A prodrug hydrogel with tumor microenvironment and near-infrared light dual-responsive action for synergistic cancer immunotherapy.

Tumor surgical resection is the major strategy for cancer treatment. Meanwhile, perioperative treatment especially the postoperative adjuvant anticancer strategies play essential roles in satisfying therapeutic results and rapid recovery. Postoperative tumor recurrence, metastasis, bleeding, inter-tissue adhesion, infection, and delayed wound healing are vital risks that could lead to poor prognosis or even treatment failure. Therefore, methods targeting these postoperative complications are in desperate need. In situ biomaterial-based drug delivery platforms are promising candidates for postoperative treatment and recovery, resulting from their excellent properties including good biocompatibility, adaptive shape, limited systemic effect, designable function, and easy drug loading. In this review, we focus on introducing the gel/hydrogel-based in situ biomaterial platforms involving their properties, advantages, and synthesis procedures. Based on the loaded contents in the gel/hydrogel such as anticancer drugs, immunologic agents, cell components, and multifunctional nanoparticles, we further discuss the applications of the in situ platforms for postoperative tumor recurrence and metastasis inhibition. Finally, other functions aiming at fast postoperative recovery were introduced, including hemostasis, antibacterial infection, adhesion prevention, tissue repair, and wound healing. In conclusion, gel/hydrogel is a developing and promising platform for postoperative treatment, exhibiting gratifying therapeutic effects and inconspicuous toxicity to normal tissues, which deserves further research and exploration. 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/EXP.20220173

Gel/hydrogel‐based in situ biomaterial platforms for cancer postoperative treatment and recovery

Recent advances in protein hydrogels: From design, structural and functional regulations to healthcare applications

With the booming development of nanomedicine, mild photothermal therapy (mPTT, 42-45°C) has exhibited promising potential in tumor therapy. Compared with traditional PTT (>50°C), mPTT has less side effects and better biological effects conducive to tumor treatment, such as loosening the dense structure in tumor tissues, enhancing blood perfusion, and improving the immunosuppressive microenvironment. However, such a relatively low temperature cannot allow mPTT to completely eradicate tumors, and therefore, substantial efforts have been conducted to optimize the application of mPTT in tumor therapy. This review extensively summarizes the latest advances of mPTT, including two sections: (1) taking mPTT as a leading role to maximize its effect by blocking the cell defense mechanisms, and (2) regarding mPTT as a supporting role to assist other therapies to achieve synergistic antitumor curative effect. Meanwhile, the special characteristics and imaging capabilities of nanoplatforms applied in various therapies are discussed. At last, this paper puts forward the bottlenecks and challenges in the current research path of mPTT, and possible solutions and research directions in future are proposed correspondingly. 

Research Progress of Nanomedicine-Based Mild Photothermal Therapy in Tumor

The development of an injectable multifunctional hydrogel with tumor therapy, antibacterial treatment and wound healing properties is essential for simultaneously eradicating melanoma and promoting wound healing of tumor-initiated skin defects. Herein, iron ion-doped polyaniline (PANI(Fe)) tethered with guar gum (GG) chains is employed for the first time as a building unit for constructing a superior hydrogel (GG@PANI(Fe)-borax) crosslinked by borate/didiol bonds. Due to the dynamic and reversible properties of boronate ester bonds, the GG@PANI(Fe)-borax hydrogels had convenient injectability, rapid self-healing ability, and reversible gel-sol transformations under thermal- or pH-stimuli. More importantly, they took advantage of the second near-infrared (NIR-II) responsive photothermal conversion capability, accompanied by the photothermal-enhanced high cytotoxic ˙OH generation in the H2O2-enriched tumor microenvironment induced by iron-doped PANI. The as-prepared hydrogels exhibited excellent photothermal effects and controllable NIR-triggered drug release, leading to distinctly synergistic photothermal/chemodynamic/chemo-therapy effects of melanoma both in vitro (98.2%) and in vivo (98.8%). In addition, the obtained hydrogels also exhibited good anti-bacterial activity (>97.1%) against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria because they were based on PANI(Fe) and borax, which exhibit antibacterial activity. Furthermore, these GG@PANI(Fe)-incorporated scaffolds could improve fibroblast cell proliferation and angiogenesis for accelerating wound repair in tumor-bearing and infected wound mice. Taken together, GG@PANI(Fe)-borax hydrogels may be used simultaneously for eradication of skin-tumor cells, inhibiting infection and accelerating wound healing. This work offers an effective and facile strategy to fabricate an "all-in-one" multifunctional hydrogel platform for synergetic multimodal integrated therapy of tumors.

A NIR-II light-modulated injectable self-healing hydrogel for synergistic photothermal/chemodynamic/chemo-therapy of melanoma and wound healing promotion.

Photodynamic therapy (PDT) has provided a promising approach for the treatment of solid tumors, while the therapeutic efficacy is often limited due to the hypoxic tumor microenvironment, resulting in tumor metastasis. Herein, we report an oxygen-producing proenzyme hydrogel (OPeH) with photoactivatable enzymatic activity for PDT enabled metastasis-inhibiting combinational therapy of breast cancer. This OPeH based on alginate is composed of protoporphyrin IX (PpIX) conjugated manganese oxide (MnO2) nanoparticles, which act as both the photosensitizer and oxygen-producing agent, and singlet oxygen (1O2)-responsive proenzyme nanoparticles. In the hypoxic and acidic tumor microenvironment, MnO2 can generate 1O2 to promote PpIX-mediated PDT with an amplified 1O2 generation efficiency, which also triggers the cleavage of 1O2-responsive linkers and cascade activation of proenzymes for cancer cell death. This combinational therapy upon photoactivation not only greatly inhibited the tumor growth, but also suppressed lung metastasis in a mouse xenograft breast tumor model, which is impossible in the case of PDT alone. This study thus provides a proenzyme hydrogel platform with photoactivatable activity for metastasis-inhibiting cancer therapy with high efficacy and safety.

Oxygen-producing proenzyme hydrogels for photodynamic-mediated metastasis-inhibiting combinational therapy

As a promising treatment option for cancer, immunotherapy can eliminate local and distant metastatic tumors and even prevent recurrence through boosting the body's immune system. However, immunotherapy often encounters the issues of limited therapeutic efficacy and severe immune-related adverse events in clinical practices, which should be mainly due to the non-specific accumulations of immunotherapeutic agents. Activatable immunomodulatory agents that are responsive to endogenous stimuli in tumor microenvironment can afford controlled immunotherapeutic actions, while they still face certain extent of off-target activation. Since light has the advantages of noninvasiveness, simple controllability and high spatio-temporal selectivity, therapeutic agents that can be activated by light, particularly near-infrared (NIR) light with minimal phototoxicity and strong tissue penetrating ability have been programmed for cancer treatment. In this mini review, we summarize the recent progress of NIR photoactivatable immunomodulatory nanoparticles for combinational cancer immunotherapy. The rational designs, constructions and working mechanisms of NIR photoactivatable agents are first briefly introduced. The uses of immunomodulatory nanoparticles with controlled immunotherapeutic actions upon NIR photoactivation for photothermal and photodynamic combinational immunotherapy of cancer are then summarized. A conclusion and discussion of the existing challenges and further perspectives for the development and clinical translation of NIR photoactivatable immunomodulatory nanoparticles are finally given.

/pdf/near-infrared-photoactivatable-immunomodulatory-1xzilrgpek.pdf

Near-Infrared Photoactivatable Immunomodulatory Nanoparticles for Combinational Immunotherapy of Cancer.

Photothermal therapy (PTT) that utilizes hyperthermia to ablate cancer cells is a promising approach for cancer therapy, while the generated high temperature may lead to damage of surrounding normal tissues and inflammation. We herein report the construction of glucose oxidase (GOx)-loaded hydrogels with a pH-sensitive photothermal conversion property for combinational cancer therapy at mild-temperature. The hydrogels (defined as CAG) were formed via coordination of alginate solution containing pH-sensitive charge-transfer nanoparticles (CTNs) as the second near-infrared (NIR-II) photothermal agents and GOx. In the tumor sites, GOx was gradually released from CAG to consume glucose for tumor starvation and aggravate acidity in tumor microenvironment that could turn on the NIR-II photothermal conversion property of CTNs. Meanwhile, the released GOx could suppress the expression of heat shock proteins to enable mild NIR-II PTT under 1,064 nm laser irradiation. As such, CAG mediated a combinational action of mild NIR-II PTT and starvation therapy, not only greatly inhibiting the growth of subcutaneously implanted tumors in a breast cancer murine model, but also completely preventing lung metastasis. This study thus provides an enzyme loaded hydrogel platform with a pH-sensitive photothermal effect for mild-temperature-mediated combinational cancer therapy.

/pdf/enzyme-loaded-ph-sensitive-photothermal-hydrogels-for-mild-f8l6xo8xs8.pdf

Enzyme-Loaded pH-Sensitive Photothermal Hydrogels for Mild-temperature-mediated Combinational Cancer Therapy.

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Oxygen-producing proenzyme hydrogels for photodynamic-mediated metastasis-inhibiting combinational therapy

Near-Infrared Photoactivatable Immunomodulatory Nanoparticles for Combinational Immunotherapy of Cancer.

Enzyme-Loaded pH-Sensitive Photothermal Hydrogels for Mild-temperature-mediated Combinational Cancer Therapy.