Drug repurposing-based nanoplatform via modulating autophagy to enhance chemo-phototherapy against colorectal cancer.

Multi-modal combination therapy is regarded as a promising approach to cancer treatment. Combining chemotherapy and phototherapy is an essential multi-modal combination therapy endeavor. Ivermectin (IVM) is a potent antiparasitic agent identified as having potential antitumor properties. However, the fact that it induces protective autophagy while killing tumor cells poses a challenge to its further application. IR780 iodide (IR780) is a near-infrared (NIR) dye with outstanding photothermal therapy (PTT) and photodynamic therapy (PDT) effects. However, the hydrophobicity, instability, and low tumor uptake of IR780 limit its clinical applications. Here, we have structurally modified IR780 with hydroxychloroquine, an autophagy inhibitor, to synthesize a novel compound H780. H780 and IVM can form H780-IVM nanoparticles (H-I NPs) via self-assembly. Using hyaluronic acid (HA) to modify the H-I NPs, a novel nano-delivery system HA/H780-IVM nanoparticles (HA/H-I NPs) was synthesized for chemotherapy-phototherapy of colorectal cancer (CRC). Under NIR laser irradiation, HA/H-I NPs effectively overcame the limitations of IR780 and IVM and exhibited potent cytotoxicity. In vitro and in vivo experiment results showed that HA/H-I NPs exhibited excellent anti-CRC effects. Therefore, our study provides a novel strategy for CRC treatment that could enhance chemo-phototherapy by modulating autophagy.

Comparing the Efficacy of Video-Assisted Thoracoscopic Surgery and Open Thoracotomy in Sleeve Lobectomy for the Treatment of Central-Type Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Objective: Central-type Non-small Cell Lung Cancer (NSCLC) treatment involves different surgical techniques, including Video-Assisted Thoracoscopic Surgery (VATS) and Open Thoracotomy Sleeve Lobectomy. However, there remains a lack of consensus on the most effective treatment modality. Methods: This study strictly adhered to PRISMA guidelines. Four electronic databases were searched without time or language limitation, and studies comparing VATS and Open Thoracotomy in patients with central-type NSCLC undergoing sleeve lobectomy were included. Primary outcomes were perioperative outcomes (blood loss, operation time, intraoperative lymph node dissection count, postoperative hospital stay, and complication rates), 3-year Progression-Free Survival (PFS) rate, and Overall Survival (OS) rate. Results: The meta-analysis included six studies with 569 patients. VATS was associated with longer operation time [SMD = 0.75, 95% CI (0.29, 1.21)], less intraoperative blood loss [SMD = -0.23; 95% CI (-0.44, -0.01)], and shorter hospital stay [SMD = -0.53; 95% CI (-0.73, -0.34)]. There were no significant differences in the number of lymph nodes dissected, postoperative complications, and 3-year PFS and OS rates between the two groups. Conclusions: VATS sleeve lobectomy for central-type NSCLC results in less surgical trauma and quicker postoperative recovery without adversely impacting tumor prognosis compared to open thoracotomy sleeve lobectomy. Despite a longer operation time, VATS could be considered an alternative to open thoracotomy sleeve lobectomy. VATS sleeve lobectomy is a safe and effective alternative to open thoracotomy in treating central-type NSCLC, as it results in less surgical trauma and quicker postoperative recovery without impacting tumor prognosis negatively. More well-designed randomized controlled trials are required to verify these findings.

Chemo-photothermal nanoplatform with diselenide as the key for ferroptosis in colorectal cancer.

Colorectal cancer (CRC) is a prevalent clinical malignancy of the gastrointestinal system, and its clinical drug resistance is the leading cause of poor prognosis. Mechanistically, CRC cells possess a specific oxidative stress defense mechanism composed of a significant number of endogenous antioxidants, such as glutathione, to combat the damage produced by drug-induced excessive reactive oxygen species (ROS). We report on a new anti-CRC nanoplatform, a multifunctional chemo-photothermal nanoplatform based on Camptothecin (CPT) and IR820, an indocyanine dye. The implementation of a GSH-triggered ferroptosis-integrated tumor chemo-photothermal nanoplatform successfully addressed the poor targeting ability of CPT and IR820 while exhibiting significant growth inhibitory effects on CRC cells. Mechanistically, to offset the oxidative stress created by the broken SeSe bonds, endogenous GSH was continuously depleted, which inactivated GPX4 to accumulate lipid peroxides and induce ferroptosis. Concurrently, exogenously administered linoleic acid was oxidized under photothermal conditions, resulting in an increase in LPO accumulation. With the breakdown of the oxidative stress defense system, chemotherapeutic efficacy could be effectively enhanced. In combination with photoacoustic imaging, the nanoplatform could eradicate solid tumors by means of ferroptosis-sensitized chemotherapy. This study indicates that chemotherapy involving a ferroptosis mechanism is a viable method for the treatment of CRC.

Photothermal-Starvation Therapy Nanomodulator Capable of Inhibiting Colorectal Cancer Recurrence and Metastasis by Energy Metabolism Reduction.

The recurrence and metastasis of colorectal cancer (CRC) have been considered as a severe challenge in clinical treatment. Recent studies have demonstrated that matrix metalloproteinases (MMPs) and lactate can promote local tumor angiogenesis, recurrence, and metastasis. The expression of MMPs is highly dependent on energy metabolism, and lactate is considered an alternative energy source for tumor proliferation and metastasis. Therefore, using a rational approach, a photothermal-starvation therapy nanomodulator that can reduce energy metabolism to suppress CRC recurrence and metastasis is designed. To design a suitable nanomodulator, glucose oxidase (GOX), indocyanine green (IR820), and α-cyano-4-hydroxycinnamic acid (CHC) into nanoparticles by a coassembly method are combined. The photothermal properties of IR820 provide the appropriate temperature and oxygen supply for the enzymatic reaction of GOX to promote intracellular glucose consumption. CHC inhibits the expression of monocarboxylate transporter 1 (MCT1), the transporter of lactic acid into cells, and also reduces oxygen consumption and promotes the GOX reaction. Additionally, altering adenosine triphosphate synthesis to block heat shock proteins expression can be an effective means to prevent IR820-mediated photothermal therapy resistance. Thus, this dual photothermal-starvation therapy nanomodulator efficiently suppresses the recurrence and metastasis of CRC by depleting intracellular nutrients.

Oxidative Stress, Inflammation, Gut Dysbiosis: What Can Polyphenols Do in Inflammatory Bowel Disease?

Inflammatory bowel disease (IBD) is a long-term, progressive, and recurrent intestinal inflammatory disorder. The pathogenic mechanisms of IBD are multifaceted and associated with oxidative stress, unbalanced gut microbiota, and aberrant immune response. Indeed, oxidative stress can affect the progression and development of IBD by regulating the homeostasis of the gut microbiota and immune response. Therefore, redox-targeted therapy is a promising treatment option for IBD. Recent evidence has verified that Chinese herbal medicine (CHM)-derived polyphenols, natural antioxidants, are able to maintain redox equilibrium in the intestinal tract to prevent abnormal gut microbiota and radical inflammatory responses. Here, we provide a comprehensive perspective for implementing natural antioxidants as potential IBD candidate medications. In addition, we demonstrate novel technologies and stratagems for promoting the antioxidative properties of CHM-derived polyphenols, including novel delivery systems, chemical modifications, and combination strategies.

Nano-Econazole Enhanced PD-L1 Checkpoint Blockade for Synergistic Antitumor Immunotherapy against Pancreatic Ductal Adenocarcinoma.

Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo-phototherapy nanoplatform is designed by which econazole and biliverdin can be co-assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD-L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin-induced PTT/PDT and boost the immunotherapeutic response of PD-L1 blockade. In addition, econazole simultaneously enhances PD-L1 expression to sensitize anti-PD-L1 therapy, leading to suppression of distant tumors, long-term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8+ T lymphocytes. The combined FBE NPs and α-PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo-phototherapy with PD-L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy.

Site-specific nanomodulator capable of modulation apoptosis for enhanced colorectal cancer chemo-photothermal therapy.

BACKGROUND: Colorectal cancer (CRC) is a common malignancy with the second highest mortality and the third highest morbidity worldwide. However, the overall survival of patients is unsatisfactory, thus requiring more effective clinical strategies. Celastrol (CLT), a natural bioactive compound, has been reported to induce reactive oxygen species (ROS)-mediated apoptosis to exhibit significant antitumor effects against CRC. However, the poor water solubility, low targeting ability, and bioavailability of CLT have limited its application, and CLT-induced protective autophagy weakens its therapeutic efficiency. RESULTS: We designed a targeted chemo-phototherapy nanoplatform (HCR NPs) to improve the application of CLT. The codelivery of IR820 and CLT in HCR NPs solved the water-soluble problem of CLT and enhanced apoptosis via IR820-mediated hyperthermia. In addition, hydroxychloroquine (HCQ) conjugated to hyaluronic acid (HA) not only increased the active targeting of HCR NPs but also inhibited CLT-induced protective autophagy to exacerbate apoptosis, thus achieving an amplified antitumor effect. Importantly, the HCR NPs exhibited an excellent therapeutic effect on CRC both in vitro and in vivo. CONCLUSION: The HCR NPs presented in this study may not merely provide a new reference for the clinical application of CLT but also result in an attractive strategy for CRC treatment.

Exploiting Polyphenol-Mediated Redox Reorientation in Cancer Therapy.

Polyphenol, one of the major components that exert the therapeutic effect of Chinese herbal medicine (CHM), comprises several categories, including flavonoids, phenolic acids, lignans and stilbenes, and has long been studied in oncology due to its significant efficacy against cancers in vitro and in vivo. Recent evidence has linked this antitumor activity to the role of polyphenols in the modulation of redox homeostasis (e.g., pro/antioxidative effect) in cancer cells. Dysregulation of redox homeostasis could lead to the overproduction of reactive oxygen species (ROS), resulting in oxidative stress, which is essential for many aspects of tumors, such as tumorigenesis, progression, and drug resistance. Thus, investigating the ROS-mediated anticancer properties of polyphenols is beneficial for the discovery and development of novel pharmacologic agents. In this review, we summarized these extensively studied polyphenols and discussed the regulatory mechanisms related to the modulation of redox homeostasis that are involved in their antitumor property. In addition, we discussed novel technologies and strategies that could promote the development of CHM-derived polyphenols to improve their versatile anticancer properties, including the development of novel delivery systems, chemical modification, and combination with other agents.

A nanoplatform reshaping intracellular osmolarity and redox homeostasis against colorectal cancer.

Colorectal cancer (CRC) is the second most deadly cancer worldwide, with chemoresistance remaining a major obstacle in CRC treatment. Sodium persulfate (Na2S2O8) is a novel agent capable of producing •SO4- and Na+ for chemodynamic therapy (CDT). This can induce pyroptosis and ferroptosis instead of conventional apoptosis in tumor cells. Meanwhile, IR780-iodide (IR780), as an excellent phototherapy agent, can generate hyperthermia and generate a large amount of reactive oxygen species (ROS) to synergize with the CDT of Na2S2O8, with potential to overcome chemoresistance in CRC. However, the low stability of Na2S2O8 and the poor solubility of IR780 limit their applications in the medical field. Accordingly, for the first time, D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS), Na2S2O8 and IR780 were rationally designed in a cascade-amplifying nanoplatform (Na2S2O8-IR780 NPs) via a co-assembly strategy. Combining Na2S2O8 and IR780 in a nanoplatform improves the stability of Na2S2O8 and the solubility of IR780. As a result, the Na2S2O8-IR780 NPs exhibited excellent antitumor efficacy in CRC cell lines and five chemo-resistant cell lines and showed potent inhibitory capability in nude mice xenograft models. This photo-chemodynamic nanoplatform provides a brand-new paradigm by manipulating osmolarity and redox homeostasis to overcome chemo-resistance and holds great potential for the treatment of CRC.

Nanoengineering a Zeolitic Imidazolate Framework-8 Capable of Manipulating Energy Metabolism against Cancer Chemo-Phototherapy Resistance.

Chemo-phototherapy has emerged as a promising approach to complement traditional cancer treatment and enhance therapeutic effects. However, it still faces the challenges of drug efflux transporter-mediated chemoresistance and heat shock proteins (HSPs)-mediated phototherapy tolerance, which both depend on an excessive supply of adenosine triphosphate. Therefore, manipulating energy metabolism to impair the expression or function of P-glycoprotein (P-gp) and HSPs may be a prospective strategy to reverse cancer therapeutic resistance. Herein, a chondroitin sulfate (CS)-functionalized zeolitic imidazolate framework-8 (ZIF-8) chemo-phototherapy nanoplatform (CS/ZIF-8@A780/DOX NPs) is rationally designed that is capable of manipulating energy metabolism against cancer therapeutic resistance by integrating the photosensitizer IR780 iodide (IR780)-conjugated atovaquone (ATO) (A780) and the chemotherapeutic agent doxorubicin (DOX). Mechanistically, ATO and zinc ions that are released in the acidic tumor microenvironment can lead to systematic energy exhaustion through disturbing mitochondrial electron transport and the glycolysis process, thus suppressing the activity of P-gp and HSP70, respectively. In addition, CS is used on the surface of ZIF-8@A780/DOX NPs to improve the targeting capability to tumor tissues. These data provide an efficient strategy for manipulating energy metabolism for cancer treatment, especially for overcoming cancer chemo-phototherapy resistance.

A targeted nanomodulator capable of manipulating tumor microenvironment against metastasis.

Recently, lactate has been considered as an alternative direct energy substance to glucose for tumor proliferation and metastasis. Meanwhile, mitochondria, as important energy-supplying organelles, are also closely related to tumor progression. Consequently, a new research direction for lactate comprises lactate deprivation coupled with mitochondria-targeted phototherapy to achieve a safer and more effective strategy against tumor metastasis. Herein, linoleic acid-conjugated hyaluronic acid (HL), disulfide bond-rich nanovehicle (mesoporous silica, MOS), mitochondria-targeted IR780 (M780) and lactate oxidase (LOD) are rationally designed as a specific-targeting metabolism nanomodulator (HL/MOS@M780&LOD NPs), fulfilling the task of simultaneous depriving cells of lactate and damaging mitochondria to prevent tumor metastasis. Interestingly, M780-mediated photodynamic therapy (PDT) and LOD-mediated starvation therapy can effectively exacerbate the hypoxia state of tumor cells, thereby increasing the free iron levels to activate ferroptosis. On one hand, pyruvic acid and H2O2 generated by LOD-mediated lactate metabolism can provide powerful conditions for iron-catalyzed ferroptosis. On the other, the depleted GSH and increased reactive oxygen species (ROS) can oxidize linoleic acid into lipid peroxides (LPO) to further augment ferroptosis. The designed nanomodulator therefore shows great promise for fighting tumor metastasis by manipulating energy metabolism and the hypoxia microenvironment.

Dietary serine supplementation: Friend or foe?

Serine lies at a critical node in biological processes involved in supplying intermediates for redox homeostasis, nucleotide, or lipid biosynthesis and one-carbon metabolism-coupled methyl donor production. Recently, dietary serine supplementation has been reported to modulate cellular serine levels and ameliorate neurological abnormalities induced by serine deficiency. Moreover, growing evidence showed that serine supplementation also alleviates fatty liver, encephalopathy, diabetes mellitus, and related complications, indicating the possibility of serine supplementation as a complementary therapeutic option. However, considering the serine addiction observed in tumorigenesis and tumor development, limitations may exist regarding the application of dietary serine supplementation in patients with cancer. Here, we assess recent research toward the mechanistic understanding of serine supplementation in various diseases to improve our cognition on modulating serine levels in different patients.

Oblongifolin M, an active compound isolated from a Chinese medical herb Garcinia oblongifolia, potently inhibits enterovirus 71 reproduction through downregulation of ERp57.

There is no effective drug to treat EV71 infection yet. Traditional Chinese herbs are great resources for novel antiviral compounds. Here we showed that Oblongifolin M (OM), an active compound isolated from Garcinia oblongifolia, potently inhibited EV71 infection in a dose dependent manner. To identify its potential effectors in the host cells, we successfully identified 18 proteins from 52 differentially expressed spots by comparative proteomics studies. Further studies showed that knockdown of ERp57 inhibited viral replication through downregulating viral IRES (internal ribosome entry site) activities, whereas ectopic expression of ERp57 increased IRES activity and partly rescued the inhibitory effects of OM on viral replication. We demonstrated that OM is an effective antiviral agent; and that ERp57 is one of its cellular effectors against EV71 infection.