX. The injectable self-healing hydrogel loading CuS and DOX@ZIF-8 NPs can achieve synergistic photothermal-photodynamic-chemo therapy for tumors and will inspire the researchers to construct a platform from hydrogel combined with multifunctional nanomaterials to realize the effective multimodal therapy for tumor.

Key words: Injectable self-healing hydrogel, Copper sulfide, Zeolitic imidazolate frameworks, Synergistic cancer therapy

Zhiyi Qian, Nuoya Zhao, Chunyao Wang, Weizhong Yuan. Injectable self-healing polysaccharide hydrogel loading CuS and pH-responsive DOX@ZIF-8 nanoparticles for synergistic photothermal-photodynamic-chemo therapy of cancer[J]. J. Mater. Sci. Technol., 2022, 127: 245-255.

Figures/Tables 9

Fig. 1. Schematic illustration of the fabrication of MC—CHO/CMC/CuS/DOX@ZIF-8 injectable self-healing nanocomposite hydrogel and the synergistic photothermal-photodynamic-chemo therapy for breast cancer.

Fig. 2. (a): (i) TEM image of ZIF-8 NPs, (ii) Rh of ZIF-8 NPs measured by DLS, (iii) nitrogen adsorption/desorption isotherms of ZIF-8 NPs at 300 K. (b): (i) TEM image of DOX@ZIF-8 NPs, (ii) Rh of DOX@ZIF-8 NPs measured by DLS, (iii) nitrogen adsorption/desorption isotherms of DOX@ZIF-8 NPs at 300 K. (c) XRD image of ZIF-8 and DOX@ZIF-8 NPs. (d): (i) TEM image, (ii) HR-TEM image, (iii) DLS, and (iv) XRD curve of CuS NPs.

Fig. 3. (a) Hydrogel formation process. (b) Self-healing property of the hydrogel: (i) Block hydrogel, (ii) repatching 0 h, (iii) 4 h, (iv) 8 h, (v) 24 h, and (vi) 48 h. (c) Injectable property of the hydrogel. (d) Rheological analysis of the hydrogels: (i) Storage modulus (G') of the hydrogels formed after mixing solutions with different concentration, (ii) continuous phase strain alternation scans between 1% and 150% (4 wt.% MC—CHO + 4 wt.% CMC), (iii) continuous phase strain alternation scans between 1% and 150% (2 wt.% MC—CHO + 2 wt.% CMC + 0.25 wt.% DOX@ZIF-8 + 0.25 wt.% CuS). (iv) hydrogel formation process of G' and G'' strain scan tests.

Fig. 4. (a) Infrared photographs of hydrogels containing different mass fractions of CuS irradiated with 1 W/cm2 808 nm NIR light for different times. (b) Temperature changes during the above irradiation process. (c) NIR light on-off cycle test.

Fig. 5. (a) Relative UV-vis absorption intensity at 408 nm of DPBF in PBS solution with different concentrations of CuS after different times of NIR light irradiation at 1 W/cm2 808 nm. (b) Cell fluorescence photos of hydrogels containing different mass fractions of CuS under the action of DCFH-DA probe after different times of NIR light irradiation at 1 W/cm2 808 nm, scale bars represent 200 μm.

Fig. 6. Relative cell viability of L929 cells after incubation with different concentrations of extracts containing different components of the hydrogel: (a) 24 h. (b) 48 h.

Fig. 7. (a) Relative cell viability of 4T1 cells in each experimental group after different treatments. Stained photographs of live and dead cells in each experimental group: (b) Control, (c) Gel, (d) Gel + DOX@ZIF-8 + CuS, (e) Gel + DOX@ZIF-8 + CuS + NIR-4 min & cooling, (f) Gel + DOX@ZIF-8 + CuS + NIR-2 min, (g) Gel + DOX@ZIF-8 + CuS + NIR-4 min, (h) Gel + DOX@ZIF-8 + CuS + NIR-6 min, (i) Gel + DOX@ZIF-8 + CuS + NIR-8 min, scale bars represent 200 μm. (***p < 0.001 and ****p < 0.0001, n = 3).

Fig. 8. (a) In vivo photothermal effect of each experimental group of nude mice. (b) Photographs of different tissues of nude mice in each experimental group after execution and autopsy on day 13 of treatment: (I) Tumor: i. PBS, ii. Gel + ZIF-8 + CuS (NIR-), iii. PBS + DOX, iv. Gel + DOX@ZIF-8, v. Gel + DOX@ZIF-8 + CuS (NIR-), vi. PBS + DOX@ZIF-8 + CuS (NIR+), vii. Gel + DOX@ZIF-8 + CuS (NIR+); (II) major organs (heart, liver, spleen, lung and kidney); (III) combined photographs of (I) and (II). (c) Average weight of tumor of each experimental group of nude mice on day 13 of treatment. (*p < 0.05, n = 5). (d) Average relative tumor volume change of each experimental group of nude mice during treatment. (**p < 0.01, n = 5). (e) Average weight change of each experimental group of nude mice during treatment during treatment. (f) HE and Tunel staining of tumor tissue sections of nude mice in each experimental group: (i) PBS, (ii) Gel + ZIF-8 + CuS (NIR-), (iii) PBS + DOX, iv. Gel + DOX@ZIF-8, (v) Gel + DOX@ZIF-8 + CuS (NIR-), (vi) PBS + DOX@ZIF-8 + CuS (NIR+), (vii) Gel + DOX@ZIF-8 + CuS (NIR+), scale bars represent 200 μm.

Fig. 9. HE staining of major organ sections of nude mice in each experimental group, scale bars represent 200 μm.

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