Autophagy inhibition mediated via an injectable and NO-releasing hydrogel for amplifying the antitumor efficacy of mild magnetic hyperthermia.

While mild hyperthermia holds great potential in the treatment of solid tumors, the thermal stress-triggered self-repairing autophagy significantly compromises its efficacy. To circumvent this obstacle, an injectable hydrogel (NO-Gel) composed of thermosensitive poly(ethylene glycol)-polypeptide copolymers modified with abundant NO donors on their side chains is developed. Meanwhile, ferrimagnetic Zn0.5Fe2.5O4 magnetic nanoparticles (MNPs) with high magnetic-heat conversion efficiency are synthesized and loaded into NO-Gel to obtain MNPs@NO-Gel. The MNPs@NO-Gel system exhibits a sol-gel transition upon heating, and has the ability to perform multiple magnetic hyperthermia therapy (MHT) after only one administration due to the even distribution and strong immobilization of MNPs in NO-Gel. NO can be continuously liberated from NO-Gel and this process is markedly accelerated by MHT. Additionally, MNPs@NO-Gel maintains its integrity in vivo for over one month and the released MNPs are metabolized by the spleen. After a single administration of MNPs@NO-Gel at the tumor site, three mild MHT treatments with similar effects are fulfilled, and the sufficient supply of NO effectively inhibits MHT-induced autophagic flux via blocking the formation of autophagosomes and synchronously destroying lysosomes, thereby substantially boosting the efficacy of mild MHT. As a consequence, CT-26 colon tumors are completely eliminated without causing severe side-effects.

Firefly-inspired bipolar information indication system actuated by white light.

The indication of information in materials is widely used in our daily life, and optical encoding materials are ideal for information loading due to their easily readable nature and adjustable optical properties. However, most of them could only indicate one type of information, either changing or unchanging due to the mutual interference. Inspired by firefly, we present a non-interfering bipolar information indication system capable of indicating both changing and unchanging information. A photochemical afterglow material is incorporated into the photonic crystal matrix through a high-throughput technique called shear-induced ordering technique, which can efficiently produce large-area photonic crystal films. The indication of changing and unchanging information is enabled by two different utilizations of white light by the afterglow material and photonic crystals, respectively, which overcome the limitations of mutual interference. As a proof of concept, this system is used to indicate the changing photodegradation level of mecobalamin (a photosensitive medicine) and unchanging intrinsic drug information with anti-counterfeiting functionality, which is a promising alternative to instantly ascertain the efficacy of medicine at home where conventional assays are impractical.

Effects of serum proteins on corrosion rates and product bioabsorbability of biodegradable metals.

Corrodible metals are the newest kind of biodegradable materials and raise a new problem of the corrosion products. However, the removal of the precipitated products has been unclear and even largely ignored in publications. Herein, we find that albumin, an abundant macromolecule in serum, enhances the solubility of corrosion products of iron in blood mimetic Hank's solution significantly. This is universal for other main biodegradable metals such as magnesium, zinc and polyester-coated iron. Albumin also influences corrosion rates in diverse trends in Hank's solution and normal saline. Based on quantitative study theoretically and experimentally, both the effects on corrosion rates and soluble fractions are interpreted by a unified mechanism, and the key factor leading to different corrosion behaviors in corrosion media is the interference of albumin to the Ca/P passivation layer on the metal surface. This work has illustrated that the interactions between metals and media macromolecules should be taken into consideration in the design of the next-generation metal-based biodegradable medical devices in the formulism of precision medicine. The improved Hank's solution in the presence of albumin and with a higher content of initial calcium salt is suggested to access biodegradable metals potentially for cardiovascular medical devices, where the content of calcium salt is calculated after consideration of chelating of calcium ions by albumin, resulting in the physiological concentration of free calcium ions.

An injectable and active hydrogel induces mutually enhanced mild magnetic hyperthermia and ferroptosis.

Magnetic hyperthermia therapy (MHT) is a promising new modality to deal with solid tumors, yet the low magnetic-heat conversion efficacy, magnetic resonance imaging (MRI) artifacts, easy leakage of magnetic nanoparticles, and thermal resistance are the main obstacles to expand its clinical applications. Herein, a synergistic strategy based on a novel injectable magnetic and ferroptotic hydrogel is proposed to overcome these bottlenecks and boost the antitumor efficacy of MHT. The injectable hydrogel (AAGel) exhibiting a sol-gel transition upon heating is made of arachidonic acid (AA)-modified amphiphilic copolymers. Ferrimagnetic Zn0.4Fe2.6O4 nanocubes with high-efficiency hysteresis loss mechanism are synthesized and co-loaded into AAGel with RSL3, a potent ferroptotic inducer. This system maintains the temperature-responsive sol-gel transition, and provides the capacity of multiple MHT and achieves accurate heating after a single injection owing to the firm anchoring and uniform dispersion of nanocubes in the gel matrix. The high magnetic-heat conversion efficacy of nanocubes coupled with the application of echo limiting effect avoids the MRI artifacts during MHT. Besides the function of magnetic heating, Zn0.4Fe2.6O4 nanocubes combined with multiple MHT can sustain supply of redox-active iron to generate reactive oxygen species and lipid peroxides and accelerate the release of RLS3 from AAGel, thus enhancing the antitumor efficacy of ferroptosis. In turn, the reinforced ferroptosis can alleviate the MHT-triggered thermal resistance of tumors by impairment of the protective heat shock protein 70. The synergy strategy achieves the complete elimination of CT-26 tumors in mice without causing local tumor recurrence and other severe side effects.

Imaging moiety-directed co-assembly for biodegradation control with synchronous four-modal biotracking.

The complexity of existing methods for biodegradation control limits the multi-functionality of biomedical materials. It is urgent to develop simple and straightforward strategies to control the biodegradation rate with precise tracking of various parameters in real-time. Here, we show an imaging moiety-directed co-assembly strategy, in which different imaging moieties bearing non-covalent interaction sites are covalently introduced into the poly (D,l-lactic acid) (PDLLA) chain as end groups, followed by alternate non-covalent interactions with polymer chains upon compression molding. This strategy takes advantage of a variety of bonding types (including CH-π, CH-F, etc.) to firmly integrate the PDLLA chains and strongly control the biodegradation rate, making the amorphous prototype degraded much slower than higher-molecular-weight counterparts, and the local inflammatory response is insignificant. On this basis, a synchronous four-modal (X-ray computed tomography + fluorescence + photoacoustics + ultrasound) imaging was achieved on the single entity in vivo, even within a millimeter-scale thick-skin tissue. These imaging signals can precisely correlate the multi parameter variation trend of material mass, volume and molecular weight, signifying that co-assembly can be utilized to develop advanced theranostic systems. SINGLE SENTENCE SUMMARY: We developed an imaging moiety-directed co-assembly strategy to control the biodegradation rate and achieve the synchronization of real-time four-modal imaging in vivo. These imaging signals can precisely correlate the multi-parameter variation trend of material mass, volume and molecular weight, which provided comprehensive biomedical information accessing both qualitatively and quantitatively.

An injectable hemostatic PEG-based hydrogel with on-demand dissolution features for emergency care.

Uncontrolled bleeding from internal noncompressible wounds is a major cause of prehospital death in military personnel and civilian populations. An ideal hemostatic sealant for emergency care should quickly control blood loss and be removed without debridement for the follow-up treatment in the operating room, yet the lack of suitable materials to meet both requirements is the bottleneck. Herein, we suggest an injectable and dissolvable hydrogel sealant for hemorrhage management of noncompressible wounds. To this end, a 4-arm poly(ethylene glycol) (PEG) crosslinker modified with thioester linkages and terminated with aldehyde groups is designed and synthesized, and to modulate the gel properties and make it suitable as a hemostatic sealant, a mixed amino component composed of poly(ethylene imine) and adipic dihydrazide is employed to react with the PEG crosslinker to form the adhesive and elastic sealant for the first time. The aldehyde groups provide the adhesion to the tissues, and the amino component affords the procoagulant ability. More importantly, the thioester moieties allow the on-demand dissolution of sealant via a thiol-thioester exchange reaction upon exposure to an exogenous thiolate solution. In the rat femoral artery puncture and liver injury models, the administration of the hydrogel sealant dramatically reduces blood loss, and its subsequent removal does not induce rebleeding. Consequently, this hydrogel sealant with the unique feature of on-demand dissolution can not only efficiently control bleeding in emergent scenarios, but also allow non-traumatic re-exposure of wounds during subsequent surgical care. STATEMENT OF SIGNIFICANCE: Sealants, adhesives or hemostatic dressings currently used in emergency situations not only require manual pressure to control bleeding, but also face removal by cutting and mechanical debridement to enable eventual surgical treatment. In this study, we design and develop an injectable and adhesive hydrogel sealant with good procoagulant capacity and on-demand dissolution feature. The application of the hydrogel sealant substantially reduces bleeding from internal noncompressible wounds without the need for direct pressure, and demonstrates for the first time that its controlled removal without debridement does not cause rebleeding. Considering that there are currently no commercial wound sealant systems with the feature of on-demand dissolution, the hydrogel sealant developed by us is expected to address an unmet clinical need.

A Micro-Environment Regulator for Filling the Clinical Treatment Gap after a Glioblastoma Operation.

The rapid postoperative recurrence and short survival time of glioblastoma (GBM) patients necessitate immediate and effective postoperative treatment. Herein, an immediate and mild postoperative local treatment strategy is developed that regulates the postoperative microenvironment and delays GBM recurrence. Briefly, an injectable hydrogel system (imGEL) loaded with Zn(II)2 -AMD3100 (AMD-Zn) and CpG oligonucleotide nanoparticles (CpG NPs) is injected into the operation cavity, with long-term function to block the recruitment of microglia/ macrophages and activate cytotoxic T cells. The finding indicated that the imGEL can regulate the immune microenvironment, inhibit GBM recurrence, and gain valuable time for subsequent adjuvant clinical chemotherapy.

An oxygen-enriched thermosensitive hydrogel for the relief of a hypoxic tumor microenvironment and enhancement of radiotherapy.

The rapid proliferation of tumor cells and tortuous vasculature in solid tumors often bring about a hypoxic tumor microenvironment, which renders tumor cells more resistant to many cancer treatments, including radiotherapy. In this study, an injectable and thermosensitive composite hydrogel composed of perfluorooctanoic acid (PFOA) modified monomethoxy poly(ethylene glycol)-poly(D,L-lactide-co-glycolide) (mPEG-PLGA-PFOA) and perfluorooctyl bromide (PFOB) that presented a thermoreversible sol-gel transition upon heating was developed to deliver exogenous oxygen for the relief of tumor hypoxia and enhancement of radiotherapy. The fluorinated modification of copolymers significantly increased the stability of PFOB in the mPEG-PLGA-PFOA aqueous solution owing to the fluorophilic interaction between PFOB and PFOA-modified copolymers. The introduction of PFOB not only efficiently heightened the oxygen loading capacity of the composite hydrogel, but also endowed it with excellent X-ray opacity, allowing the visual observation of the hydrogel via micro-CT imaging. After peritumoral injection of the oxygen-enriched composite hydrogel, the continuous supply of oxygen effectively relieved tumor hypoxia and down-regulated the expression of hypoxia-inducible factor-1α. Profiting from this, the hyposensitivity of tumor cells to radiation was successfully reversed, and the tumor growth in mice was significantly suppressed and the survival of mice was prolonged when combined with multiple X-ray exposure. As a result, the oxygen-enriched composite hydrogel shows a great potential for radiosensitization to improve the radiotherapeutic efficacy.

Injectable hydrogels for the sustained delivery of a HER2-targeted antibody for preventing local relapse of HER2+ breast cancer after breast-conserving surgery.

A high risk of local relapse is the main challenge of HER2+ breast cancer after breast-conserving surgery. We aimed to develop a long-acting delivery system for Herceptin, a HER2-targeting antibody, using injectable and thermosensitive hydrogels as the carrier to prevent the local relapse of HER2+ breast tumors while minimizing systemic side effects, especially cardiotoxicity. Methods: Two poly(lactic acid-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers with different PEG/PLGA proportions were synthesized. Their mixtures with rational mix proportions displayed sol-gel transitions in water with rising of temperature and the Herceptin-loaded hydrogel systems were then prepared. Both the in vivo antitumor and anti-relapse efficacies were evaluated after hypodermic injection of the Herceptin-loaded hydrogel, and the cardiotoxicity was also detected. Results: The gel performance, degradation rate and drug release kinetics of hydrogels were easily adjustable by simply varying the mix proportion. The hydrogel matrix with a specific mix proportion not only avoided initial burst release but also achieved sustained release of Herceptin in vitro for up to 80 days, which is the longest period of Herceptin delivery that has ever been reported. In vivo biodistribution studies performed in SK-BR-3 tumor-bearing mice revealed that a single hypodermic administration of the Herceptin-loaded hydrogel adjacent to the tumor tissue promoted the intratumoral antibody accumulation. This resulted in a better antitumor efficacy compared to weekly hypodermic injections of Herceptin solution for 28 days. A tumor relapse model was also established by imitative breast-conserving surgery on tumor-bearing mice, and both the single injection of the Herceptin-loaded hydrogel and the weekly injection of the Herceptin solution achieved superior anti-relapse efficacy. Furthermore, both antitumor and anti-relapse experiments demonstrated that the weekly pulsed administration of the Herceptin solution caused cardiotoxicity; however, the sustained release of Herceptin from the hydrogel effectively prevented this side effect. Conclusion: The Herceptin-loaded hydrogel has great potential for preventing the relapse of HER2+ breast tumors after breast-conserving surgery with enhanced therapeutic efficacy, improved patient compliance and significantly reduced side effects.