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Breast cancer (BCa) is known as a complex and prevalent disease requiring the development of novel anticancer therapeutic approaches. Bispecific antibodies (BsAbs) have emerged as a favorable strategy for BCa treatment due to their unique ability to target two different antigens simultaneously. By targeting tumorassociated antigens (TAAs) on cancer cells, engaging immune effector cells, or blocking critical signaling pathways, BsAbs offer enhanced tumor specificity and immune system involvement, improving anti-cancer activity. Preclinical and clinical studies have demonstrated the potential of BsAbs in BCa. For example, BsAbs targeting human epidermal growth factor receptor 2 (HER2) have shown the ability to redirect immune cells to HER2-positive BCa cells, resulting in effective tumor cell killing. Moreover, targeting the PD-1/PD-L1 pathway by BsAbs has demonstrated promising outcomes in overcoming immunosuppression and enhancing immune-mediated tumor clearance. Combining BsAbs with existing therapeutic approaches, such as chemotherapy, targeted therapies, or immune checkpoint inhibitors (ICIs), has also revealed synergistic effects in preclinical models and early clinical trials, emphasizing the usefulness and potential of BsAbs in BCa treatment. This review summarizes the latest evidence about BsAbs in treating BCa and the challenges and opportunities of their use in BCa. [ABSTRACT FROM AUTHOR]

Emerging chemo- and radiotherapy resistance exacerbated the cancer risk and necessitated novel treatment strategies. Although RNA therapeutics against pro-oncogenic genes are highly effective, tumor-specific delivery remains a barrier to the implementation of this valuable tool. In this study, we report a tryptophan-auxotrophic Salmonella typhimurium strain as an onco-therapeutic delivery system with tumor-targeting ability using 4T1 mice breast-cancer model. The receptor-binding cancer antigen expressed on SiSo cell (RCAS1) is a cancer-specific protein that induces the apoptosis of peripheral lymphocytes and confers tumor immune evasion. We designed a long non-coding antisense-RNA against RCAS1 (asRCAS1) and delivered by Salmonella using a non-antibiotic, auxotrophic-selective, eukaryotic expression plasmid, pJHL204. After in vivo tumor-to-tumor passaging, the JOL2888 (ΔtrpA, ΔtrpE, Δasd + asRCAS1) strain exhibited high sustainability in tumors, but did not last in healthy organs, thereby demonstrating tumor specificity and safety. RCAS1 inhibition in the tumor was confirmed by western blotting and qPCR. In mice, JOL2888 treatment reduced tumor-associated macrophages, improved the T cell population, elicited cell-mediated immunity, and suppressed cancer-promoting genes. Consequently, the JOL2888 treatment significantly decreased the tumor volume by 80%, decreased splenomegaly by 30%, and completely arrested lung metastasis. These findings highlight the intrinsic tumor-targeting ability of tryptophan-auxotrophic Salmonella for delivering onco-therapeutic macromolecules.

Background: The role of the epithelial cell adhesion molecule (EpCAM) in cancer is still unclear. EpCAM cleavage through regulated intramembrane proteolysis results in fragments which interact with both oncogenic and tumor suppressive pathways. Additionally, the EpCAM molecule itself is used as a descriptive therapeutic target in urothelial cancer (UC), while data on its actual tumor specificity remain limited. Methods: Samples from diagnostic formalin-fixed paraffin-embedded (FFPE) UC tissue and fresh-frozen UC cells were immunoblotted and used for qualitative characterization of five different EpCAM fragments. These expression patterns were quantified across a cohort of 76 samples with 52 UC and 24 normal urothelial samples. Cell viability effects of the extracellular EpEX fragment were assessed in the UC cell lines T24 and HT1376. Results: The proteolytic EpCAM fragments could be identified in clinical FFPE tissue specimens too. Neither overall nor fragment-specific EpCAM expression showed relevant tumor specificity. EpEX and its deglycosylated variant showed an inverse relationship across healthy and tumor tissue with a decrease of deglycosylated EpEX in tumors. However, extracellular EpEX did not show a relevant effect in vitro. Conclusions: EpCAM should not be regarded as tumor-specific in UC without patient-specific predictive testing. EpCAM fragment patterns indicate cancer-specific changes and could be involved in its complex tumor-biological role. [ABSTRACT FROM AUTHOR]

Abstract Background The WNT signal pathway has myriad family members, which are broadly involved in embryonic development and human cancer. Over-activation of WNT-β-Catenin signaling promotes cancer cell proliferation and survival. However, how diverse components of WNT signaling specifically engaged in distinct tumor types remains incompletely understood. Methods We analyzed the transcriptomic profiling of WNT ligands and receptors/co-receptors among 26 different tumor types to identify their expression pattern, and further verified these results using clinical oral squamous cell carcinoma (OSCC) and lung squamous cell carcinoma (LUSC) samples. At the same time, we also detected WNT7B expression in oral inflammation and carcinoma, and constructed stable WNT7B knockdown OSCC cell lines to study the effects of WNT7B on the cell migration and invasion ability. Results We found a group of tumor-specific WNT members, including a panel of squamous cell carcinomas (SCCs) specific upregulated WNT ligands and receptors, WNT5A, WNT7B, FZD7 and GPC1. We further revealed a significant correlation between these protein expression characteristics and clinical outcomes of OSCC and LUSC patients. Moreover, WNT7B was demonstrated to contribute to the development of oral chronic inflammation and OSCC, partly due to promoting the invasion ability of tumor cells. Conclusions These results demonstrate that the function of WNT ligands and receptors in specific tumors depends on the origination of tumor tissue type. Collectively, they support the use of WNT components as a highly specific target for pan-tissue-type originated tumors.

Abstract Extensive research have been devoted to the exploration of multifunctional theranostic agents for cancer, but the poor tumor specificity and unsatisfactory treatment efficacy are some of the critical obstacles for their clinical translations. Herein, ferrocene‐carbon dot‐crosslinked nanoparticles (Fc‐CD NPs) were designed and fabricated for achieving highly specific and photothermal‐augmented chemodynamic therapy (CDT). The Fc‐CD NPs were found not only to inherit the immanent fluorescence, photoacoustic, and photothermal properties of carbon dots (CDs), but also be endowed with CDT that could occur selectively in tumor microenvironment (TME) due to the presence of Fc for triggering Fenton reaction. Moreover, the enlarged particle size of Fc‐CD NPs facilitated their effective accumulation at tumor sites, thus realizing great improvement for antitumor treatment outcomes. Once docking at tumor and being exposed to 660 nm laser irradiation, significantly amplified CDT effect of Fc‐CD NPs was observed due to heat‐accelerating generation of reactive oxygen species (ROS). More interestingly, since the produced ROS could in turn alleviate the thermal‐resistance of photothermal therapy (PTT), the therapeutic efficiency of integrated PTT and CDT was synergized to the maximum extent. This study on the one hand provides a facile approach to fabricate CDs‐based multifunctional theranostic nanoplatform with enhanced tumor accumulation and specificity, on the other hand emphasizes the merits of synergizing mutually beneficial therapeutic modalities for more efficient cancer therapy.

Abstract Background Despite the increasing interest in combination therapy for the treatment of cancer, controlled delivery of different therapeutics with high body-clearance efficacy and cancer cell specificity remained a great challenge. In this study, a novel codelivery system was synthesized through one-pot coordination-driven self-assembly of 2-methylimidazole, zinc ion and chemotherapeutic drug (doxorubicin, DOX), followed by a surface decoration of photothermal agent (indocyanine green, ICG). To improve the targeting specificity performance, folic acid-conjugated polyethylene glycol (FA-PEG) antennas was connected on the surface of nanoparticles. Results The hybrid nanoparticles keep stable under neutral physiological condition but decompose when exposed to acidic environment, resulting in the on-demand release of DOX and ICG for chemo-photothermal combined therapy. Moreover, by switching the initial large size (~ 94 nm) to an ultrasmall size (∼10 nm) in cancer cells, the nanoparticles hold great potential to avoid nanotoxicity for clinical applications. Conclusions This work provides a new strategy for co-delivery of different therapeutics for combined cancer therapy with high cancer cell specificity and low nanotoxicity.

Complexes formed by the alpha1 N‐terminal peptide of alpha‐lactalbumin and oleic acid (alpha1‐oleate) interact with lipid bilayers. Plasma membrane perturbations trigger tumor cell death but normal differentiated cells are more resistant, and their plasma membranes are less strongly affected. This study examined membrane lipid composition as a determinant of tumor cell reactivity. Bladder cancer tissue showed a higher abundance of unsaturated lipids enriched in phosphatidylcholine, PC (36:4) and PC (38:4), and sphingomyelin, SM (36:1) than healthy bladder tissue, where saturated lipids predominated and the lipid extracts from bladder cancer tissue inhibited the tumoricidal effect of the complex more effectively than healthy tissue extracts. Furthermore, unsaturated PC in solution inhibited tumor cell death, and the complex interacted with giant unilamellar vesicles formed by PC, confirming the affinity of alpha1‐oleate for fluid membranes enriched in PC. Quartz Crystal Microbalance with dissipation monitoring (QCM‐D) detected a preference of the complex for the liquid‐disordered phase, suggesting that the insertion into PC‐based membranes and the resulting membrane perturbations are influenced by membrane lipid saturation. The results suggest that the membrane lipid composition is functionally important and that specific unsaturated membrane lipids may serve as "recognition motifs" for broad‐spectrum tumoricidal molecules such as alpha1‐oleate. [ABSTRACT FROM AUTHOR]

Background: The WNT signal pathway has myriad family members, which are broadly involved in embryonic development and human cancer. Over-activation of WNT-β-Catenin signaling promotes cancer cell proliferation and survival. However, how diverse components of WNT signaling specifically engaged in distinct tumor types remains incompletely understood.Methods: We analyzed the transcriptomic profiling of WNT ligands and receptors/co-receptors among 26 different tumor types to identify their expression pattern, and further verified these results using clinical oral squamous cell carcinoma (OSCC) and lung squamous cell carcinoma (LUSC) samples. At the same time, we also detected WNT7B expression in oral inflammation and carcinoma, and constructed stable WNT7B knockdown OSCC cell lines to study the effects of WNT7B on the cell migration and invasion ability.Results: We found a group of tumor-specific WNT members, including a panel of squamous cell carcinomas (SCCs) specific upregulated WNT ligands and receptors, WNT5A, WNT7B, FZD7 and GPC1. We further revealed a significant correlation between these protein expression characteristics and clinical outcomes of OSCC and LUSC patients. Moreover, WNT7B was demonstrated to contribute to the development of oral chronic inflammation and OSCC, partly due to promoting the invasion ability of tumor cells.Conclusions: These results demonstrate that the function of WNT ligands and receptors in specific tumors depends on the origination of tumor tissue type. Collectively, they support the use of WNT components as a highly specific target for pan-tissue-type originated tumors. [ABSTRACT FROM AUTHOR]

Background: Despite the increasing interest in combination therapy for the treatment of cancer, controlled delivery of different therapeutics with high body-clearance efficacy and cancer cell specificity remained a great challenge. In this study, a novel codelivery system was synthesized through one-pot coordination-driven self-assembly of 2-methylimidazole, zinc ion and chemotherapeutic drug (doxorubicin, DOX), followed by a surface decoration of photothermal agent (indocyanine green, ICG). To improve the targeting specificity performance, folic acid-conjugated polyethylene glycol (FA-PEG) antennas was connected on the surface of nanoparticles. Results: The hybrid nanoparticles keep stable under neutral physiological condition but decompose when exposed to acidic environment, resulting in the on-demand release of DOX and ICG for chemo-photothermal combined therapy. Moreover, by switching the initial large size (~ 94 nm) to an ultrasmall size (∼10 nm) in cancer cells, the nanoparticles hold great potential to avoid nanotoxicity for clinical applications. Conclusions: This work provides a new strategy for co-delivery of different therapeutics for combined cancer therapy with high cancer cell specificity and low nanotoxicity. [ABSTRACT FROM AUTHOR]

Extensive research have been devoted to the exploration of multifunctional theranostic agents for cancer, but the poor tumor specificity and unsatisfactory treatment efficacy are some of the critical obstacles for their clinical translations. Herein, ferrocene‐carbon dot‐crosslinked nanoparticles (Fc‐CD NPs) were designed and fabricated for achieving highly specific and photothermal‐augmented chemodynamic therapy (CDT). The Fc‐CD NPs were found not only to inherit the immanent fluorescence, photoacoustic, and photothermal properties of carbon dots (CDs), but also be endowed with CDT that could occur selectively in tumor microenvironment (TME) due to the presence of Fc for triggering Fenton reaction. Moreover, the enlarged particle size of Fc‐CD NPs facilitated their effective accumulation at tumor sites, thus realizing great improvement for antitumor treatment outcomes. Once docking at tumor and being exposed to 660 nm laser irradiation, significantly amplified CDT effect of Fc‐CD NPs was observed due to heat‐accelerating generation of reactive oxygen species (ROS). More interestingly, since the produced ROS could in turn alleviate the thermal‐resistance of photothermal therapy (PTT), the therapeutic efficiency of integrated PTT and CDT was synergized to the maximum extent. This study on the one hand provides a facile approach to fabricate CDs‐based multifunctional theranostic nanoplatform with enhanced tumor accumulation and specificity, on the other hand emphasizes the merits of synergizing mutually beneficial therapeutic modalities for more efficient cancer therapy. [ABSTRACT FROM AUTHOR]

Off‐target toxicity and insufficient hydroxyl radicals (.OH) generation limit the further clinical application of nanozymes in chemodynamic therapy (CDT). Herein, we designed and constructed a microRNA‐triggered nanozyme cascade platform for enhanced tumor‐specific chemodynamic therapy. The nanozyme‐based cascade reaction could be triggered successfully by the high expression of microRNA in cancer cells to generate more.OH, thus exhibiting excellent tumor‐specific therapeutic performance. Our work provides a new dimension for tumor‐specific chemodynamic therapy. [ABSTRACT FROM AUTHOR]

Yuedi Ding ,1 Jun Fan ,1 Lili Deng ,1 Ying Peng ,1 Bin Zhou ,1 Biao Huang 1 NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, People’s Republic of ChinaCorrespondence: Biao Huang; Yuedi DingNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine,Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, People’s Republic of ChinaEmail huangbiao@jsinm.org; dingyuedi@jsinm.orgPurpose: Oncolytic viruses are emerging as promising options for clinical cancer treatment due to their inherent ability of tumor tropism and oncolytic property. Aside from tumor lysis, oncolytic viruses can induce host immune responses against tumor cells and may thus be viewed as a form of immunotherapy.Methods: The attenuated vaccinia VG9-Luc, which originated from Chinese vaccinia Tian Tan strain, was constructed to express firefly luciferase for bioluminescence imaging and to disrupt the thymidine kinase gene for promoting tumor specificity. An in vivo bioluminescence imaging was performed to observe the virus distribution in live mice. The titers of neutralizing antiviral and antitumor antibodies in plasma were determined by time-resolved fluoroimmunoassay.Results: Except BALB/c mice treated with intravenous virus injection, all immunocompromised and immunocompetent mice showed obvious tumor targeting ability of vaccinia VG9-Luc. Besides, host immune response activated by vaccinia VG9-Luc showed the production of antiviral and antitumor antibodies, the process of which was similar between intravenous and intratumoral viral delivery systems. The results indicated that virus infection promoted tumor-specific immunity by increasing the production of antitumor antibodies. Moreover, virus reinjection was performed and a more rapid viral clearance was observed in immunocompetent mice compared with first virus infection.Conclusion: The thymidine kinase-deleted vaccinia Guang9 strain, which has the properties of tumor specificity and antitumor immunity, is a promising candidate vector for cancer therapy.Keywords: oncolytic virotherapy, vaccinia virus, tumor specificity, bioluminescence imaging, antitumor immunity

Background: Selective therapy has always been the main challenge in cancer treatments. Recently, it has been shown that Human Gyrovirus-derived protein apoptin (HGV-Apoptin) has selective cytotoxic effects on cancer cells similar to its homologue, Chicken Anemia Virus-derived Apoptin (CAV-Apoptin). However, apoptotic effects of Human Gyrovirus apoptin have been only evaluated on a few cancerous cell lines and need to be further investigated. In this study, we have evaluated the apoptotic effects of HGV-Apoptin and CAV-Apoptin expression on lung cancer (A549) and normal (HEK-293) cell lines, in order to provide more information about the specificity of these proteins on cancerous cells. Methods: Target cells were transfected by the calcium-phosphate precipitation method with constructed plasmids expressing HGV-Apoptin and CAV-Apoptin proteins as well as the control plasmid. Transfection efficiency was followed and imaged by fluorescence microscopy. Quantification of apoptosis was performed by flow cytometry. Measurements were compared by paired Student t-test. Results: Cells were successfully transfected with control and constructed plasmids. Flowcytometry analysis showed that A549 cells transfected with HGV-Apoptin and CAV-Apoptin expressing plasmids, undergone the apoptosis compared to A549 cells transfected with control plasmid (P

Breast cancer (BCa) is known as a complex and prevalent disease requiring the development of novel anticancer therapeutic approaches. Bispecific antibodies (BsAbs) have emerged as a favorable strategy for BCa treatment due to their unique ability to target two different antigens simultaneously. By targeting tumor-associated antigens (TAAs) on cancer cells, engaging immune effector cells, or blocking critical signaling pathways, BsAbs offer enhanced tumor specificity and immune system involvement, improving anti-cancer activity. Preclinical and clinical studies have demonstrated the potential of BsAbs in BCa. For example, BsAbs targeting human epidermal growth factor receptor 2 (HER2) have shown the ability to redirect immune cells to HER2-positive BCa cells, resulting in effective tumor cell killing. Moreover, targeting the PD-1/PD-L1 pathway by BsAbs has demonstrated promising outcomes in overcoming immunosuppression and enhancing immune-mediated tumor clearance. Combining BsAbs with existing therapeutic approaches, such as chemotherapy, targeted therapies, or immune checkpoint inhibitors (ICIs), has also revealed synergistic effects in preclinical models and early clinical trials, emphasizing the usefulness and potential of BsAbs in BCa treatment. This review summarizes the latest evidence about BsAbs in treating BCa and the challenges and opportunities of their use in BCa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lan, Chen, Yao, Chen and Jin.)

Emerging chemo- and radiotherapy resistance exacerbated the cancer risk and necessitated novel treatment strategies. Although RNA therapeutics against pro-oncogenic genes are highly effective, tumor-specific delivery remains a barrier to the implementation of this valuable tool. In this study, we report a tryptophan-auxotrophic Salmonella typhimurium strain as an onco-therapeutic delivery system with tumor-targeting ability using 4T1 mice breast-cancer model. The receptor-binding cancer antigen expressed on SiSo cell (RCAS1) is a cancer-specific protein that induces the apoptosis of peripheral lymphocytes and confers tumor immune evasion. We designed a long non-coding antisense-RNA against RCAS1 (asRCAS1) and delivered by Salmonella using a non-antibiotic, auxotrophic-selective, eukaryotic expression plasmid, pJHL204. After in vivo tumor-to-tumor passaging, the JOL2888 (Δ trpA , Δ trpE , Δ asd  + asRCAS1) strain exhibited high sustainability in tumors, but did not last in healthy organs, thereby demonstrating tumor specificity and safety. RCAS1 inhibition in the tumor was confirmed by western blotting and qPCR. In mice, JOL2888 treatment reduced tumor-associated macrophages, improved the T cell population, elicited cell-mediated immunity, and suppressed cancer-promoting genes. Consequently, the JOL2888 treatment significantly decreased the tumor volume by 80%, decreased splenomegaly by 30%, and completely arrested lung metastasis. These findings highlight the intrinsic tumor-targeting ability of tryptophan-auxotrophic Salmonella for delivering onco-therapeutic macromolecules., Competing Interests: The authors declare that they have no competing interests., (© 2023 The Author(s).)

Highlights from the article: Keywords: prostate cancer; apoptosis; Bcl-2 proteins; targeted therapy; tumor specificity The fact that the activation of the effectors Bax and Bak is prevented by Bcl-2, Bcl-xl, and Mcl-1 leads to an alternative therapeutic strategy to induce the programmed cell death by direct inhibition of the anti-apoptotic proteins. Similar to the Bcl-2 activator proteins, these small molecules can bind to the anti-apoptotic proteins Bcl-2, Bcl-xl, or Mcl-1 followed by a release of Bax and Bak ([32]). One such approach is the "BH3 profiling" of tumor cells, in which BH3 peptides interacting with Bcl-2, Bcl-xl, or Mcl-1 are used to identify the dependence of tumor cells on the respective anti-apoptotic Bcl-2 proteins.

Since many anticancer drugs show severe adverse effects such as mucositis, peripheral neurotoxicity, and extravasation, it was crucial to explore new compounds with much reduced adverse effects. Comprehensive investigation with human malignant and nonmalignant cells demonstrated that derivatives of chromone, back-bone structure of flavonoid, showed much higher tumor specificity as compared with three major polyphenols in the natural kingdom, such as lignin-carbohydrate complex, tannin, and flavonoid. A total 291 newly synthesized compounds of 17 groups (consisting of 12 chromones, 2 esters, and 3 amides) gave a wide range of the intensity of tumor specificity, possibly reflecting the fitness for the optimal 3D structure and electric state. Among them, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (compound 22), which belongs to 3-styrylchromones, showed the highest tumor specificity. 22 induced subG1 and G2 + M cell population in human oral squamous cell carcinoma cell line, with much less keratinocyte toxicity as compared with doxorubicin and 5-FU. However, 12 active compounds selected did not necessarily induce apoptosis and mitotic arrest. This compound can be used as a lead compound to manufacture more active compound.

Polyether ionophore salinomycin (SAL) and its semi-synthetic derivatives are recognized as very promising anticancer drug candidates due to their activity against various types of cancer cells, including multidrug-resistant populations. Ovarian cancer is the deadliest among gynecologic malignancies, which is connected with the development of chemoresistant forms of the disease in over 70% of patients after initial treatment regimen. Thus, we decided to examine the anticancer properties of SAL and selected SAL derivatives against a series of drug-sensitive (A2780, SK-OV-3) and derived drug-resistant (A2780 CDDP, SK-OV-3 CDDP) ovarian cancer cell lines. Although SAL analogs showed less promising IC50 values than SAL, they were identified as the antitumor agents that significantly overcome the resistance to platinum-based drugs in ovarian cancer, more potent than unmodified SAL and commonly used anticancer drugs—5-fluorouracil, gemcitabine, and cisplatin. Moreover, when compared with SAL used alone, our experiments proved for the first time increased selectivity of SAL-based dual therapy with 5-fluorouracil or gemcitabine, especially towards A2780 cell line. Looking closer at the results, SAL acted synergistically with 5-fluorouracil towards the drug-resistant A2780 cell line. Our results suggest that combinations of SAL with other antineoplastics may become a new therapeutic option for patients with ovarian cancer.

Abstract The main obstacles for practical uses of cytosol-penetrating peptides and proteins include their lack of cell- or tissue-specific targeting and limited cytosolic access owing to the poor endosomal escape ability. We have previously reported a cytosol-penetrating, human IgG1 antibody TMab4-WYW, generally referred to as a cytotransmab (CT), which reaches the cytosol of living cells but nonspecifically because it is endocytosed via a ubiquitously expressed receptor called heparan sulfate proteoglycan (HSPG). Here, our aim was to construct a next-generation CT with tumor cell specificity and improved endosomal escape efficiency. We first substantially reduced the HSPG-binding activity of TMab4-WYW and then fused a cyclic peptide specifically recognizing tumor-associated epithelial cell adhesion molecule (EpCAM) to the N terminus of the light chain for EpCAM-mediated endocytosis, while maintaining the endosomal escape ability in the light chain variable domain (VL), thus generating epCT05. Then, we separately engineered another CT, dubbed epCT65-AAA, with an endosomal escape ability only in the heavy chain variable domain (VH) but not in VL, by functional grafting of the endosomal escape motif of epCT05 VL to the VH. We finally combined the heavy chain of epCT65-AAA and the light chain of epCT05 to create epCT65 with endosomal escape capacity in both the VH and VL. epCT65 effectively localized to the cytosol of only EpCAM-expressing tumor cells and showed approximately twofold improved endosomal escape efficiency, as compared with CTs with endosomal escape motifs in either VH or VL. The full–IgG format CT, epCT65, with a tumor cell–specific cytosol-penetrating activity, has a great potential for practical medical applications, e.g., as a carrier for cytosolic delivery of payloads. Graphical abstract Image 1 Highlights • Generation of a tumor cell–specific, cytosol-penetrating antibody, cytotransmab. • Engineering of a cytotransmab with the VH-mediated endosomal escape activity. • Creation of a cytotransmab with endosomal escape motif in both VH and VL. • Generation of a cytotransmab with a high endosomal escaping efficiency (∼17.5%). • Development of a cytosol-penetrating antibody in a druggable human IgG format. [ABSTRACT FROM AUTHOR]

Highlights: [•] A new VO(IV) complex with the natural antioxidant morin is characterized. [•] The complexation improves the antioxidant activity in vitro and in the cells. [•] In breast cancer cells a specific anti-cancer behavior is found. [•] No DNA damage is observed in the T47D and SKBR3 cell lines. [•] Apoptotic cell death process with caspase 3/7 activation is proposed. [Copyright &y& Elsevier]

Magnetic resonance is a key imaging tool for the detection of prostate cancer; however, better tools focusing on cancer specificity are required to distinguish benign from cancerous regions. We found higher expression of claudin-3 (CLDN-3) and -4 (CLDN-4) in higher grade than lower-grade human prostate cancer biopsies (n = 174), leading to the design of functionalized nanoparticles (NPs) with a non-toxic truncated version of the natural ligand Clostridium perfringens enterotoxin (C-CPE) that has a strong binding affinity to Cldn-3 and Cldn-4 receptors. We developed a first-of-its-type, C-CPE-NP-based MRI detection tool in a prostate tumor-bearing mouse model. NPs with an average diameter of 152.9 ± 15.7 nm (RS1) had a 2-fold enhancement of tumor specificity compared to larger (421.2 ± 33.8 nm) NPs (RS4). There was a 1.8-fold (P < 0.01) and 1.6-fold (P < 0.01) upregulation of the tumor-to-liver signal intensities of C-RS1 and C-RS4 (functionalized NPs) compared to controls, respectively. Also, tumor specificity was 3.1-fold higher (P < 0.001) when comparing C-RS1 to C-RS4. This detection tool improved tumor localization of contrast-enhanced MRI, supporting potential clinical applicability. We developed functionalized nanoparticles (NPs) with a non-toxic truncated version of the natural ligand clostridium perfringens enterotoxin (C-CPE) that has a strong binding affinity to the Cldn-3 and Cldn-4 receptors. The C-CPE NP-based MRI detection tool provided 70% tumor coverage using a prostate tumor-bearing mouse model. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Hyaluronic acid nanoparticles (HA-NPs), which are formed by the self-assembly of hydrophobically modified HA derivatives, were prepared to investigate their physicochemical characteristics and fates in tumor-bearing mice after systemic administration. The particle sizes of HA-NPs were controlled in the range of 237–424nm by varying the degree of substitution of the hydrophobic moiety. When SCC7 cancer cells over-expressing CD44 (the receptor for HA) were treated with fluorescently labeled Cy5.5-HA-NPs, strong fluorescence signals were observed in the cytosol of these cells, suggesting efficient intracellular uptake of HA-NPs by receptor-mediated endocytosis. In contrast, no significant fluorescence signals were observed when Cy5.5-labeled HA-NPs were incubated with normal fibroblast cells (CV-1) or with excess free-HA treated SCC7 cells. Following systemic administration of Cy5.5-labeled HA-NPs with different particle sizes into a tumor-bearing mouse, their biodistribution was monitored as a function of time using a non-invasive near-infrared fluorescence imaging system. Irrespective of the particle size, significant amounts of HA-NPs circulated for two days in the bloodstream and were selectively accumulated into the tumor site. The smaller HA-NPs were able to reach the tumor site more effectively than larger HA-NPs. Interestingly, the concentration of HA-NPs in the tumor site was dramatically reduced when mice were pretreated with an excess of free-HA. These results imply that HA-NPs can accumulate into the tumor site by a combination of passive and active targeting mechanisms. [Copyright &y& Elsevier]

Arsenic trioxide (As2O3) is an effective therapy in acute promyelocytic leukemia (APL), but its use in other malignancies is limited by the higher concentrations required to induce apoptosis. We have reported that trolox, an analogue of α-tocopherol, increases As2O3-mediated apoptosis in a variety of APL, myeloma and breast cancer cell lines, while non-malignant cells may be protected. In the present study, we extended previous results to show that trolox increases As2O3-mediated apoptosis in the P388 lymphoma cell line in vitro, as evidenced by decrease of mitochondrial membrane potential and release of cytochrome c. We then sought to determine whether this combination can enhance antitumor effects while protecting normal cells in vivo. In BDF1 mice, trolox treatment decreased As2O3-induced hepatomegaly, markers of oxidative stress and hepatocellular damage. In P388 tumor-bearing mice, As2O3 treatment prolonged survival, and the addition of trolox provided a further significant increase in lifespan. In addition, the combination of As2O3 and trolox inhibited metastatic spread, and protected the tumor-bearing mice from As2O3 liver toxicity. Our results suggest, for the first time, that trolox might prevent some of the clinical manifestations of As2O3-related toxicity while increasing its pro-apoptotic capacity and clinical efficacy in hematological malignancies.Leukemia (2007) 21, 2117–2127; doi:10.1038/sj.leu.2404891; published online 9 August 2007 [ABSTRACT FROM AUTHOR]

Magnetic resonance is a key imaging tool for the detection of prostate cancer; however, better tools focusing on cancer specificity are required to distinguish benign from cancerous regions. We found higher expression of claudin-3 (CLDN-3) and -4 (CLDN-4) in higher grade than lower-grade human prostate cancer biopsies (n = 174), leading to the design of functionalized nanoparticles (NPs) with a non-toxic truncated version of the natural ligand Clostridium perfringens enterotoxin (C-CPE) that has a strong binding affinity to Cldn-3 and Cldn-4 receptors. We developed a first-of-its-type, C-CPE-NP-based MRI detection tool in a prostate tumor-bearing mouse model. NPs with an average diameter of 152.9 ± 15.7 nm (RS1) had a 2-fold enhancement of tumor specificity compared to larger (421.2 ± 33.8 nm) NPs (RS4). There was a 1.8-fold (P < 0.01) and 1.6-fold (P < 0.01) upregulation of the tumor-to-liver signal intensities of C-RS1 and C-RS4 (functionalized NPs) compared to controls, respectively. Also, tumor specificity was 3.1-fold higher (P < 0.001) when comparing C-RS1 to C-RS4. This detection tool improved tumor localization of contrast-enhanced MRI, supporting potential clinical applicability., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Nanoparticles are widely studied as theranostic vehicles for cancer; however, clinical translation has been limited due to poor tumor specificity. Features that maximize tumor uptake remain controversial, particularly when using clinically relevant models. We report a systematic study that assesses two major features for the impact on tumor specificity, i . e ., active vs passive targeting and nanoparticle size, to evaluate relative influences in vivo . Active targeting via the V7 peptide is superior to passive targeting for uptake by pancreatic tumors, irrespective of nanoparticle size, observed through in vivo imaging. Size has a secondary effect on uptake for actively targeted nanoparticles in which 26 nm nanoparticles outperform larger 45 and 73 nm nanoparticles. Nanoparticle size had no significant effect on uptake for passively targeted nanoparticles. Results highlight the superiority of active targeting over nanoparticle size for tumor uptake. These findings suggest a framework for optimizing similar nonaggregate nanoparticles for theranostic treatment of recalcitrant cancers.

The tumor specificity of twelve different monoclonal antibodies (Mabs) against carcinoembryonic antigen (CEA) was assessed by immunohistochemistry. The Mabs had previously been classified into three specificity groups (I-III) on the basis of their reactivity with purified CEA-related antigens by ELISA. Mabs belonging to specificity group III (n = 4) did not cross-react with any CEA-related antigen, including normal cross-reactive antigen of 160 kD molecular weight (NCA-160 = meconium antigen). All Mabs, except one, gave positive immunohistochemical staining of 75-100% of individual tissue samples of colorectal carcinomas and gastric adenocarcinomas. However, when tested against different normal adult tissues, the Mabs displayed marked differences in reactivity. Group III Mabs stained normal colon epithelium, but not parenchymal cells in other organs or, with one exception, cells belonging to the granulocyte and/or macrophage series. Group I and II Mabs, in contrast, stained parenchymal cells in normal colon, submandibular salivary gland, placenta, and pancreas (group I Mab only). They also stained infiltrating and circulating granulocytes and/or macrophages. Lack of cross-reactivity with NCA-160 is the single-best criterion for selecting anti-CEA Mabs with a high degree of tumor specificity. To ensure tumor specificity, CEA-positive, NCA-160-negative Mabs should be checked by immunohistochemistry against cryostat sections of colorectal carcinoma, normal pancreas, submandibular salivary gland, spleen, and liver and for reactivity against circulating granulocytes. Copyright © 1990 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We studied immunohistochemical stains for TPA and CA125 in patients with benign and malignant gynecologic diseases. The results were as follows: (1) CA125 was not found in ovarian mucinous cystadenocarcinoma but was demonstrated immunohistochemically in 82% of ovarian serous cystadenocarcinomas and 83% of Krukenberg's tumors. (2) TPA was demonstrated in 65% of ovarian serous and 75% of ovarian mucinous cystadenocarcinomas, and in 58% of endometrial carcinomas. (3) TPA was found in all trophoblastic tumors examined, while CA125 was found in none. Eighty-three percent of patients with trophoblastic diseases had raised serum TPA levels. (4) When serum CA125 levels were raised CA125 was demonstrated immunohistochemically in 71% of patients with ovarian serous cystadenocarcinomas, 67% of patients with Krukenberg's tumors and 100% of patients with tubal carcinomas. (5) Despite elevated serum levels, CA125 and TPA were not identified by immunohistochemistry in 64% cases of benign ovarian disease and in 80% of patients with uterine myomata. (6) It would seem that CA125 was more easily released from tumor cells than TPA. [ABSTRACT FROM AUTHOR]

• A distance-controlled switchable MRI nanoprobe was prepared. • High Gd loading content and tumor-targeting ability. • Tumor-specific responsibility for high-resolution imaging. Magnetic resonance imaging (MRI) contrast agents (CAs) are a powerful tool for disease diagnosis. However, the "always on" state of clinically used CAs affects the specificity of tumor MR imaging in vivo. Herein, we constructed a tumor microenvironment "switch-on" type nanoprobe (TSN) with a distance-dominated property for specific tumor MR imaging, by employed a superparamagnetic hollow mesoporous iron oxide nanoparticle (HMIN) as the carrier to encapsulate T 1 -field CA (Gd), followed by blocking of the mesoporous channel with biocompatible hyaluronic acid (HA). In normal tissues with low-level hyaluronidase (HAase), Gd was restricted inside the HMIN, the distance between the two substances became quite close, and the magnetic field of Gd was interfered by the superparamagnetic HMIN, turning "off" the T 1 -field signal is "turned off"; in contrast, in tumor tissues with high-level HAase, Gd was rapidly released from the HMIN by specifically responding to overexpressed HAase, the distance between the two substances became significantly enlarged, and the magnetic field of Gd was not interfered, thus turning "on" the T 1 -field signal to achieve tumor-specific "switch on" MR imaging in a distance-controlled manner. The tumor/normal T 1 -field signal ratio after TSN treatment increased by 1.9-fold compared with free Gd-DTPA, because of its high Gd loading content, tumor-targeting ability of HA and the tumor-specific property. This distance-controlled switchable nanoprobe provides an alternative strategy for high-resolution tumor imaging with high specificity. [ABSTRACT FROM AUTHOR]

Polyether ionophore salinomycin (SAL) and its semi-synthetic derivatives are recognized as very promising anticancer drug candidates due to their activity against various types of cancer cells, including multidrug-resistant populations. Ovarian cancer is the deadliest among gynecologic malignancies, which is connected with the development of chemoresistant forms of the disease in over 70% of patients after initial treatment regimen. Thus, we decided to examine the anticancer properties of SAL and selected SAL derivatives against a series of drug-sensitive (A2780, SK-OV-3) and derived drug-resistant (A2780 CDDP, SK-OV-3 CDDP) ovarian cancer cell lines. Although SAL analogs showed less promising IC50 values than SAL, they were identified as the antitumor agents that significantly overcome the resistance to platinum-based drugs in ovarian cancer, more potent than unmodified SAL and commonly used anticancer drugs—5-fluorouracil, gemcitabine, and cisplatin. Moreover, when compared with SAL used alone, our experiments proved for the first time increased selectivity of SAL-based dual therapy with 5-fluorouracil or gemcitabine, especially towards A2780 cell line. Looking closer at the results, SAL acted synergistically with 5-fluorouracil towards the drug-resistant A2780 cell line. Our results suggest that combinations of SAL with other antineoplastics may become a new therapeutic option for patients with ovarian cancer. [ABSTRACT FROM AUTHOR]

Since many anticancer drugs show severe adverse effects such as mucositis, peripheral neurotoxicity, and extravasation, it was crucial to explore new compounds with much reduced adverse effects. Comprehensive investigation with human malignant and nonmalignant cells demonstrated that derivatives of chromone, back-bone structure of flavonoid, showed much higher tumor specificity as compared with three major polyphenols in the natural kingdom, such as lignin-carbohydrate complex, tannin, and flavonoid. A total 291 newly synthesized compounds of 17 groups (consisting of 12 chromones, 2 esters, and 3 amides) gave a wide range of the intensity of tumor specificity, possibly reflecting the fitness for the optimal 3D structure and electric state. Among them, 7-methoxy-3-[(1 E )-2-phenylethenyl]-4 H -1-benzopyran-4-one (compound 22 ), which belongs to 3-styrylchromones, showed the highest tumor specificity. 22 induced subG1 and G2 + M cell population in human oral squamous cell carcinoma cell line, with much less keratinocyte toxicity as compared with doxorubicin and 5-FU. However, 12 active compounds selected did not necessarily induce apoptosis and mitotic arrest. This compound can be used as a lead compound to manufacture more active compound.

Background/aim: Guaiazulene (1,4-dimethyl-7-isopropylazulene) is present in several essential oils of medicinal and aromatic plants. There exist few studies that investigated the anticancer activity of guaiazulenes. We investigated the relative cytotoxicity of 10 alkylaminoguaiazulene derivatives towards both cancer and normal cells., Materials and Methods: Cytotoxicity towards four human oral squamous cell carcinoma (OSCC) cell lines and five types of human normal oral cells (gingival fibroblasts, periodontal ligament fibroblasts, pulp cells and keratinocytes, gingival epithelial progenitors) was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated as the ratio of the mean 50% cytotoxic concentration against normal oral cells to that against OSCC cell lines. Apoptosis-inducing activity was evaluated by cleavage of poly ADP-ribose polymerase and caspsase-3 with western blot analysis., Results: Validity of the present TS measurement method was confirmed using methotrexate. With increasing length of the alkyl group of alkylaminoguaiazulene derivatives, cytotoxicity increased. Introduction of oxygen, nitrogen or sulfur atom into the alkyl group slightly reduced cytotoxicity. Most compounds had very low TS, no synergistic action with methotrexate and doxorubicin, nor did they induce apoptosis of OSCC cells. On the other hand, compound [ 10 ], containing a morpholino group, induced apoptosis of OSCC cells., Conclusion: The cytotoxicity of alkylaminoguaiazulenes is not always coupled with TS and apoptosis-inducing activity., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)