Platelet membrane-coated oncolytic vaccinia virus with indocyanine green for the second near-infrared imaging guided multi-modal therapy of colorectal cancer.

Colorectal cancer (CRC) is a prevalent malignancy with insidious onset and diagnostic challenges, highlighting the need for therapeutic approaches to enhance theranostic outcomes. In this study, we elucidated the unique temperature-resistant properties of the oncolytic vaccinia virus (OVV), which can synergistically target tumors under photothermal conditions. To capitalize on this characteristic, we harnessed the potential of the OVV by surface-loading it with indocyanine green (ICG) and encapsulating it within a platelet membrane (PLTM), resulting in the creation of PLTM-ICG-OVV (PIOVV). This complex seamlessly integrates virotherapy, photodynamic therapy (PDT), and photothermal therapy (PTT). The morphology, size, dispersion stability, optical properties, and cellular uptake of PIOVV were evaluated using transmission electron microscopy (TEM). In vitro and in vivo experiments revealed specificity of PIOVV for cancer cells; it effectively induced apoptosis and suppressed CT26 cell proliferation. In mouse models, PIOVV exhibits enhanced fluorescence at tumor sites, accompanied by prolonged blood circulation. Under 808 nm laser irradiation, PIOVV significantly inhibited tumor growth. This strategy holds the potential for advancing phototherapy, oncolytic virology, drug delivery, and tumor-specific targeting, particularly in the context of CRC theranostics.

Tumor-targeted delivery of copper-manganese biomineralized oncolytic adenovirus for colorectal cancer immunotherapy.

Oncolytic viral therapy (OVT) is a novel anti-tumor immunotherapy approach, specifically replicating within tumor cells. Currently, oncolytic viruses are mainly administered by intratumoral injection. However, achieving good results for distant metastatic tumors is challenging. In this study, a multifunctional oncolytic adenovirus, OA@CuMnCs, was developed using bimetallic ions copper and manganese. These metal cations form a biomineralized coating on the virus's surface, reducing immune clearance. It is known that viruses upregulate the expression of PD-L1. Copper ions in OA@CuMnCs can decrease the PD-L1 expression of tumor cells, thereby promoting immune cell-related factor release. This process involves antigen presentation and the combination of immature dendritic cells, transforming them into mature dendritic cells. It changes "cold" tumors into "hot" tumors, further inducing immunogenic cell death. While oncolytic virus replication requires oxygen, manganese ions in OA@CuMnCs can react with endogenous hydrogen peroxide. This reaction produces oxygen, enhancing the virus's replication ability and the tumor lysis effect. Thus, this multifunctionally coated OA@CuMnCs demonstrates potent amplification in immunotherapy efficacy, and shows great potential for further clinical OVT. STATEMENT OF SIGNIFICANCE: Oncolytic virus therapy (OVs) is a new anti-tumor immunotherapy method that can specifically replicate in tumor cells. Although the oncolytic virus can achieve a therapeutic effect on some non-metastatic tumors through direct intratumoral injection, there are still three major defects in the treatment of metastatic tumors: immune response, hypoxia effect, and administration route. Various studies have shown that the immune response in vivo can be overcome by modifying or wrapping the surface protein of the oncolytic virus. In this paper, a multifunctional coating of copper and manganese was prepared by combining the advantages of copper and manganese ions. The coating has a simple preparation method and mild conditions, and can effectively enhance tumor immunotherapy.

Engineered Luminescent Oncolytic Vaccinia Virus Activation of Photodynamic-Immune Combination Therapy for Colorectal Cancer.

Oncolytic virus therapy is currently regarded as a promising approach in cancer immunotherapy. It has greater therapeutic advantages for colorectal cancer that is prone to distant metastasis. However, the therapeutic efficacy and clinical application of viral agents alone for colorectal cancer remain suboptimal. In this study, an engineered oncolytic vaccinia virus (OVV-Luc) that expresses the firefly luciferase gene is developed and loaded Chlorin e6 (Ce6) onto the virus surface through covalent coupling, resulting in OVV-Luc@Ce6 (OV@C). The OV@C infiltrates tumor tissue and induces endogenous luminescence through substrate catalysis, resulting in the production of reactive oxygen species. This unique system eliminates the need for an external light source, making it suitable for photodynamic therapy (PDT) in deep tissues. Moreover, this synergistic effect between PDT and viral immunotherapy enhances dendritic cell maturation, macrophage polarization, and reversal of the immunosuppressive microenvironment. This synergistic effect has the potential to convert a "cold" into a "hot" tumor, it offers valuable insights for clinical translation and application.

All-in-One Nanomedicine: Multifunctional Single-Component Nanoparticles for Cancer Theranostics.

The development of cancer diagnostic imaging and treatment is a major concern worldwide. By integrating imaging and therapy into one theranostic nanoplatform for simultaneously detecting tumors, evaluating the targeting ability and timely monitoring therapeutic responses provide more opportunities for precision medicine. Among various theranostic nanosystems, a series of single-component nanoparticles (NPs) have been developed for "all-in-one" theranostics, which presents the unique properties of facile preparation, simple composition, defined structure, high reproducibility, and excellent biocompatibility. Specifically, utilizing single-component NPs for both diagnostics and therapeutics can reduce the possible numerous untoward side effects and risks to the living body. In this review, the recent progress of multifunctional single-component NPs in the applications of cancer theranostics is systematically summarized. Notably, the structure design, categories of NPs, targeted strategies, biomedical applications, potential barriers, challenges, and prospects for the future clinical practice of this rapidly growing field are discussed.

Mitochondria-targeted and ultrasound-responsive nanoparticles for oxygen and nitric oxide codelivery to reverse immunosuppression and enhance sonodynamic therapy for immune activation.

Background: Sonodynamic therapy (SDT) is a promising strategy to inhibit tumor growth and activate antitumor immune responses for immunotherapy. However, the hypoxic and immunosuppressive tumor microenvironment limits its therapeutic efficacy and suppresses immune response. Methods: In this study, mitochondria-targeted and ultrasound-responsive nanoparticles were developed to co-deliver oxygen (O2) and nitric oxide (NO) to enhance SDT and immune response. This system (PIH-NO) was constructed with a human serum albumin-based NO donor (HSA-NO) to encapsulate perfluorodecalin (FDC) and the sonosensitizer (IR780). In vitro, the burst release of O2 and NO with US treatment to generate reactive oxygen species (ROS), the mitochondria targeting properties and mitochondrial dysfunction were evaluated in tumor cells. Moreover, in vivo, tumor accumulation, therapeutic efficacy, the immunosuppressive tumor microenvironment, immunogenic cell death, and immune activation after PIH-NO treatment were also studied in 4T1 tumor bearing mice. Results: PIH-NO could accumulate in the mitochondria and relive hypoxia. After US irradiation, O2 and NO displayed burst release to enhance SDT, generated strongly oxidizing peroxynitrite anions, and led to mitochondrial dysfunction. The release of NO increased blood perfusion and enhanced the accumulation of the formed nanoparticles. Owing to O2 and NO release with US, PIH-NO enhanced SDT to inhibit tumor growth and amplify immunogenic cell death in vitro and in vivo. Additionally, PIH-NO promoted the maturation of dendritic cells and increased the number of infiltrating immune cells. More importantly, PIH-NO polarized M2 macrophages into M1 phenotype and depleted myeloid-derived suppressor cells to reverse immunosuppression and enhance immune response. Conclusion: Our findings provide a simple strategy to co-deliver O2 and NO to enhance SDT and reverse immunosuppression, leading to an increase in the immune response for cancer immunotherapy.

The mechanisms and reversal strategies of tumor radioresistance in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of most lethal malignancies with high aggressive potential in the world. Radiotherapy is used as one curative treatment modality for ESCC patients. Due to radioresistance, the 5-year survival rates of patients after radiotherapy is less than 20%. Tumor radioresistance is very complex and heterogeneous. Cancer-associated fibroblasts (CAFs), as one major component of tumor microenvironment (TME), play critical roles in regulating tumor radioresponse through multiple mechanisms and are increasingly considered as important anti-cancer targets. Cancer stemness, which renders cancer cells to be extremely resistant to conventional therapies, is involved in ESCC radioresistance due to the activation of Wnt/ß-catenin, Notch, Hedgehog and Hippo (HH) pathways, or the induction of epithelial-mesenchymal transition (EMT), hypoxia and autophagy. Non-protein-coding RNAs (ncRNAs), which account for more than 90% of the genome, are involved in esophageal cancer initiation and progression through regulating the activation or inactivation of downstream signaling pathways and the expressions of target genes. Herein, we mainly reviewed the role of CAFs, cancer stemness, non-coding RNAs as well as others in the development of radioresistance and clarify the involved mechanisms. Furthermore, we summarized the potential strategies which were reported to reverse radioresistance in ESCC. Together, this review gives a systematic coverage of radioresistance mechanisms and reversal strategies and contributes to better understanding of tumor radioresistance for the exploitation of novel intervention strategies in ESCC.

Oncolytic Virotherapy in Solid Tumors: The Challenges and Achievements.

Oncolytic virotherapy (OVT) is a promising approach in cancer immunotherapy. Oncolytic viruses (OVs) could be applied in cancer immunotherapy without in-depth knowledge of tumor antigens. The capability of genetic modification makes OVs exciting therapeutic tools with a high potential for manipulation. Improving efficacy, employing immunostimulatory elements, changing the immunosuppressive tumor microenvironment (TME) to inflammatory TME, optimizing their delivery system, and increasing the safety are the main areas of OVs manipulations. Recently, the reciprocal interaction of OVs and TME has become a hot topic for investigators to enhance the efficacy of OVT with less off-target adverse events. Current investigations suggest that the main application of OVT is to provoke the antitumor immune response in the TME, which synergize the effects of other immunotherapies such as immune-checkpoint blockers and adoptive cell therapy. In this review, we focused on the effects of OVs on the TME and antitumor immune responses. Furthermore, OVT challenges, including its moderate efficiency, safety concerns, and delivery strategies, along with recent achievements to overcome challenges, are thoroughly discussed.

A versatile chitosan nanogel capable of generating AgNPs in-situ and long-acting slow-release of Ag+ for highly efficient antibacterial.

Development of multifunctional antibacterial agent with long-lasting antibacterial activity and biofilm ablation performance is significant for the effective treatment of bacterial infections. Here, by utilizing the electrostatic interaction between sulfonated chitosan (SCS) and Ag+ and chitosan (CS), and the sodium borohydride reduction method, a versatile antibacterial agent (AgNPs@CS/SCS) capable of generating silver nanoparticles (AgNPs) in-situ and long-acting slow-release Ag+ was developed. AgNPs@CS/SCS has a good physiological stability and can long-acting slow-release of Ag+ due to the pH-dependent Ag+ release behavior of AgNPs. Noteworthy, AgNPs@CS/SCS can exert both excellent short- and long-term antibacterial and biofilm ablation activity. Importantly, it also exhibits superior antibacterial activity in the treatment of implant infections, accompanied by good biocompatibility. Together, this study suggest that AgNPs@CS/CSC is indeed a versatile antibacterial agent, and is expected to provide an effective treatment modality for implant infections in the clinic settings.

Interface cisplatin-crosslinked doxorubicin-loaded triblock copolymer micelles for synergistic cancer therapy.

Combination chemotherapy is an effective way to improve the therapeutic efficiency in anticancer treatment. Herein, we synthesized a novel amphiphilic triblock copolymer via a two-step ring-opening polymerization (ROP) followed by post-modification. Doxorubicin (DOX) was encapsulated into the copolymeric micelles through hydrophobic interactions, cisplatin (CDDP) was employed to in situ crosslink the interface of DOX-loaded micelles through Pt-carboxyl coordination interaction. The CDDP-mediated crosslinking improved the stability of the micelles and also reduced the release of DOX at physiological pH. After being taken up into the endosome/lysosome, the low environmental pH weakened the Pt-carboxyl coordination interactions, resulting in the destruction of the micelles and the release of CDDP and DOX. Moreover, these micelles loaded with dual drugs enabled a synergistic anticancer effect, showing promise as a potential drug delivery platform for cancer therapy.

Application of star poly(ethylene glycol) derivatives in drug delivery and controlled release.

Multi-arm star poly(ethylene glycol) (PEG) polymers have a number of advantages over linear PEG polymers when used as carriers for drug delivery and controlled release. For instance, they have more terminals that can be modified to form multi-functional delivery systems with significantly increased drug loading. They can form micelles with higher stability and lower critical micelle concentration (CMC), which helps to improve the blood circulation and reduce the unfavorable burst drug release. Moreover, star PEG polymers can form three-dimensional hydrogels with controllable size and adjustable functions through cross-linking. Indeed, these unique advantages of star PEG polymers have promoted investigations on star PEG-based drug delivery systems. Herein, for the first time, we carefully reviewed the advances on the research and development of star PEG polymers, especially the 4-, 6- and 8-armed star PEG polymers, in delivery and controlled release of a series of bioactive agents, including both small molecules and biomacromolecules. Opportunities and challenges for successful translation of star PEG-based drug formulations into clinical use were also discussed.

Correction to: KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer.

After the publication of this work [1].

Advances in delivery of Irinotecan (CPT-11) active metabolite 7-ethyl-10-hydroxycamptothecin.

CPT-11 is a first-line chemotherapy for advanced or metastatic colorectal cancers. 7-Ethyl-10-hydroxycamptothecin (SN38), the active metabolite of CPT-11, has an anticancer efficacy 100-1000 folds more than CPT-11 in vitro. However, the drawbacks such as ultralow solubility and poor stability, greatly limit the clinical applications of SN38. Recently, SN38-based nanomedicines have greatly improved the pharmaceutical and therapeutic characteristics of SN38. In addition, these nanosized delivery systems can target tumor tissues via the EPR effect and/or active-targeting strategies, thereby significantly improving anticancer efficacy, reducing side effects and reversing drug resistance. This review focuses on the advances of nano-delivery systems for SN38. We categorize the published studies into two groups, physical encapsulation and chemical conjugation, for the development of SN38 nano-delivery systems, and particularly summarize those for active tumor targeting. The advantages and shortcomings of current SN38 nano-delivery systems, aiming to develop more potent SN38 nano-delivery systems, are also discussed.

Functionalized Nanoparticles Efficiently Enhancing the Targeted Delivery, Tumor Penetration, and Anticancer Activity of 7-Ethyl-10-Hydroxycamptothecin.

The enhanced permeability and retention (EPR) effect of tumors is much more complex than initially defined, and it alone is not sufficient for targeted delivery of nanosized agents. Meanwhile, poor tumor penetration is another major challenge for the treatment of solid tumors using nanoparticles. Development of delivery systems for SN38, the active metabolite of CPT-11 in human and a very potent anticancer molecule, has become an attractive research area. PEGx -p(HEMASN38)y (x and y are viable), a prodrug synthesized by using polyethylene glycol (PEG) as initiator and SN38 as monomer through atom transfer radical polymeration (ATRP) method, is previously reported. Using PEG2.4K -p(HEMASN38)3K as a model prodrug, herein an active-targeted strategy decorated with cys-arg-gly-asp-lys (CRGDK), a peptide specifically binds to neuropilin-1 overexpressed by tumor vessels and tumor cells, is successfully established to further improve the delivery and efficacy of SN38. CRGDK-functionalized PEG2.4K -p(HEMASN38)3K (C-SN38) nanoparticles and nonfunctionalized control (B-SN38) are prepared with two distinct sizes, 30 and 100 nm. Their physiochemical and biological characteristics are investigated in vitro and in vivo with multiple tumor models. It is demonstrated for the first time that CRGDK functionalization can be a promising strategy for efficient delivery of SN38, and C-SN38 is a potent drug candidate for the treatment of neuropilin-1 overexpressing tumors.

A non-cytotoxic dendrimer with innate and potent anticancer and anti-metastatic activities.

The structural perfection and multivalency of dendrimers have made them useful for biodelivery and bioactivity via peripheral functionalization and the modulation of core-forming structures and dendrimer generations. Yet only few dendrimers have shown inherent therapeutic activity arising from their inner repeating units. Here, we report the synthesis and characterization of a polyacylthiourea dendrimer with inherent potent anticancer activity and the absence of cytotoxicity in mice. The poly(ethylene glycol)-functionalized fourth generation of the dendrimer, which can be efficiently synthesized from sequential click reactions of orthogonal monomers, displays low in vivo acute and subacute toxicities yet potently inhibits tumour growth and metastasis. The dendrimer's in vivo anticancer activity arises from the depletion of bioavailable copper and the subsequent inhibition of angiogenesis and cellular proliferation. When compared with some clinically used cytotoxin drugs, the dendrimer exerts inherent anticancer activity via non-cytotoxic pathways and leads to higher therapeutic efficacy, yet without cytotoxin-induced side effects.

Self-Assembling Doxorubicin Prodrug Forming Nanoparticles and Effectively Reversing Drug Resistance In Vitro and In Vivo.

Doxorubicin (DOX) is a widely used chemotherapeutic drug to treat a range of cancers. However, its unfavorable effects, particularly the cardiotoxicity and the induction of multidrug resistance (MDR), significantly limit its clinical applications. Herein, a novel doxorubicin prodrug, PEG2K -DOX, is synthesized by conjugating a deprotonated doxorubicin molecule with the polyethylene glycol (PEG, MW: 2K) chain via pH-responsive hydrazone bond, and its potential as a better alternative than doxorubicin is evaluated. The data show that the amphiphilic PEG2K -DOX can self-assemble into stable nanoparticles with a high and fixed doxorubicin loading content (≈20 wt%), a favorable size of 91.5 nm with a narrow polydispersity (PDI = 0.14), good stability, and pH-dependent release behavior due to the acid-cleavable linkage between PEG and doxorubicin. Although doxorubicin hardly accumulates in MDR cells, PEG2K -DOX nanoparticles significantly increase the cellular uptake and cell-killing activity of doxorubicin in two MDR cancer cell lines MCF-7/ADR and KBv200, with the IC50 values dropped to 1.130% and 42.467% of doxorubicin, respectively. More impressively, PEG2K -DOX nanoparticles exhibit significantly improved plasma pharmacokinetics, increased in vivo therapeutic efficacy against MDR xenograft tumors, and better in vivo safety compared with doxorubicin. PEG2K -DOX nanoparticles hold the promise to become a better alternative than doxorubicin for cancer treatment, especially for MDR tumors.

Macrophages as Active Nanocarriers for Targeted Early and Adjuvant Cancer Chemotherapy.

Taking advantage of the highly permeable vasculature and lack of lymphatic drainage in solid tumors (EPR effect), nanosized drug delivery systems or nanomedicines have been extensively explored for tumor-targeted drug delivery. However, in most clinical cases tumors such as the early stage tumors and post-surgery microscopic residual tumors have not yet developed such pathological EPR features, i.e., EPR-deficient. Therefore, nanomedicines may not be applicable for such these tumors. Macrophages by nature can actively home and extravasate through the tight vascular wall into tumors and migrate to their hypoxic regions, and possess perfect stealth ability for long blood circulation and impressive phagocytosis for drug loadings. Thus, nanomedicines loaded in macrophages would harness both merits and gain the active tumor homing capability independent of the EPR effect for treatments of the EPR-deficient tumors. Herein, the critical considerations, current progress, challenges and future prospects of macrophages as carriers for nanomedicines are summarized, aiming at rational design of EPR-independent tumor-targeting active nanomedicines for targeted early and adjuvant cancer chemotherapy.

KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer.

BACKGROUND: Lung cancer in nonsmokers tends to be driven by a single somatic mutation or a gene fusion. KIF5B-RET fusion is an oncogene identified in non-small cell lung cancers. In this study, we verified the oncogenic activity of KIF5B-RET fusion and investigated how KIF5B-RET activates the specific signaling pathways for cellular transformation. We aimed to provide a basis for the further development of the therapy for KIF5B-RET positive lung cancer patients. METHODS: RT-PCR was used to screen for KIF5B-RET fusions in Chinese lung cancer patients. To verify the oncogenic activity of KIF5B-RET kinase in lung cancer cells, we manipulated its expression genetically followed by colony formation and tumor formation assays. The mechanism by which KIF5B-RET kinase induces proliferation was investigated by western blot, coimmunoprecipitation, and administration of RET, MAPK and STAT3 inhibitors. RESULTS: Our study identified a KIF5B-RET fusion in Chinese NSCLC patients and demonstrated that KIF5B-RET transfected cells showed a significantly increased proliferation rate and colony-forming ability. Furthermore, we found that KIF5B-RET fusion kinase induced multilevel activation of STAT3 at both Tyr705 and Ser727, and KIF5B-RET-STAT3 signaling related inhibitors repressed the proliferation and tumorigenicity of lung cancer cells significantly. CONCLUSIONS: Our data suggest that KIF5B-RET promotes the cell growth and tumorigenicity of non-small cell lung cancers through multilevel activation of STAT3 signaling, providing possible strategies for the treatment of KIF5B-RET positive lung cancers.

RETRACTED: Ca(2+)/calmodulin-dependent protein kinase IIγ, a critical mediator of the NF-κB network, is a novel therapeutic target in non-small cell lung cancer.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been regretfully retracted at the request of the authors due to mistakes which occurred during the figure preparation. Although the authors published a corrigendum about these mistakes (Cancer Lett. 2016 Aug 1. pii: S0304-3835(16)30443-8), they now feel that it is more appropriate to retract the paper to keep their research at a high standard. All authors have agreed to this decision and apologize for any inconvenience caused by retraction of this article.