ROS-responsive sprayable hydrogel as ROS scavenger and GATA6+ macrophages trap for the prevention of postoperative abdominal adhesions.

Postoperative abdominal adhesions are a common clinical problem after surgery and can cause many serious complications. Current most commonly used antiadhesion products are less effective due to their short residence time and focus primary on barrier function. Herein, we developed a sprayable hydrogel barrier (sHA-ADH/OHA-E) with self-regulated drug release based on ROS levels at the trauma site, to serve as a smart inflammatory microenvironment modulator and GATA6+ macrophages trap for non-adherent recovery from abdominal surgery. Sulfonated hyaluronic acid (HA) conjugates modified with adipic dihydrazide (sHA-ADH), and oxidized HA conjugates grafted with epigallocatechin-3-gallate (EGCG) via ROS-cleavable boronate bonds (OHA-E) were synthesized. sHA-ADH/OHA-E hydrogel was facilely fabricated within 5 s after simply mixing sHA-ADH and OHA-E through forming dynamic covalent acylhydrazones. With good biocompatibility, appropriate mechanical strength, tunable shear-thinning, self-healing, asymmetric adhesion, and reasonable in vivo retention time, sHA-ADH/OHA-E hydrogel meets the requirements of a perfect physical barrier. Intriguingly, sulfonic acid groups endowed the hydrogel with satisfactory anti-fibroblast and macrophage attachment capability, and were demonstrated for the first time to act as polyanion traps to prevent GATA6+ macrophages aggregation. Importantly, EGCG could be intelligently released by ROS triggering to alleviate oxidative stress and promote proinflammatory M1 macrophage polarize to antiinflammatory M2 phenotype. Further, the fibrinolytic system balance was restored to reduce fibrosis. Thanks to the above advantages, the sHA-ADH/OHA-E hydrogel exhibited excellent anti-adhesion effects in a rat sidewall defect-cecum abrasion model and is expected to be a promising and clinically translatable antiadhesion barrier.

Bortezomib prodrug catalytic nanoreactor for chemo/chemodynamic therapy and macrophage re-education.

Chemodynamic therapy (CDT), an emerging tumor-specific therapeutic modality, is frequently restrained by insufficient intratumoral Fenton catalysts and increasingly inefficient catalysis caused by the continuous consumption of limited H2O2 within tumors. Herein, we engineered a pH-responsive bortezomib (BTZ) polymer prodrug catalytic nanoreactor (HeZn@HA-BTZ) capable of self-supplying Fenton catalyst and H2O2. It is aimed for tumor-specific chemo/chemodynamic therapy via oxidative stress and endoplasmic reticulum (ER) stress dual-amplification and macrophage repolarization. A catechol­boronate bond-based hyaluronic acid-BTZ prodrug HA-DA-BTZ was modified on Hemin and Zn2+ coordination nanoscale framework (HeZn), an innovative CDT inducer, to construct He-Zn@HA-BTZ. He-Zn@HA-BTZ with good stability and superior peroxidase-like activity preferentially accumulated at tumor sites and be actively internalized by tumor cells. Under the cleavage of catechol­boronate bond in acidic endo/lysosomes, pre-masked BTZ was rapidly released to induce ubiquitinated protein aggregation, robust ER stress and elevated H2O2 levels. The amplified H2O2 was further catalyzed by HeZn via Fenton-catalytic reactions to produce hypertoxic •OH, enabling cascaded oxidative stress amplification and long-lasting effective CDT, which in turn aggravated BTZ-induced ER stress. Eventually, a dual-amplification of oxidative stress and ER stress was achieved to initiate cell apoptosis/necrosis with reduced BTZ toxicity. Intriguingly, He-Zn@HA-BTZ could repolarize macrophages from M2 to antitumor M1 phenotype for potential tumor therapy. This "all in one" prodrug nanocatalytic reactor not only enriches the CDT inducer library, but provides inspirational strategy for simultaneous oxidative stress and ER stress based excellent cancer therapy.

A DNA damage nanoamplifier for the chemotherapy of triple-negative breast cancer via DNA damage induction and repair blocking.

Due to a powerful DNA damage repair system and a lack of surface markers, there is currently no effective chemotherapy or tailored targeted therapies available for triple-negative breast cancer (TNBC) treatment. Herein, a tailored DNA damage nanoamplifier (Lipo@Nir/Pt(IV)C18) was engineered to simultaneously induce DNA damage and inhibit DNA reparation for highly efficient TNBC treatment. A newly synthesized Pt(IV)C18 prodrug, the DNA damaging inducer, and the hydrophobic poly(ADP-ribose) polymerases (PARPs) inhibitor niraparib, which is used as the DNA repair blocker, were concurrently encapsulated in highly biocompatible PEGylated liposomes to prepare Lipo@Nir/Pt(IV)C18, for enhanced cancer therapy and future clinical translation. Lipo@Nir/Pt(IV)C18 with an appropriate size and excellent stability, effectively accumulated at the tumor site. After internalization by tumor cells, niraparib, a highly-selective hydrophobic PARP1 inhibitor, could exacerbate the accumulation of platinum-induced DNA lesions to induce excessive genome damage for synergistic cell apoptosis, which was evidenced by the upregulated γ-H2AX and cleaved-PARP levels. Importantly, Lipo@Nir/Pt(IV)C18 exhibited remarkable antitumor efficacy on TNBC without BRCA mutants in vivo with little systemic toxicity. Inspired by the concept of "synthetic lethality", this study provides an inspirational and clinically transformable nanobased DNA damaging amplification strategy for the expansion of TNBC beneficiaries and highly efficient TNBC treatment via DNA damage induction and DNA repair blocking.

Reactive oxygen species-activated self-amplifying prodrug nanoagent for tumor-specific Cu-chelate chemotherapy and cascaded photodynamic therapy.

Disulfiram (DSF), an effective FDA-approved anti-alcoholism drug, shows potent antitumor activity by producing Cu(DTC)2, a chelate of its metabolite diethyldithiocarbamate (DTC) and copper. However, the rapid metabolism and unselective distribution of DSF and the insufficient endogenous copper severely restrict enough bioactive Cu(DTC)2 generation in tumor tissues to achieve satisfactory antitumor effect. Moreover, directly Cu(DTC)2 administration also suffers from serious systemic toxicity. Herein, a reactive oxygen species (ROS)-activatable self-amplifying prodrug nanoagent (HA-DQ@MOF) was developed for the stable co-delivery of DTC prodrug and Cu-quenched photosensitizer, aiming to achieve tumor-specific dual-activation of highly-toxic Cu(DTC)2-mediated chemotherapy and cascaded photodynamic therapy (PDT). The ROS-cleavable hyaluronic acid-conjugated DTC prodrug (HA-DQ) was decorated on Cu2+ and photosensitizer Zn-TCPP coordinated MOF (PDT-shielded state) to construct HA-DQ@MOF. HA-DQ@MOF could specifically activated in ROS-overexpressed tumor cells to rapidly release DTC, while remaining relatively stable in normal cells. The free DTC immediately grabbed Cu2+ from MOF to in situ generate highly-cytotoxic Cu(DTC)2 chelate, accompanied by MOF dissociation to restore the PDT effect of Zn-TCPP. Importantly, ROS produced by PDT could in turn trigger more DTC release, which further promoted Zn-TCPP liberation, forming a self-amplifying prodrug/photosensitizer activation positive feedback loop. Experimental results confirmed the dual-activated and combined tumor-killing effect of Cu(DTC)2-mediated chemotherapy and Zn-TCPP-based PDT with little systemic toxicity. This work provides a dual-activated "low toxic-to-toxic" transformable treatment pattern for tumor-specific chemo-photodynamic therapy.

Glutathione-responsive copper-disulfiram nanoparticles for enhanced tumor chemotherapy.

Disulfiram (DSF), a familiar FDA-approved drug used for alcohol withdrawal, has recently been verified with potent antitumor therapeutic effect by generating Cu(DTC)2, which is the complex of its metabolite diethyldithiocarbamate (DTC) and copper. However, its poor tumor selectivity and insufficient endogenous Cu2+ concentration within tumor site largely hinders the application of DSF-based antitumor therapy. Therefore, a GSH-responsive coordination nanoparticles (Cu-IXZ@DSF) was established as a copper carrier to achieve synchronous but separate delivery of Cu2+ and DSF without antitumor ability, further to realize selectively triggered tumor in situ Cu(DTC)2 generation for antitumor therapy. A widely-used proteasome inhibitor ixazomib (IXZ) was chosen as ligands and Cu2+ was used as coordination nodes to form nanosized Cu-IXZ@DSF. The DSF encapsulated in Cu-IXZ@DSF could be reduced to DTC by intracellular GSH, which could contend for Cu2+ and realize in situ high toxic Cu(DTC)2 generation. Meanwhile, the chelation could lead to the disassembly of Cu-IXZ@DSF and release of IXZ to eventually achieve tumor specific "transformation from low toxicity to high toxicity" chemotherapy. The results of in vitro and in vivo experiments demonstrated that the as-prepared nanoplatform Cu-IXZ@DSF showed good biosafety and excellent antitumor effect via endoplasmic reticulum stress (ERS) as well as reactive oxygen species (ROS) generation pathway. Therefore, this nanocarrier provides an inspiring strategy with specific-triggered antitumor Cu(DTC)2 generation for DSF-based chemotherapy with high therapeutic effect and biosafety and showing great potential of treating cancer.

Discovery of a Potent Glutathione Peroxidase 4 Inhibitor as a Selective Ferroptosis Inducer.

Potent and selective ferroptosis regulators promote an intensive understanding of the regulation and mechanisms underlying ferroptosis, which is highly associated with various diseases. In this study, through a stepwise structure optimization, a potent and selective ferroptosis inducer was developed targeting to inhibit glutathione peroxidase 4 (GPX4), and the structure-activity relationship (SAR) of these compounds was uncovered. Compound 26a exhibited outstanding GPX4 inhibitory activity with a percent inhibition up to 71.7% at 1.0 µM compared to 45.9% of RSL-3. At the cellular level, 26a could significantly induce lipid peroxide (LPO) increase and effectively induce ferroptosis with satisfactory selectivity (the value of 31.5). The morphological analysis confirmed the ferroptosis induced by 26a. Furthermore, 26a significantly restrained tumor growth in a mouse 4T1 xenograft model without obvious toxicity.

Phototriggered Self-Adaptive Functionalized MOC-Based Drug Delivery Platform Promises High Antitumor Efficacy.

Due to their great stability and special cavities, metal-organic cages (MOCs) are increasingly considered as promising nanocarriers for drug delivery. However, the size and surface dilemmas restrict their further biomedical applications. The ultrasmall size of MOCs facilitates tumor penetration but suffers from quick clearance and poor accumulation at the tumor site. Hydrophobicity of MOC surfaces improves internalization into tumor cells while causing low blood circulation time as well as poor biocompatibility. Therefore, it remains challenging for the MOC-based drug delivery nanoplatform to realize high therapeutic efficacy because it requires different or even opposite dimensions and surface characteristics in different steps of circulation, penetration, accumulation, and internalization processes. In this study, an unprecedented phototriggered self-adaptive platform (ZnPc@polySCage) is developed by integrating functionalized MOCs and a photodynamic therapy based reactive oxygen species responsive strategy to realize high-efficiency tumor-specific therapy. ZnPc@polySCage remains hydrophilic and stealthy during circulation, and retains its small original size for tumor penetration, while transforming to a larger size for effective accumulation and hydrophobic for enhanced internalization under laser irradiation in tumor tissue. With these essential transitions, ZnPc@polySCage demonstrates prominent antitumor effects. Overall, the work provides an advantageous strategy for functional MOC-based platforms and biomedical applications.

Engineered macrophages as near-infrared light activated drug vectors for chemo-photodynamic therapy of primary and bone metastatic breast cancer.

Patients with primary and bone metastatic breast cancer have significantly reduced survival and life quality. Due to the poor drug delivery efficiency of anti-metastasis therapy and the limited response rate of immunotherapy for breast cancer, effective treatment remains a formidable challenge. In this work, engineered macrophages (Oxa(IV)@ZnPc@M) carrying nanomedicine containing oxaliplatin prodrug and photosensitizer are designed as near-infrared (NIR) light-activated drug vectors, aiming to achieve enhanced chemo/photo/immunotherapy of primary and bone metastatic tumors. Oxa(IV)@ZnPc@M exhibits an anti-tumor M1 phenotype polarization and can efficiently home to primary and bone metastatic tumors. Additionally, therapeutics inside Oxa(IV)@ZnPc@M undergo NIR triggered release, which can kill primary tumors via combined chemo-photodynamic therapy and induce immunogenic cell death simultaneously. Oxa(IV)@ZnPc@M combined with anti-PD-L1 can eliminate primary and bone metastatic tumors, activate tumor-specific antitumor immune response, and improve overall survival with limited systemic toxicity. Therefore, this all-in-one macrophage provides a treatment platform for effective therapy of primary and bone metastatic tumors.

Reduction-responsive dehydroepiandrosterone prodrug nanoparticles loaded with camptothecin for cancer therapy by enhancing oxidation therapy and cell replication inhibition.

The pentose phosphate pathway (PPP) plays a critical role by providing ribulose-5-phosphate (Ru5P) and NADPH for nucleotide synthesis and reduction energy, respectively. Accordingly, blocking the PPP process may be an effective strategy for enhancing oxidation therapy and inhibiting cell replication. Here, we designed a novel reduction-responsive PEGylated prodrug and constructed nanoparticles PsD@CPT to simultaneously deliver a PPP blocker, dehydroepiandrosterone (DHEA), and chemotherapeutic camptothecin (CPT) to integrate amplification of oxidation therapy and enhance cell replication inhibition. Following cellular uptake, DHEA and CPT were released from PsD@CPT in the presence of high glutathione (GSH) levels. As expected, DHEA-mediated reduction level decreases and CPT-induced oxidation level increases synergistically, breaking the redox balance to aggravate cancer oxidative stress. In addition, suppressing nucleotide synthesis by DHEA through the reduction of Ru5P and blocking DNA replication by CPT further motivates a synergistic inhibition effect on tumor cell proliferation. The results showed that PsD@CPT featuring multimodal treatment has satisfactory antitumor activity both in vitro and in vivo. This study provides a new tumor treatment strategy, which combines the amplification of oxidative stress and enhancement of inhibition of cell proliferation based on inhibition of the PPP process.

Bone-seeking nanoplatform co-delivering cisplatin and zoledronate for synergistic therapy of breast cancer bone metastasis and bone resorption.

The "vicious cycle" established between tumor growth and osteolysis aggravates the process of breast cancer bone metastasis, leading to life-threatening skeletal-related events that severely reduce survival and quality of life. To effectively interrupt the "vicious cycle", innovative therapeutic strategies that not only reduce osteolysis but also relieve tumor burden are urgently needed. Herein, a bone-seeking moiety, alendronate (ALN), functionalized coordination polymer nanoparticles (DZ@ALN) co-delivering cisplatin prodrug (DSP) and antiresorptive agent zoledronate (ZOL) via Zn2+ crosslinking for combination therapy was reported. The versatile DZ@ALN with a diameter of about 40 nm can cross the fissure in the bone marrow sinus capillaries, and possesses an excellent bone-seeking ability both in vitro and in vivo. Additionally, DZ@ALN could synergistically inhibit the proliferation of cancer cells, suppress the formation of osteoclast-like cells and induce the apoptosis of osteoclasts in vitro. Importantly, it could preferentially accumulate in bone affected site, remarkably inhibit the proliferation of tumor cells, relieving bone pain, and significantly inhibit the activation of osteoclasts, protecting the bone from destruction in vivo, eventually leading to the breakdown of "vicious cycle" without inducing obvious systemic toxicity. This innovative nanoagent combines chemotherapy and osteolysis inhibition, exhibiting an inspiring strategy for effective treatment of bone metastasis.

Broaden sources and reduce expenditure: Tumor-specific transformable oxidative stress nanoamplifier enabling economized photodynamic therapy for reinforced oxidation therapy.

Cancer cells immersed in inherent oxidative stress are more vulnerable to exogenous oxidative damages than normal cells. Reactive oxygen species (ROS)-mediated oxidation therapy preferentially aggravating tumor oxidative stress to disrupt redox homeostasis, has emerged as an effective and specific anticancer treatment. Herein, following an ingenious strategy of "broaden sources and reduce expenditure", we designed a versatile tumor-specific oxidative stress nanoamplifier enabling economized photodynamic therapy (PDT), to achieve synergistic oxidative stress explosion for superior oxidation therapy. Methods: Cinnamaldehyde (CA) as a therapeutic ROS generator was first conjugated to hyaluronic acid (HA) through acid-labile hydrazone bond to synthesize tailored amphiphilic HA@CA conjugates, which could surprisingly self-assemble into uniform nanofibers in aqueous media. Photosensitizer protoporphyrin (PpIX) was efficiently encapsulated into HA@CA nanofibers and transformed HA@CA nanofibers to final spherical HA@CAP. Results: With beneficial pH-responsiveness and morphology transformation, improved bioavailability and selective tumor accumulation, HA@CAP combining ROS-based dual chemo/photodynamic treatment modalities could induce cytotoxic ROS generation in a two-pronged approach to amplify tumor oxidative stress, termed "broaden sources". Moreover, utilizing CA-induced H2O2 production and cascaded Fenton reaction in mitochondria to consume intracellular overloaded Fe(II), HA@CAP could skillfully block endogenic heme biosynthesis pathway on site to restrain undesired elimination of PpIX for economized PDT, termed "reduce expenditure". Both in vitro and in vivo results demonstrated the superior antitumor performance of HA@CAP. Conclusion: This study offered an inspiring strategy of "broaden sources and reduce expenditure" to specifically boost tumor oxidative stress for reinforced oxidation therapy.

A light-triggered self-reinforced nanoagent for targeted chemo-photodynamic therapy of breast cancer bone metastases via ER stress and mitochondria mediated apoptotic pathways.

Current therapeutic strategies for the treatment of bone metastases are often limited by the lack of selectivity, severe systemic toxicity and suboptimal efficacy. Nanomedicine meditated chemo-photodynamic therapy provides a promising therapeutic opportunity for enhanced cancer therapy. Herein, we constructed an alendronate (ALN)-functionalized bone-seeking nanoagent (BTZ@ZnPc-ALN) to co-deliver the proteasome inhibitor bortezomib (BTZ) and the photosensitizer Zinc phthalocyanine (ZnPc) for synergistic chemo-photodynamic therapy of bone metastases. Results showed that BTZ@ZnPc-ALN possessed favorable bone affinity both in vitro and in vivo and could release drug in a pH-responsive manner. Under irradiation, BTZ@ZnPc-ALN could generate reactive oxygen species (ROS) to cause mitochondrial damage, and increase the cytosolic Ca2+ levels and the expression of GRP78 protein to induce excessive endoplasmic reticulum (ER) stress, thereby synergistically inhibiting cell proliferation. More importantly, BTZ@ZnPc-ALN could prolong blood circulation time and preferentially navigate to the bone affected site. As a result, tumor growth was significantly inhibited by bone targeted chemo-photodynamic therapy, with tumor volume cut down by 85% compared with PBS group and bone remained undamaged. Besides, the systemic toxicity of BTZ was significantly reduced. Therefore, the versatile nanoagent is expected to be a promising nanoplatform to concern multiple intracellular stress for remarkable synergistic chemo-photodynamic therapy of bone metastases.