Multifunctional Photothermal Hydrogel in the Second Near-Infrared Window for Localized Tumor Therapy.

A copper selenide-embedded gellan gum hydrogel (Cu2-xSe@GG) is designed as an "all-in-one" antitumor agent. The obtained nanocomposite hydrogel exhibits strong near-infrared light absorption and high photothermal conversion efficiency in both the NIR-I and NIR-II biowindows. The photothermal conversion efficiency achieves 58.8% under the irradiation of 0.75 W/cm2 with a 1064 nm laser. Furthermore, the nanocomposite hydrogel has catalase- and peroxidase-mimicking activities, which could alter the tumor microenvironment by reducing hypoxia and/or increasing the production of reactive oxygen species. Moreover, the multifunctional Cu2-xSe@GG nanocomposite hydrogel can also be used as an immune agonist resiquimod (R848) carrier to promote immune regulation and enhance the therapeutic effect. The single-syringe R848/Cu2-xSe@GG treatment achieves synergetic photothermal immunotherapy, showing 97.4% of tumor regression rate from an initial large tumor of 300 mm3.

Injectable hydrogel platform with biodegradable Dawson-type polyoxometalate and R848 for combinational photothermal-immunotherapy of cancer.

Photothermal therapy (PTT) is a powerful strategy for cancer treatment with minimal invasiveness but still limited by lack of long-term efficacy against tumor recurrence and toxicity concerns about the slow biodegradability of the PTT agents. Herein, an injectable hydrogel platform (R848/POM@GG) of gellan gum co-loaded with Dawson-type {P2Mo18} polyoxometalate (POM) and Toll-like receptors agonist resiquimod (R848) is developed for combinational photothermal-immunotherapy of cancer. The POM-based gellan gum hydrogel (POM@GG) exhibits high photothermal conversion efficiency (63.1%) at a safe power density of 0.3 W cm-2 and good photostability during five cycles. By further incorporation of R848, the obtained R848/POM@GG exerts synergetic photothermal-immunotherapy on solid tumors, giving a high tumor inhibition rate of 99.3% and negligible lung metastases in the breast cancer mice models. A strong antitumor immune system with significantly elevated TNF-α, IL-2, and IL-6 levels is activated by R848. Additionally, the POM clusters gradually degrade to nontoxic molybdate in the physiological environment. Overall, the injectable hydrogel platform of R848/POM@GG has great translational potential for localized antitumor treatments.

A Bi2S3-embedded gellan gum hydrogel for localized tumor photothermal/antiangiogenic therapy.

An injectable gellan gum-based nanocomposite hydrogel (Bi2S3@GG) was designed for X-ray computed tomography (CT) imaging and photothermal/antiangiogenic therapy. The linear anionic polysaccharide gellan gum (GG) was used as a stabilizer, embedded with ultra-small bismuth sulfide (Bi2S3) nanodots (∼2 nm) through a one-pot synthesis method. The as-prepared Bi2S3@GG hydrogel displays excellent capability for both photothermal therapy (PTT) (with a photothermal conversion efficiency of 44.3%) and X-ray computed tomography (with an X-ray absorption coefficient of 51.5 HU L g-1), integrated with real-time monitoring drug retention and tunable therapeutic functions. After the incorporation of sorafenib (SF), the hydrogel shows a sustained release of SF over 15 days. A tumor suppression rate of 98.2% is shown at day 22 postinjection in the mice received the combined treatments of photothermal/antiangiogenic therapy. In contrast, tumor growth and recurrence are observed in the single treatment. Our work presents a new strategy to construct a multifunctional hydrogel platform for a safe and precise antitumor therapy.

A robust hybrid nanozyme@hydrogel platform as a biomimetic cascade bioreactor for combination antitumor therapy.

The development of highly effective and minimally invasive approaches for cancer treatment is the ultimate goal. Herein, an injectable hybrid hydrogel as a biomimetic cascade bioreactor is designed for combination antitumor therapy by providing spatiotemporally-controlled and long-term delivery of therapeutic agents. This hybrid nanozyme@hydrogel (hPB@gellan) is doped with Prussian blue (PB) nanoparticles via the in situ nanoprecipitation method in the polysaccharide gellan matrix. The obtained PB nanoparticles have a small size of 10 nm and play dual roles as a photothermal agent with a photothermal conversion efficiency of 59.6% and as a nanozyme to decompose hydrogen peroxide into oxygen. By incorporating glucose oxidase (GOD) into the hybrid hydrogel, a cascade bioreactor is formed for PB-promoted glucose consumption. Owing to its shear-thinning and self-recovery properties, the hybrid hydrogel is locally administered into tumors, and shows long-term resistance against body clearance and metabolism. The in vivo antitumor results demonstrate that the tumors in the group of combined photothermal and starvation therapy (GOD/hPB@gellan + NIR) are greatly eliminated with a tumor suppression rate of 99.7% 22 days after the treatment. The outstanding antitumor performance is attributed to the main attack by NIR-triggered hyperthermia and the holding attack by GOD-mediated starvation from the catalytic bioreactor of the hybrid hydrogel. Taking into consideration the advantages of biosafety, simple synthetic approaches and facile manipulation in treatment, the hybrid hydrogel has great potential for clinical translation.

Minimally Invasive Antitumor Therapy Using Biodegradable Nanocomposite Micellar Hydrogel with Functionalities of NIR-II Photothermal Ablation and Vascular Disruption.

A powerful minimally invasive approach holds great promise toward the treatment of solid tumors in the aims of reducing the systemic toxicity of drugs and the risk of infections in surgeries. Herein, we design a PLEL-based thermosensitive nanocomposite micellar hydrogel delivery platform, in which the two-dimensional nanosheet-based photothermal agent and vascular disrupting agent (combretastatin A4, CA4) are loaded for synergistic antitumor therapy. Ultrathin Ti3C2 MXene with a thickness less than 5 nm is synthesized through a combination of an acid/alkaline etching method. The obtained Ti3C2/CA4@PLEL micellar hydrogel exhibits a loading efficiency of 99.6%, long-acting sustained release, and favorable photothermal effect in the NIR-II biowindow (a photothermal conversion efficiency of 41.4% at 1064 nm). Besides, the CA4-loaded micelles allow efficient cellular uptake for drugs and selectively kill the tumor vascular endothelial cells using the human umbilical vein endothelial cells (HUVECs) as a cell model. Moreover, the in vivo studies demonstrate that the combinational group of the Ti3C2/CA4@PLEL micellar hydrogel eliminates the solid tumor thoroughly from an initial volume of 200 mm3, superior to other groups. This work highlights the potential of the biodegradable micellar hydrogel networks assembled with multifunctional objects for antitumor therapy.

Integrated Hydrogel Platform for Programmed Antitumor Therapy Based on Near Infrared-Triggered Hyperthermia and Vascular Disruption.

Complete tumor regression is a great challenge faced by single therapy of near-infrared (NIR)-triggered hyperthermia or vascular disrupting agents. An injectable nanocomposite (NC) hydrogel is rationally designed for combined anticancer therapy based on NIR-triggered hyperthermia and vascular disruption. The NC hydrogel, codelivered with Prussian blue (PB) nanoparticles and combretastatin A4 (CA4), has good shear-thinning, self-recovery, and excellent photothermal properties. Because of the remarkable tumor-site retention and sustained release of CA4 (about 10% over 12 days), the NC hydrogel has a tumor suppression rate of 99.6%. The programmed combinational therapy conveys the concept of "attack + guard", where PB-based NIR irradiation imposes intensive attack on most of cancer cells, and CA4 serves as a guard against the tumor growth by cutting off the energy supply. Moreover, the biosafety and eco-friendliness of the hydrogel platform pave the way toward clinical applications.