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Triple-negative breast cancer (TNBC) is a highly aggressive subset of breast cancer with limited therapeutic options. However, its immune evasion mechanisms, characterized by the over-expression of the immune checkpoint molecules PD-L1 and CD47, can be targeted in order to facilitate cancer elimination by cells of innate and adaptive immunity. In this paper, we describe the design, preparation, and evaluation of three novel dual-targeting fusion proteins that were based on the structure frame of prototype IAB (innate and adaptive dependent bispecific fusion protein) and the “Orcutt-type IgG-scFv” molecular model. Three molecules with different spatial conformations were designed to improve antigen–antibody affinity by the addition of Ag–Ab binding sites from the variable region sequences of the anti-PD-L1 monoclonal antibody (mAb) atezolizumab and CV1, a high-affinity receptor of CD47. The results showed that the best-performing among the three proteins designed in this study was protein Pro3; its CV1 N-terminus and Fc domain C-terminus were not sterically hindered. Pro3 was better at boosting T cell proliferation and the engulfment of macrophages than the IAB prototype and, at the same time, retained a level of ADCC activity similar to that of IAB. Through improved design, the novel constructed dual-targeting immunomodulatory protein Pro3 was superior at activating the anti-tumor immune response and has thus shown potential for use in clinical applications.

Natural products, as a gift of nature to humanity, have long been used as drugs or pharmacological actives to help people cure various diseases. Yet we still know comparatively little about their ability to be materials. In recent years, some small molecule natural products isolated from traditional Chinese medicines have been found to have new features, namely, self-assembly to form gels (i.e., natural product gels, NPG). However, the application development of these natural products is seriously lacking, which greatly weakens their practical value and delays the maturity of the field. Here, a series of self-assembled triterpenoid natural products are used as materials (gel scaffolds) to construct drug delivery systems. Surprisingly, these NPG not only exhibit the excellent self-healing, controlled gelation, good safety and sustained release, but also achieve synergistic treatment of tumors through bioactive natural products. Compared with non-bioactive gel scaffolds, NPG scaffolds show great advantages in tumor therapy, including optimal tumor inhibition, preferable health, better body recovery, stronger immune function, less toxic side effects and longer survival. The successful construction of NPG scaffolds not only takes full advantage of the self-assembled natural products, but also takes an important step in the development of new applications for natural products., Graphical abstract Self-assembled small molecule natural products isolated from traditional Chinese medicine are constructed into injectable gel scaffolds. These natural product gel (NPG) scaffolds not only exhibit the excellent self-healing, controlled gelation, good safety and sustained release, but also achieve synergistic treatment of tumors through bioactive natural products.Image 1

Photothermal therapy directly acting on the nucleus is a potential anti-tumor treatment with higher killing efficiency. However, in practical applications, it is often difficult to achieve precise nuclear photothermal therapy because agents are difficult to accurately anchor to the nucleus. Therefore, it is urgent to develop a nanoheater that can accurately locate the nucleus. Here, we designed an amphiphilic arginine-rich dendritic peptide (RDP) with the sequence CRRK(RRCG(Fmoc))2, and prepared a nucleus-targeting nanoplatform RDP/I by encapsulating the photothermal agent IR780 in RDP for precise photothermal therapy of the tumor nucleus. The hydrophobic group Fmoc of the dendritic peptide provides strong hydrophobic force to firmly encapsulate IR780, which improves the solubility and stability of IR780. Moreover, the arginine-rich structure facilitates cellular uptake of RDP/I and endows it with the ability to quickly anchor to the nucleus. The nucleus-targeting nanoplatform RDP/I showed efficient nuclear enrichment ability and a significant tumor inhibition effect.

In this study, we demonstrate that Raman microscopy combined with computational analysis is a useful approach to discriminating accurately between brain tumor bio-specimens and to identifying structural changes in glioblastoma (GBM) bio-signatures after nordihydroguaiaretic acid (NDGA) administration. NDGA phenolic lignan was selected as a potential therapeutic agent because of its reported beneficial effects in alleviating and inhibiting the formation of multi-organ malignant tumors. The current analysis of NDGA’s impact on GBM human cells demonstrates a reduction in the quantity of altered protein content and of reactive oxygen species (ROS)-damaged phenylalanine; results that correlate with the ROS scavenger and anti-oxidant properties of NDGA. A novel outcome presented here is the use of phenylalanine as a biomarker for differentiating between samples and assessing drug efficacy. Treatment with a low NDGA dose shows a decline in abnormal lipid-protein metabolism, which is inferred by the formation of lipid droplets and a decrease in altered protein content. A very high dose results in cell structural and membrane damage that favors transformed protein overexpression. The information gained through this work is of substantial value for understanding NDGA’s beneficial as well as detrimental bio-effects as a potential therapeutic drug for brain cancer.

Targeted tumor cell killing using polymeric micelles with active targeting strategies has been demonstrated to be effectively therapeutic for liver cancers. To implement this strategy, enhancing the cellular uptake of the drug delivery system with targeted anticancer drugs, such as doxorubicin toward nuclear targeting, is of vital importance for increasing drug efficiency and reducing the systemic side effects of encapsulated drugs. In this study, a multifunctional polymeric drug delivery system was designed with actively targeted cell penetration and nuclear targeting for efficient cancer therapy. The nanocarriers were self-assembled from poly(ethylene glycol)

[Objective]: Although great progress has been made in the field of siRNA gene therapy, safe, efficient, and targeted delivery of siRNA are still major challenges in siRNA therapeutics., [Methods]: We developed an up-conversion nanoparticle-based nanocage system. This system protected the siRNA from being degraded by nucleases in organisms and selectively delivered the siRNAs to the tumor sites, due to modifications of targeted molecules on the surfaces of nanocages and local inhalation., [Results]: The siRNAs delivered by the up-conversion nanoparticle nanocages were protected from degradation in transit to the tumor sites, where they accumulated. Compared with the passive target and control groups, the up-conversion nanoparticles based on the nanocage system showed a tumor suppressive effect after approximately 3 weeks of treatment., [Conclusions]: The up-conversion nanoparticle nanocages efficiently delivered vascular endothelial growth factor siRNAs to tumor sites. Mice with lung tumors treated with tumors targeting up-conversion nanoparticle nanocages showed steady body weight changes, high tumor inhibition ratios, and longer survival times., This work is supported by the National Key Basic Research Program (973 Project) (Grant Nos. 2015CB931802 and 2017FYA0205301), the Special Fund for Science and Technology Innovation of Shanghai Jiao Tong University (Grant Nos. YG2017MS70, YG2015MS62, and AF0300179), the Shanghai Municipal Bureau of Economy and Information Technology (Grant No. XC-ZXSJ-02-2016-05), the National Natural Scientific Foundation of China (Grant Nos. 8202010801, 81921002, 81225010, 81028009, and 31170961), the 863 Project of China (Grant No. 2014AA020700), and the Shanghai Science and Technology Fund (Grant No. 13NM1401500).

Objective: The efficacy of anlotinib as a treatment for head-and-neck squamous cell carcinoma (HNSCC) has been little explored. Here, we used patient-derived xenografts (PDXs) to this end.Methods: Fresh tumor tissues of HNSCC patients were screened in terms of in vitro drug sensitivity using the MTT assay. Patient PDXs were used to confirm the anti-tumor effects of anlotinib in vivo. After the medication regimen was complete, the tumor volume changes in mice were calculated. Apoptosis was measured using the TUNEL assay. The cell proliferation and apoptosis levels of PDXs yielded data on the utility of anlotinib treatment in vivo.Results: Anlotinib suppressed the in vitro proliferation of nine tumor tissues by an average of 51.05 ± 13.74%. Anlotinib also significantly inhibited the growth of three PDXs in mice (tumor growth inhibition 79.02%). The expression levels of Ki-67 and proliferating cell nuclear antigen after anlotinib treatment were significantly lower than those in the controls. The negative and positive controls exhibited no and some apoptosis, respectively, whereas the anlotinib group evidenced extensive apoptosis.Conclusion: Anlotinib suppressed HNSCC growth in vitro and in vivo (by inhibiting cell proliferation and promoting apoptosis), suggesting that anlotinib can potentially treat HNSCC.

BackgroundAs DNA demethylation protein, Ten-eleven translocation 1 (TET1) has been widely reported that is related to tumorigenesis and tumor metastasis. This study is to investigate the role and regulation mechanism of TET1 in colon cancer.Methods The TET1 and Catenin beta-1 (CTNNB1) expression level in colon cancer samples and cancer cell lines HCT116/SW480 were observed to discover the relationship between these two genes. Knockdown and overexpression of TET1 through shRNA and CRISPR technology were used to elucidate the effect of TET1 on WNT/β-catenin pathway. The 5-hmC/5-mC level were explored by bisulfate sequencing (BSP) and Chromatin immunoprecipitation (ChIP) to further explain the regulation mechanism. Combined with the reverse assay and transwell invasion assay, the cell migration and invasion ability were tested. Finally, the role of TET1 on DOX resistance was analyzed.Results TET1 downregulated in colon cancer and showed an opposite expression trend with WNT pathway associated gene CTNNB1. TET1 bound to CTNNB1 promotor and catalyzed demethylation to activate transcription of CTNNB1, inhibiting WNT/β‐catenin signaling pathways. Colon cancer cells proliferation was promoted by TET1 downregulation, which was further verified as shTET1 could upregulate the tumor invasion. The DOX addition could rescue the cell migration, compared with normal expression of TET1. Meanwhile, TET1 down-regulation was related to DOX resistances.Conclusion TET1 played as a DNA hydroxymethylation activates inhibitors of the WNT/β-catenin signaling pathway in colon tumor and TET1 down-regulation contributed to DOX-resistance, which might provide reference to targeting therapy in clinical practice.

Nanoparticles, presenting catalytic activity to induce intracellular oxidative species, have been extensively explored for tumor treatment, but suffer daunting challenges in the limited intracellular H2O2 and thus suppressed therapeutic efficacy. Here in this study, a type of composite nanoparticles, consisting CaO2 core and Co-ferrocene shell, is designed and synthesized for combinational tumor treatment. The findings indicate that CaO2 core can be hydrolyzed to produce large amounts of H2O2 and calcium ions at the acidic tumor sites. Meanwhile, Co-ferrocene shell acts as an excellent Fenton catalyst, inducing considerable ROS generation following its reaction with H2O2. Excessive cellular oxidative stress triggers agitated calcium accumulation in addition to the calcium ions released from the particles. The combined effect of intracellular ROS and calcium overload causes significant tumor inhibition both in vitro and in vivo.

Cullin-RING E3 ubiquitin ligase 4 (CRL4) plays an essential role in cell cycle progression. Recent efforts using high throughput screening and follow up hit-to-lead studies have led to identification of small molecules 33-11 and KH-4-43 that inhibit E3 CRL4’s core ligase complex and exhibit anticancer potential. This review provides: 1) an updated perspective of E3 CRL4, including structural organization, major substrate targets and role in cancer; 2) a discussion of the challenges and strategies for finding the CRL inhibitor; and 3) a summary of the properties of the identified CRL4 inhibitors as well as a perspective on their potential utility to probe CRL4 biology and act as therapeutic agents.

Nanotechnology has a remarkable impact on the preclinical development of future medicines. However, the complicated preparation and systemic toxicity to living systems prevent them from translation to clinical applications. In the present report, we developed a polyepicatechin-based on/off switchable ultra-sensitive magnetic resonance imaging (MRI) visible theranostic nanoparticle (PEMN) for image-guided photothermal therapy (PTT) using our strategy of integrating polymerization and biomineralization into the protein template. We have exploited natural polyphenols as the near infra-red (NIR) switchable photothermal source and MnO2 for the MRI-guided theranostics. PEMN demonstrates excellent MRI contrast ability with a longitudinal relaxivity value up to 30.01 mM-1 s-1. PEMN has shown great tumor inhibition on orthotopic breast tumors and the treatment could be made switchable with an on/off interchangeable mode as needed. PEMN was found to be excretable mainly through the kidneys, avoiding potential systemic toxicity. Thus, PEMN could be extremely useful for developing on-demand therapeutics via'see it and treat it' means with distinguished MRI capability and on/off switchable photothermal properties.

Aim: This study aimed to develop indocyanine green- and doxorubicin-loaded liposomes (DILPs) as theranostic nanoplatform for the detection of hepatocellular carcinoma (HCC) and as an efficient chemotherapeutic to enhance microwave ablation. Materials & methods: DILPs were synthesized and thoroughly characterized. Biocompatibility, tumor uptake and accumulation, and synergistic ablation-chemotherapeutic efficiency were systematically explored in them. In addition, human HCC surgical samples were used to test the affinity of DILPs for HCC. Results: The combination of microwave ablation and DILPs enhanced the ablation efficiency of HCC with apparent tumor inhibition. DILPs exhibited excellent diagnostic ability and could detect 2.5-mm HCC lesions via optoacoustic tomography imaging. DILPs had better affinity for human HCC surgical samples compared with normal liver tissue. Conclusion: Theranostic DILPs could serve as promising nanoparticles for treatment and management of HCC in the clinic.

Song Kwon,1,* Kwai Han Yoo,2,* Sun Jin Sym,2 Dongwoo Khang1,3,41Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, South Korea; 2Department of Internal Medicine, Division of Hematology, School of Medicine, Gachon University Gil Medical Center, Incheon, 21565, South Korea; 3Department of Gachon Advanced Institute for Health Science & Technology (Gaihst), Gachon University, Incheon 21999, South Korea; 4Department of Physiology, School of Medicine, Gachon University, Incheon 21999, South Korea*These authors contributed equally to this workAbstract: Mesenchymal stem cells (MSCs) intrinsically possess unique features that not only help in their migration towards the tumor-rich environment but they also secrete versatile types of secretomes to induce nerve regeneration and analgesic effects at inflammatory sites. As a matter of course, engineering MSCs to enhance their intrinsic abilities is growing in interest in the oncology and regenerative field. However, the concern of possible tumorigenesis of genetically modified MSCs prompted the development of non-viral transfected MSCs armed with nanotechnology for more effective cancer and regenerative treatment. Despite the fact that a large number of successful studies have expanded our current knowledge in tumor-specific targeting, targeting damaged brain site remains enigmatic due to the presence of a blood–brain barrier (BBB). A BBB is a barrier that separates blood from brain, but MSCs with intrinsic features of transmigration across the BBB can efficiently deliver desired drugs to target sites. Importantly, MSCs, when mediated by nanoparticles, can further enhance tumor tropism and can regenerate the damaged neurons in the central nervous system through the promotion of axon growth. This review highlights the homing and nerve regenerative abilities of MSCs in order to provide a better understanding of potential cell therapeutic applications of non-genetically engineered MSCs with the aid of nanotechnology.Keywords: glioblastoma multiforme, tumor inhibition, mesenchymal stem cell, nanocarrier, nerve regeneration, anti-inflammation

Pea-like nanocabins (HA@APT§DOX) were designed for deep tumor inhibition. The AS1411 aptamer (APT) constituted "core shelf" which guaranteed DOX "beans" could be embedded, while the outer HA acted as "pea shell" coating. During the circulation (primary orbit), HA@APT§DOX could autonomously cruise until leak through tumor vasculature. Upon tumor superficial site, the "pea shell" could be degraded by highly expressed hyaluronic acid enzymes (HAase) and peel-off, resulting in orbit changing of released APT§DOX to reach the deep tumor tissue. Furthermore, APT§DOX could be specifically uptaken into A549 tumor cells (secondary orbit). Finally, DOX was released under the acidic environment of lysosome, and delivered into nuclear (targeting orbit) to achieve drug pushing for deep tumor inhibition. More importantly, the in vivo imaging and anti-tumor effects evaluations showed that these nanocabins could effectively enhance drugs accumulation in tumor sites and inhibit tumor growth, with reduced systemic toxicity in 4T1 tumor-bearing mice.

Nanoparticles, presenting catalytic activity to induce intracellular oxidative species, have been extensively explored for tumor treatment, but suffer daunting challenges in the limited intracellular H2O2 and thus suppressed therapeutic efficacy. Here in this study, a type of composite nanoparticles, consisting CaO2 core and Co-ferrocene shell, is designed and synthesized for combinational tumor treatment. The findings indicate that CaO2 core can be hydrolyzed to produce large amounts of H2O2 and calcium ions at the acidic tumor sites. Meanwhile, Co-ferrocene shell acts as an excellent Fenton catalyst, inducing considerable ROS generation following its reaction with H2O2. Excessive cellular oxidative stress triggers agitated calcium accumulation in addition to the calcium ions released from the particles. The combined effect of intracellular ROS and calcium overload causes significant tumor inhibition both in vitro and in vivo. Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-01055-4.

Nanotheranostics, which can provide great insight into cancer therapy, has been deemed as a promising technology to settle the unmet medical needs. The rational design of high performance nanotheranostics with multiple complementary imaging features and satisfactory therapeutic efficacy is particularly valuable. Herein, versatile nanotheranostic agents DPPB-Gd-I NPs were fabricated by using gadolinium-diethylenetriaminepentaacetic acid chelates and an iodine-decorated copolymer as encapsulation matrixes to encapsulate a polymer DPPB through one-step nanoprecipitation. We have demonstrated that such nanoagents are able to efficiently damage tumors under single dose injection and NIR laser illumination conditions due to the enhanced photodynamic therapy and enhanced photothermal therapy (the tumor inhibition rate was as high as 94.5%). Moreover, these nanoagents can be utilized as dual-modal NIR-II fluorescence/magnetic resonance imaging probes for tumor diagnosis with high sensitivity, deep tissue penetration, and excellent spatial resolution. Overall, this work offers a powerful tactic to fabricate high performance nanotheranostics for clinical application.

The radiotherapy enhancement effect of numerous nanosensitizers is based on the excessive production of reactive oxygen species (ROS), and only a few systematic reviews have focused on the key strategy in nanosensitizer-mediated radiotherapy. To clarify the mechanism underlying this effect, it is necessary to understand the role of ROS in radiosensitization before clinical application. Thus, the source of ROS and their principle of tumor inhibition are first introduced. Then, nanomaterial-mediated ROS generation in radiotherapy is reviewed. The double-edged sword effect of ROS and the potential dangers they may pose to cancer patients are subsequently addressed. Finally, future perspectives regarding ROS-regulated nanosensitizer applications and development are discussed.

Significance Cullin-RING E3 ubiquitin ligases (CRLs) direct protein degradation to impact a myriad of physiological and pathological processes including cancer. This work reports the small-molecule compounds 33-11 and KH-4-43 as inhibitors of E3 CRL4 with anticancer potential. These compounds have provided an opportunity for developing tool compounds to address mechanistic and phenotypic questions about CRL4 in biochemical, cell-based, and animal studies. The results of correlation studies between cullin4 protein level and the compounds’ cytotoxic response as well as cullin4 depletion experiments suggest a role for low E3 abundance in sensitizing tumor cells for apoptosis. Collectively, the 33-11/KH-4-43–based CRL4 inhibitors may provide new exploitable therapeutic opportunities to target a subset of tumor lines characterized by low CUL4 expression., Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. These compounds bind to CRL4’s core catalytic complex, inhibit CRL4-mediated ubiquitination, and cause stabilization of CRL4’s substrate CDT1 in cells. Treatment with 33-11 or KH-4-43 in a panel of 36 tumor cell lines revealed cytotoxicity. The antitumor activity was validated by the ability of the compounds to suppress the growth of human tumor xenografts in mice. Mechanistically, the compounds’ cytotoxicity was linked to aberrant accumulation of CDT1 that is known to trigger apoptosis. Moreover, a subset of tumor cells was found to express cullin4 proteins at levels as much as 70-fold lower than those in other tumor lines. The low-cullin4–expressing tumor cells appeared to exhibit increased sensitivity to 33-11/KH-4-43, raising a provocative hypothesis for the role of low E3 abundance as a cancer vulnerability.

FOXA1 is a key pioneer factor in androgen-receptor activity but has been an elusive drug target. A new study shows that inhibition of the associated cofactor LSD1 modifies the methylation state of FOXA1, thus resulting in chromatin dissociation and tumor inhibition, even in models of treatment-resistant prostate cancer.

Excretory/Secretory Products (ESPs) of the nematode Trichinella spiralis contain antitumor-active substances that inhibit tumor growth. Mature dendritic cells (DCs) play a critical role in the antitumor immunity of the organism. As pathogen-derived products, it ought to be discussed whether T. spiralis ESPs will reduce the antitumor effect of mature DCs from the host before it is applied to patients' tumors. Therefore, the aim of this work was to evaluate the immunological effect of DCs stimulated by T. spiralis ESPs in H22 tumor-bearing mice. H22 tumor model mice in this study were randomly divided into four groups according to the treatment: PBS control group, ESP group, DCs group, and DCs stimulated with T. spiralis ESP (ESP+DCs group). The antitumor effect was evaluated by tumor inhibition rate and cytokine detection using ELISA. The results showed significant inhibition in tumor growth in the ESP+DCs, DCs and ESP groups when compared with the PBS control group (p 0.01, p 0.01, and p 0.05, respectively). However, no significant difference was observed on tumor inhibition rates between the ESP+DCs and DCs groups. The decrease in IL-4, IL-6, and IL-10, and the increase in IFN-γ between the DCs and ESP+DCs groups were also not significant. Therefore, DCs stimulated by ESP did not reduce the antitumor effect of mature DCs, which demonstrated that the T. spiralis ESP would not affect the antitumor effect of mature DCs by modulating the immune response of the host, and that ESPs are safe in antitumor immunology when applied in a tumor model mice.Traitement des hépatomes murins avec des cellules dendritiques mûres stimulées par des produits d’excrétion-sécrétion de Trichinella spiralis.Les produits d’excrétion-sécrétion (PES) du nématode Trichinella spiralis contiennent des substances actives antitumorales qui inhibent la croissance tumorale. Les cellules dendritiques (CD) mûres jouent un rôle essentiel dans l’immunité anti-tumorale de l’organisme. En tant que produits dérivés d’agents pathogènes, il convient de déterminer si les PES de T. spiralis réduisent l’effet antitumoral des CD mûrs de l’hôte, avant leur application aux tumeurs des patients. Par conséquent, l’objectif de ce travail était d’évaluer l’effet immunologique des CD stimulées par les PES de T. spiralis chez des souris porteuses de tumeurs H22. Les souris modèles à tumeurs H22 dans cette étude ont été réparties au hasard en quatre groupes selon le traitement : groupe témoin PBS, groupe PES, groupe CD et groupe CD stimulés par les PES de T. spiralis (CD+PES). L’effet antitumoral a été évalué par le taux d’inhibition des tumeurs et la détection des cytokines en utilisant un dosage ELISA. Les résultats ont montré une inhibition significative de la croissance tumorale dans les groupes CD+PES, CD et PES par rapport au groupe témoin PBS (p 0,01, p 0,01 et p 0,05, respectivement). Cependant, aucune différence significative n’a été observée sur le taux d’inhibition de la tumeur entre les groupes CD+PES et CD. La diminution de l’IL-4, de l’IL-6, de l’IL-10 et l’augmentation de l’IFN-γ entre les groupes CD et CD+PES n’étaient pas non plus significatives. Ainsi, les CD stimulées par les PES n’ont pas réduit l’effet antitumoral des CD mûrs, ce qui a démontré que les PES de T. spiralis n’affectaient pas l’effet antitumoral des CD mûrs en modulant la réponse immunitaire de l’hôte et que les PES sont sûrs en immunologie antitumorale quand ils sont appliqués à des souris modèles tumorales.

Tumor hypoxia compromises the effects of photodynamic therapy that consumes oxygen in the therapeutic process. Herein, a platinum (Pt)-carbon-integrated nanozyme with favorable catalase-like activity and photosensitizing properties was successfully constructed by immobilizing an ultrasmall Pt nanozyme into a MOF-derived carbon nanozyme through an in situ reduction strategy. The integration of a Pt nanozyme significantly improves the catalase activity of a carbon nanozyme that can effectively catalyze the decomposition of endogenous hydrogen peroxide to produce oxygen to improve the effects of photodynamic therapy. In addition, the integration of a Pt nanozyme also enhances the intrinsic photothermal performance of a carbon nanozyme. Combining the improved catalase-like activity with the enhanced photothermal properties together, the Pt-carbon nanozyme exhibits remarkable tumor inhibition ability in vivo. Thus, utilizing the enzymatic activity and photothermal/photosensitizing properties of nanozymes has great potential to overcome the limitations of traditional therapeutic strategies, and could inspire new directions for nanozyme-based biomedical applications.

The Fe element is essential for human beings, but overdose of Fe leads to unwanted toxicity. However, overwhelming Fe accumulation in tumor cells could arouse strong oxidative stress for cancer therapy. Therefore, the fast and specific accumulation of Fe in tumor cells without systemic toxicity is critical for this purpose. Herein, we report that a carbon nanoparticles-Fe(II) complex (CNSI-Fe) could efficiently load Fe into tumor cells and inhibit tumor growth with low toxicity in H22 tumor-bearing mice. Upon intratumoral injection, CNSI-Fe only induced meaningful Fe increase in the tumor to significantly inhibit tumor growth with competitive efficiency to cis-dichlorodiammineplatinum(II). Fe accumulation stimulated the hydroxyl radical generation and serious oxidative stress in the tumor. Due to the lack of Fe accumulation in other tissues, CNSI-Fe was of low systemic toxicity to tumor-bearing mice. With the clinical success of CNSI for decades, CNSI-Fe might be used for cancer therapy through "off label" use to benefit patients immediately.

Hongfeng Wu,1 Zhongtao Li,2 Jiaoqing Tang,2 Xiao Yang,1 Yong Zhou,3 Bo Guo,4 Lin Wang,2 Xiangdong Zhu,1 Chongqi Tu,3 Xingdong Zhang1 1National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China; 2Department of Dermatology, West China Hospital of Sichuan University, Chengdu 610041, China; 3Department of Orthopaedics, West China Hospital of Sichuan University, Chengdu 610041, China; 4Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610041, China Background: Treatment for melanoma is a challenging clinical problem, and some new strategies are worth exploring.Purpose: The objective of this study was to investigate the in vitro and in vivo anti-melanoma effects of hydroxyapatite nanoparticles (HANPs) and discuss the involved material factors.Materials and methods: Five types of HANPs, ie, HA-A, HA-B, HA-C, HA-D, and HA-E, were prepared by wet chemical method combining with polymer template and appropriate post-treatments. The in vitro effects of the as-prepared five HANPs on inhibiting the viability of A375 melanoma cells and inducing the apoptosis of the cells were evaluated by Cell Counting Kit-8 analysis, cell nucleus morphology observation, flow cytometer, and PCR analysis. The in vivo anti-melanoma effects of HANPs were studied in the tumor model of nude mice.Results: The five HANPs had different physicochemical properties, including morphology, size, specific surface area (SSA), crystallinity, and so on. By the in vitro cell study, it was found that the material factors played important roles in the anti-melanoma effect of HANPs. Among the as-prepared five HANPs, HA-A with granular shape, smaller size, higher SSA, and lower crystallinity exhibited best effect on inhibiting the viability of A375 cells. At the concentration of 200 µg/mL, HA-A resulted in the lowest cell viability (34.90%) at day 3. All the HANPs could induce the apoptosis of A375 cells, and the relatively higher apoptosis rates of the cells were found in HA-A (20.10%) and HA-B (19.41%) at day 3. However, all the HANPs showed no inhibitory effect on the viability of the normal human epidermal fibroblasts. The preliminary in vivo evaluation showed that both HA-A and HA-C could delay the formation and growth speed of melanoma tissue significantly. Likely, HA-A exhibited better effect on inhibiting the growth of melanoma tissue than HA-C. The inhibition rate of HA-A for tumor tissue growth reached 49.1% at day 23.Conclusion: The current study confirmed the anti-melanoma effect of HANPs and provided a new idea for the clinical treatment of melanoma. Keywords: hydroxyapatite, nanoparticles, melanoma cells, fibroblasts, viability, apoptosis, tumor, suppression

A bean-shaped and dual-functionalized organic-inorganic hybrid supramolecular system with a GSH-dependent turn-on fluorescence enhancement property and stimuli-responsive drug delivery function endowed with leaning towerarene-based switches has been constructed for simultaneous tumor inhibition and imaging.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer without effective targeted drugs. While breast cancer patients often use acupuncture for the relief of cancer-induced pain or the side effects of chemo- or radiation therapy, little information is known regarding the direct effects of electroacupuncture on TNBC tumor and its potential mechanisms. Here, we created a mice model of TNBC and electroacupuncture with encircled needling around the tumors was given to the animals daily for 3 weeks at 15-20 Hz (3 min, each time). For sham electroacupuncture control, the skin was punctured to a depth of 5 mm and then the needle was quickly withdrawn without electrical stimulation or manual needle manipulation. We found that electroacupuncture significantly inhibited TNBC tumor growth and the inhibitory rate increased gradually overtime. Mechanistic analysis showed that electroacupuncture inhibited tumor angiogenesis by reducing the expression of vascular endothelial growth factor A (VEGF-A), its receptor VEGF-R and neuropilin 1 (NRP-1). Electroacupuncture also led to a significant decrease of matrix metalloproteinase-2 (MMP-2) expression and an increase of tissue inhibitor of MMP (TIMP-2) expression. Additionally, the expression of semaphorin 3A (Sema3A) and nerve growth factor receptor (NGFR) p75 in TNBC tissue was significantly upregulated in response to electroacupuncture. Furthermore, tumor necrosis factor (TNF)-alpha level in the serum was dramatically reduced after electroacupuncture. These results showed that electroacupuncture could directly inhibit TNBC tumor growth through the inhibition of proteins related to tumor angiogenesis and extracellular matrix, the suppression of TNBC-induced inflammation and the upregulation of nerve growth factor receptors.

Background Gegen Qinlian decoction (GQT), is a classic traditional Chinese medicine formula chronicled in Shang Han Lun, and is widely used to treat diarrhea and inflammation symptoms in various gastrointestinal disorders. Although it has been found to inhibit delayed-onset mice diarrhea resulted from irinotecan (CPT-11) administration in preliminary experiments, the underlying mechanisms and chemical components remain elusive. Methods The effective fraction of GQT by macroporous resin elution was obtained and screened using a diarrhea mouse model induced by CPT-11 and quantified by UPLC analysis. The protective effect of GQT extract towards alleviating diarrhea in mice following CPT-11 administration was further investigated. The levels of inflammatory cytokines and intestinal tight junction related proteins in colonic tissues were determined. The inhibitory effect of GQT extract against hCE2 was evaluated by a fluorescence-based method. Lastly, the synergistic effect of GQT extract combined with CPT-11 against tumor growth in a colorectal tumor mouse model, induced by HT-29 colon cancer cells xenograft subcutaneously, was investigated. Results The obtained GQT extract, which profoundly ameliorated the gut toxicity induced by CPT-11, contained puerarin, liquiritin, berberine, and baicalin of 27.2 mg/g, 4.6 mg/g, 491.4 mg/g, and 304.2 mg/g, respectively. After 5 days of administration of GQT extract to mice with diarrhea induced by CPT-11, aberrantly elevated levels of pro-inflammatory cytokines, including IL-1β, COX-2, ICAM-1, and TNF-α, were significantly decreased. Meanwhile, GQT extract also exhibited a remarkable anti-oxidative stress effect, involving activating the Keap1/Nrf2 pathway, and up-regulating the intestinal barrier function by enhancing the expression of tight junction proteins ZO-1, HO-1, and occludin. Additionally, a potent inhibitory effect of GQT extract against hCE2 was observedin vitro, with its IC50 value of 0.187 mg/ml, suggesting alleviating activity on hCE2-mediated severe diarrhea in patients suffered from CPT-11. Moreover, GQT extract was shown to improve inhibition of the colonic tumor growth synergistically with CPT-11. Conclusion The present study indicates that GQT extract can ameliorate CPT-11 induced gut toxicity in mice and improve CPT-11 efficacy in colorectal cancer treatment.

Photodynamic therapy (PDT) is commonly employed in clinics to treat the cancer, but because of the hypoxic tumor microenvironment prevalent inside tumors, PDT therapeutic efficiency is not adequate hence limiting the effectiveness of PDT. Therefore, we designed a nanocomposite consisting of reduced nanographene oxide (rGO) modified with polyethylene glycol (PEG), manganese dioxide (MnO2), upconversion nanoparticles (UCNPs), and Chlorin e6 (Ce6) to spark oxygen production from H2O2 with the aim of relieving the tumor hypoxic microenvironments. For in vivo tumor PDT and photothermal therapy (PTT), UCNPs-Ce6-labeled rGO-MnO2-PEG nanocomposites were used as a therapeutic agent, augmenting the therapeutic efficiency of PDT via redox progression through the catalytic H2O2 decomposition pathway and further achieving excellent tumor inhibition. It is important to mention that degradation of MnO2 in an acidic cellular microenvironment leads to the creation of a massive volume of Mn2+ which was employed as a contrast mediator for magnetic resonance imaging (MRI). Our research postulates an approach to spark O2 formation through an internal stimulus to augment the efficiency of MRI- and computerized tomography (CT)-imaging-guided PDT and PTT.

Pd nanosheets (Pd NSs) have attracted extensive attention due to their promising application in photothermal therapy. However, their photodynamic properties have rarely been reported. Herein, holey Pd NSs (H-Pd NSs) with intrinsic photodynamic and hypoxia-resistant capacities are fabricated for the first time using an anisotropic oxidative etching strategy, which introduces one-dimensional nanoholes with active (100) facets on the hole walls. Gradual degradation of H-Pd NSs is observed in simulated physiological media due to the oxidative etching. In vitro and in vivo studies indicate that the single-component H-Pd NSs can act as a photothermal/photodynamic agent for imaging-guided hypoxic tumor therapy, with a high tumor inhibition rate of 99.7%. This work provides ideas for introducing active facets in metallic pore walls, broadening the application of Pd NSs and the design of biodegradable noble metal nanotheranostic agents for cancer therapy.

Conjugation of cisplatin to macromolecular carriers has been extensively studied for reducing systemic side effects. Here, a cisplatin-stitched α-poly(glutamatic acid) nanoconjugate with reduced adverse reactions and effective anti-tumor efficacy was synthesized via ionic interaction between platinum ion of cisplatin with carboxylic groups of α-poly(glutamatic acid). The nanoconjugate exhibited good water solubility, suitable size and polydispersity, almost spherical morphologies, and a sustained release profile without burst release. In vitro cytotoxicity and cell apoptosis assays performed in MCF-7 cells showed significantly decreased cytotoxicity of nanoconjugate compared with free cisplatin, and larger ratio of early apoptosis than late apoptosis. Quantitative cellular uptake assay also supported that conjugation of cisplatin to α-poly(glutamatic acid) reduced its cytotoxicity. Further studies revealed that the unique space structure of nanoconjugate acted as a shield for cisplatin against GSH detoxification under physiological conditions. In vivo studies regarding maximum tolerated dose, hematological parameters evaluation and histopathology assay demonstrated the superior safety of nanoconjugates. Furthermore, the nanoconjugates also achieved comparable antitumor efficacy with no apparent weight loss and death at a high equivalent cisplatin dose of 25 mg/kg. Moreover, the survival rate of mice treated with nanoconjugate was greatly larger than that of free cisplatin. These findings suggest that the cisplatin-stitched α-poly(glutamatic acid) nanoconjugate may hold great potential in clinical application for cancer therapy.

One of the major challenges in vaccine design has been the over dependence on incorporation of abundant adjuvants, which in fact is in violation of the "minimalist" principle. In the present study, a compact nanovaccine derived from a near whole antigen (up to 97 wt %) was developed. The nanovaccine structure was stabilized by free cysteines within each antigen (ovalbumin, OVA), which were tempospatially exposed and heat-driven to form an extensive intermolecular disulfide network. This process enables the engineering of a nanovaccine upon integration of the danger signal (CpG-SH) into the network during the synthetic process. The 50 nm-sized nanovaccine was developed comprising approximately 500 antigen molecules per nanoparticle. The nanovaccine prophylactically protected 70% of mice from tumorigenesis (0% for the control group) in murine B16-OVA melanoma. Significant tumor inhibition was achieved by strongly nanovaccine-induced cytotoxic T lymphocytes. This strategy can be adapted for the future design of vaccine for a minimalist composition in clinical settings.

The development of robust photothermal agents for near-infrared (NIR) imaging is a great challenge. Herein, we report the design and synthesis of a new photothermal agent, based on the aza-boron-dipyrromethene framework (azaBDP). This compound possessed excellent photostability and high photothermal-conversion efficiency (50 %) under NIR laser irradiation. When the photothermal properties of this compound were utilized for tumor inhibition, stable long-term fluorescence was observed in living animals. Photothermal treatment efficiently suppressed tumor growth, as evidenced by in vitro and in vivo experiments. Furthermore, NIR emission could be detected by using an imaging system and therapeutic self-monitoring was achieved by using NIR imaging.

Recently, Zhejiang University scientists developed a local “landmine.” They engineered a patch device consisting of microneedle arrays integrated with palladium nanoparticles supported by TiO2 nanosheets to catalyze a local prodrug-into-drug conversion via bio-orthogonal reaction for tumor inhibition. This study provides a novel paradigm for biological application of bio-orthogonal chemistry in local tumor treatment.

Snowman-like Au-BNP (bovine serum albumin nanoparticle) Janus nanoparticles (AuBJNPs) are prepared through a facile adsorption-reduction seeds mediated growth method. The formation of the snowman-like structure is driven by a thermodynamic spontaneous process controlled by the reduction kinetics of AuCl4- ions. Thereafter, the AuBJNP nanoparticles have been selectively modified with thiol-aptamer AS1411 for specific tumor-targeting and NIR dye, Indocyanine green-amine (ICG-NH2), for improving the photothermal effect. The final obtained AS1411-AuBJNP-ICG Janus nanoparticles possess a tumor-targeting head and a biodegradable and NIR responsive body which similar to T2-phage both in morphology and composition. In addition, DOX(doxorubin)-loaded AS1411-AuBJNP-ICG under 808 nm NIR laser irradiation exhibited higher tumor inhibition ability and specific tumor-targeting ability at cellular and animal levels, implying that the multifunctional T2-phage-like AS1411-AuBJNP-ICG can provide a potential bio-inspired nanoplatform in the field of active tumor-targeting and chemo-photothermal cancer synergistic therapy.

A novel series of tetrahydroquinolines containing acetohydrazide, oxopyrazole, oxothioxodihydropyrazole, and thioxotriazole have been synthesized. Antileishmanial, antitumor, and cytotoxicity activities of synthesized compounds were evaluated in vitro. Antileishmanial activity of the most synthesized compounds showed tremendous activity towards Leishmania major. Most of the test compounds exhibited significant level of tumor inhibition. The tetrahydropyrano[2,3-b]quinolin-2-one 6 and 4-oxo-4H-pyrazol-3-yloxytetrahydroquinoline-3-carbonitrile derivatives 18 showed 100% tumor inhibition comparable with standard drug vincristine (100% tumor inhibition). Tetrahydroquinolines under investigation showed cytotoxicity with LD50 values in the range 0.56–3.01 μg/mL compared with standard drug MS-222 with LD50 value of 4.30 μg/mL. The presence of a pyrazole ring markedly improved the activity profiles of tetrahydroquinoline. All newly synthesized compounds were characterized by IR, 1H NMR, and MS.

Inhibiting the formation of new tumor blood vessels (so-called antiangiogenesis) and obstructing the established ones are two primary strategies in tumor vasculature targeted therapy. However, the therapeutic outcome of conventional methodologies relying on only one mechanism is rather limited. Herein, the first example of ultrasmall responsively aggregatable nanochelators that can intrinsically fulfill both antivasculature functions as well as high renal clearable efficiency is introduced. The nanochelators with sub-6 nm sizes exhibit not only systemic copper depletion activity for tumor antiangiogenesis but also, more surprisingly, the capability to transform from a "dispersed" state to an "aggregated" state to form large secondary particles in response to tumor microenvironment with elevated copper and phosphate levels for blood vessel obstruction. Compared to a benchmark antiangiogenic agent that can only inhibit the formation of tumor blood vessels, the nanochelators with unprecedented synergistic functions demonstrate significantly enhanced tumor inhibition activity in both breast cancer and colon cancer tumor models. Moreover, these ultrasmall nanochelators are noncytotoxic and renal clearable, ensuring superior biocompatibility. It is envisaged that the design of nanomaterials with ground-breaking properties and the synergistic antivasculature functions would offer a substantial conceptual advance for tumor vasculature targeted therapy and may provide vast opportunities for developing advanced nanomedicines.

Supramolecular protein nanodrugs provide opportunities for improving antitumor therapeutic efficiency and lowering toxicity. However, protein nanodrugs that have robust structural stability and enhanced therapeutic efficiency are still in infancy. In this study, photothermal protein nanodrugs are constructed through a supramolecular approach along with heating by using proteins, photosensitizers, and metal ions as the building blocks. The metal coordination and heating improve not only the structural stability but also photothermal performance of the resulting nanodrugs. By virtue of the first integration of coordination- and heating-enhanced photothermal effects, the nanodrugs show superior photothermal conversion efficiency, enhanced tumor accumulation, and improved tumor inhibition. Metal coordination and heating are versatile to be applied for various protein nanodrugs. Hence, this study provides insights for the construction of highly efficient photothermal nanodrugs and thus will be beneficial to precision theranostics.

Targeted drug delivery systems (TDDSs) provide a promising approach to overcome the side effect of traditional chemotherapy by specific tumor targeting and drug release. Hyaluronan (HA), as a selective CD44 targeting group, has been widely used in TDDSs for chemotherapy. However, different molecular weight HAs would demonstrate different binding ability to CD44, which may result in different therapeutic effects. Herein, a silica/hydroxyapatite (MSNs/HAP) hybrid carrier loaded with anticancer drug doxorubicin (DOX) (DOX@MSNs/HAP) is fabricated. HA and oligo HA (oHA) are coated onto the nanoparticles (HA‐DOX@MSNs/HAP, oHA‐DOX@MSNs/HAP), respectively, to investigate their performance in tumor targeting ability. oHA‐DOX@MSNs/HAP shows much higher efficiency cellular uptake and drug release in tumor regions due to more effective CD44 targeting of oHA. Thus, the anticancer effect of oHA‐DOX@MSNs/HAP is significantly enhanced compared to HA‐DOX@MSNs/HAP, as demonstrated in a tumor‐bearing mouse model. This study may enable the rational design of nanodrug systems for future tumor‐targeted chemotherapy.

Mesenchymal stem cells (MSCs) intrinsically possess unique features that not only help in their migration towards the tumor-rich environment but they also secrete versatile types of secretomes to induce nerve regeneration and analgesic effects at inflammatory sites. As a matter of course, engineering MSCs to enhance their intrinsic abilities is growing in interest in the oncology and regenerative field. However, the concern of possible tumorigenesis of genetically modified MSCs prompted the development of non-viral transfected MSCs armed with nanotechnology for more effective cancer and regenerative treatment. Despite the fact that a large number of successful studies have expanded our current knowledge in tumor-specific targeting, targeting damaged brain site remains enigmatic due to the presence of a blood–brain barrier (BBB). A BBB is a barrier that separates blood from brain, but MSCs with intrinsic features of transmigration across the BBB can efficiently deliver desired drugs to target sites. Importantly, MSCs, when mediated by nanoparticles, can further enhance tumor tropism and can regenerate the damaged neurons in the central nervous system through the promotion of axon growth. This review highlights the homing and nerve regenerative abilities of MSCs in order to provide a better understanding of potential cell therapeutic applications of non-genetically engineered MSCs with the aid of nanotechnology.

Background: Human epidermal growth factor receptor 2 (HER2) is overexpressed in several human malignancies and numerous studies have indicated that it plays important roles in the development and maintenance of the malignant phenotype. Targeting of HER2 molecules with monoclonal antibodies (mAbs) is a promising therapeutic approach. However, anti-HER2 mAbs affect cancer cells differently, depending on the distinct epitopes which are the targets. Methods: Reactivity of a panel of 8 mouse anti-HER2 mAbs was investigated by ELISA and Western blotting using different subdomains of the extracellular domain (ECD) of HER2. All subdomains, including I, II, III, IV, I+II, III+IV and full HER2-ECD were constructed and expressed in CHO cells. Cross-reactivity of the mAbs with other members of the human HER family and Cynomolgus HER2 was also studied by ELISA. The mAbs were also tested by immunohistochemistry (IHC) using HER2 positive breast cancer tissues. Results: Our results demonstrated that 3 out of 8 mAbs detected conformational epitopes (1T0, 2A8 and 1B5), while 5 mAbs identified linear epitopes (1F2, 1H9, 4C7, 1H6 and 2A9). Three of the mAbs recognized subdomain I, one reacted with subdomain I+II, 2 recognized either subdomain III or IV and 2 recognized subdomain III+IV. However, none of our mAbs recognized the subdomain II alone. The mAbs displayed either inhibitory or stimulatory effects on HER2-overexpressing tumor cells and did not react with other members of the human HER family. The pattern of IHC results implied better reactivity of the mAbs recognizing linear epitopes. Conclusions: Our findings suggest that paired subdomains of HER2 are essential for mapping of mAbs recognizing conformational epitopes. Moreover, there seems to be no association between subdomain specificity and antitumor activity of our anti-HER2 mAbs.

Poly(vinyl pyrrolidone) (PVP) and stearoyl chloride (SC) double-grafted chitosan (PCS) nanoparticles (NPs) were prepared for paclitaxel (PTX) delivery. PTX could be effectively loaded into PCS NPs with encapsulation efficiency of 92.8%. PTX-loaded PCS NPs (PTX/PCS NPs), which possessed particle sizes of 144 nm and Zeta potentials of −7.5 mV, exhibited a sustained release behavior. In H-22 tumor bearing mice, significantly enhanced antitumor efficacies were achieved by PTX/PCS NPs with the tumor inhibition ratio (TIR) of 76.1% as compared with PTX injection. Furthermore, no signs of sub-acute toxicity were detected in healthy mice, indicating the safety of PCS NPs. Therefore, PCS NPs could be served as an effective and safe carrier for PTX delivery.

Objectives: To investigate the tumor-suppressive properties of enzalutamide in androgen-driven ovarian cancer. Methods: Mice were implanted subcutaneously with OVCAR-3 cells and treated with dihydrotestosterone in combination with enzalutamide or vehicle control. Tumor volumes were measured twice weekly until day 56. Results: Dihydrotestosterone exposure led to a significant increase in tumor growth, while concomitant treatment with enzalutamide led to significant reductions in tumor volume compared to the androgen-exposed groups. Conclusions: We present the first evidence that the second-generation anti-androgen enzalutamide may possess efficacy in the treatment of ovarian cancer, paving the way for the future clinical trials.

International audience; Cancer chemotherapeutic drug containing PEGylated lipidic nanocapsules (D-LNCs) were formulated by the controlled addition of organic phase (combined solution of paclitaxel and curcumin in a mixture of oleic acid and MPEG2000-DSPE (90:2.5 molar ratio) in acetone) to the aqueous phase (consist of Poloxamer 407 as emulsifying agents and glycerol as a co-solvent) at a temperature of 55-60°C followed by evaporation of organic solvent. The obtained pre-colloidal dispersion of D-LNCs was processed through high pressure homogenization to get more uniformly and nano-sized particles. Effect of concentration of emulsifying agent and process variables of high pressure homogenization (pressure and number of cycles) on average particle size and entrapment efficiency was further investigated by constructing Box-Behnken experimental design to achieve the optimum manufacturing process. D-LNCs were characterized by dynamic light scattering, scanning and transmission electron microscopy, Fourier transform infrared spectroscopy, and differential scanning calorimetry. In vitro release studies showed a sustained release pattern of drug from the PEGylated D-LNCs, whereas in vivo pharmacokinetic studies after a single-dose intravenous (i.v.) administration of paclitaxel (15mg/kg) in Ehrlich ascites tumor (EAT)-bearing female Swiss albino mice showed a prolonged circulation time and slower elimination of paclitaxel from D-LNCs as compared with marketed formulation (Paclitec®). From the plasma concentration vs. time profile, i.v. bioavailability (AUC0-∞) of paclitaxel from D-LNCs was found to be increased approximately 2.91-fold (P

// Zhong Liu 1, * , Ge Liu 1, * , Guang-Lin Zhang 1, * , Jun Li 1 , Yan-Qing He 2 , Shu-Shu Zhang 3 , Yi Wang 1 , Wei-Yi He 1 , Guo-Hua Cheng 4 , Xuesong Yang 2 , Jun Xu 3 , Ju Wang 1 1 Institute of Biomedicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China 2 Key Laboratory for Regenerative Medicine of the Ministry of Education, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou 510632, China 3 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China 4 College of Pharmacy, Jinan University, Guangzhou 510632, China * These authors contributed equally to this work Correspondence to: Ju Wang, email: wangju1688@163.com Keywords: heterocomplex, FGF-2, soluble FGFR2, tumor inhibition, angiogenesis Received: April 03, 2016 Accepted: August 24, 2016 Published: September 16, 2016 ABSTRACT FGFRs are considered essential targets for cancer therapy. We previously reported that msFGFR2c, a Ser252Trp mutant soluble ectodomain of FGFR2IIIc, inhibited tumor growth by blocking FGF signaling pathway. However, the underlying molecular mechanism is still obscure. In this study, we reported that msFGFR2c but not wild-type soluble ectodomain of FGFR2IIIc (wsFGFR2c) could selectively bind to c subtype of FGFRs in the presence of FGF-2. Thermodynamic analysis demonstrated that msFGFR2c bound to wsFGFR2c in the presence of FGF-2 with a K value of 6.61 × 10 5 M −1 . Molecular dynamics simulations revealed that the mutated residue Trp252 of msFGFR2c preferred a π-π interaction with His254 of wsFGFR2c. Concomitantly, Arg255 of msFGFR2c and Glu250 of wsFGFR2c adjusted their conformations and formed three H-bonds. These two interactions therefore stabilized the final structure of wsFGFR2c and msFGFR2c heterocomplex. In FGFR2IIIc-positive/high FGF-2-secreted BT-549 cells, msFGFR2c significantly inhibited the proliferation and induced apoptosis by the blockage of FGF-2-activated FGFRs phosphorylation, also the growth and angiogenesis of its xenograft tumors implanted in chick embryo chorioallantoic membrane model. While weaker the above inhibitory effects of msFGFR2c were observed on FGFR2IIIc-negative/low FGF-2-secreted MCF-7 and MDA-MB-231 cell lines in vitro and in vivo . Moreover, msFGFR2c significantly inhibited the proliferation of FGFR1IIIc-positive NCI-H1299 lung cancer cells by the suppression of FGF-2-induced FGFR1 activation and suppressed the growth of NCI-H1299 transplanted tumors in nude mice. In sum, msFGFR2c is a potential anti-tumor agent targeting FGFR2c/FGFR1c-positive tumor cells. These findings also provide a molecular basis for msFGFR2c to disrupt the activation of FGF signaling.

The combination of Endostatin (ES) and Herpes Simplex Virus thymidine kinase (HSV‐TK) gene therapy is known to have antitumor activity in bladder cancer. The potential effect of ES and TK therapy in glioma has not yet been investigated. In this study, pTK‐internal ribosome entry site (IRES), pIRES‐ES, and pTK‐IRES‐ES plasmids were constructed; pIRES empty vector served as the negative control. The recombinant constructs were transfected into human umbilical vein endothelial cells (HUVECs) ECV304 and C6 rat glioma cell line. Ganciclovir (GCV) was used to induce cell death in transfected C6 cells. We found that ECV304 cells expressing either ES or TK‐ES showed reduced proliferation, decreased migration capacity, and increased apoptosis, as compared to untransfected cells or controls. pTK‐IRES‐ES/GCV or pTK‐IRES/GCV significantly suppressed cell proliferation and induced cell apoptosis in C6 cells, as compared to the control. In addition, the administration of pIRES‐ES, pTK‐IRES/GCV, or pTK‐IRES‐ES/GCV therapy improved animal activity and behavior; was associated with prolonged animal survival, and a lower microvessel density (MVD) value in tumor tissues of C6 glioma rats. In comparison to others, dual gene therapy in form of pTK‐IRES‐ES/GCV had a significant antitumor activity against C6 glioma. These findings indicate combined TK and ES gene therapy was associated with a superior antitumor efficacy as compared to single gene therapy in C6 glioma.

Most medulloblastoma protocols worldwide include vincristine during radiation and chemotherapy. A significant dose-limiting toxicity is peripheral neuropathy; however, there is a paucity of data to support the view that omission of vincristine does not impact survival. Herein we report two adolescent patients with Group 4 and SHH medulloblastoma, where vinblastine successfully replaced vincristine with resolution of their peripheral neuropathy. We furthermore show vinblastine is highly active in vitro and demonstrates equivalent antitumoral activity compared to vincristine. Substitution of vincristine with vinblastine in future studies should be considered for all patients with medulloblastoma, particularly those with hereditary neuropathy, severe vincristine toxicity, and adults.

Earlier studies on elucidating the role of lymphocytes in tumor immunity predominantly focused on T cells. However, the role of B cells in tumor immunity has increasingly received better attention in recent studies. The B cells that infiltrate tumor tissues are called tumor-infiltrating B cells (TIBs). It is found that TIBs play a multifaceted dual role in regulating tumor immunity rather than just tumor inhibition or promotion. In this article, latest research advances focusing on the relationship between TIBs and tumor complexity are reviewed, and light is shed on some novel ideas for exploiting TIBs as a possible tumor biomarker and potential therapeutic target against tumors.

Several studies have reported the Mesenchymal Stem Cell (MSC) triggered and inhibited tumor growth. We therefore performed a systematic review and meta-analysis of experimental studies evaluating the effects of MSC on tumors. Method: We collected the relevant studies by searching ProQuest, PubMed Publisher, and GoogleScholar. A meta-analysis was performed for the outcome measure: tumor volume and tumor weight. The search resulted in 440 references, of which 22 could be included in the meta-analysis. Of these 22 experiments, 18 (40%) showed a significant decrease of tumor growth and 27 (60%) experiments showed a significant increase of tumor growth. The engineered MSC and the late phase of MSC injection have a significant contribution to tumor inhibition effect. The meta-analysis showed that there are no significant effect of mesenchymal stem cell therapy to the tumor animal volume (SMD-0.23[-0.55, 0.09]; n=15), and to the tumor animal weight (SMD -0.19 [-0.77,0.39]; n=7). Conclusion: MSC appears to have a relative dependent effect in animal models.