Survival Rate Of Tumor-bearing Mice Research Articles

A Transformable Specific-Responsive Peptide for One-Step Synergistic Therapy of Bladder Cancer.

Synergistic therapy has shown greater advantages compared with monotherapy. However, the complex multiple-administration plan and potential side effects limit its clinical application. A transformable specific-responsive peptide (TSRP) is utilized to one-step achieve synergistic therapy integrating anti-tumor, anti-angiogenesis and immune response. The TSRP is composed of: i) Recognition unit could specifically target and inhibit the biological function of FGFR-1; ii) Transformable unit could self-assembly and trigger nanofibers formation; iii) Reactive unit could specifically cleaved by MMP-2/9 in tumor micro-environment; iv) Immune unit, stimulate the release of immune cells when LTX-315 (Immune-associated oncolytic peptide) exposed. Once its binding to FGFR-1, the TSRP could cleaved by MMP-2/9 to form the nanofibers on the cell membrane, with a retention time of up to 12 h. Through suppressing the phosphorylation levels of ERK 1/2 and PI3K/AKT signaling pathways downstream of FGFR-1, the TSRP significant inhibit the growth of tumor cells and the formation of angioginesis. Furthermore, LTX-315 is exposed after TSRP cleavage, resulting in Calreticulin activation and CD8+ T cells infiltration. All above processes together contribute to the increasing survival rate of tumor-bearing mice by nearly 4-folds. This work presented a unique design for the biological application of one-step synergistic therapy of bladder cancer.

Intelligent gold nanocluster for effective treatment of malignant tumor via tumor-specific photothermal-chemodynamic therapy with AIE guidance.

Precise and efficient therapy of malignant tumors is always a challenge. Herein, gold nanoclusters co-modified by aggregation-induced-emission (AIE) molecules, copper ion chelator (acylthiourea) and tumor-targeting agent (folic acid) were fabricated to perform AIE-guided and tumor-specific synergistic therapy with great spatio-temporal controllability for the targeted elimination and metastasis inhibition of malignant tumors. During therapy, the functional gold nanoclusters (AuNTF) would rapidly accumulate in the tumor tissue due to the enhanced permeability and retention effect as well as folic acid-mediated tumor targeting, which was followed by endocytosis by tumor cells. After that, the overexpressed copper ions in the tumor cells would trigger the aggregation of these intracellular AuNTF via a chelation process that not only generated the photothermal agent in situ to perform the tumor-specific photothermal therapy damaging the primary tumor, but also led to the copper deficiency of tumor cells to inhibit its metastasis. Moreover, the copper ions were reduced to cuprous ions along with the chelation, which further catalysed the excess H2O2 in the tumor cells to produce cytotoxic reactive oxygen species, resulting in additional chemodynamic therapy for enhanced antitumor efficiency. The aggregation of AuNTF also activated the AIE molecules to present fluorescence, which not only imaged the therapeutic area for real-time monitoring of this tumor-specific synergistic therapy, but also allowed us to perform near-infrared radiation at the correct time point and location to achieve optimal photothermal therapy. Both in vitro and in vivo results revealed the strong tumor elimination, effective metastasis inhibition and high survival rate of tumor-bearing mice after treatment using the AuNTF nanoclusters, indicating that this AIE-guided and tumor-specific synergistic strategy could offer a promising approach for tumor therapy.

The preventive effects of inulin, cellulose, and their mixture on colorectal cancer liver metastasis in mice by regulating gut microbiota.

Many studies have found that dietary fiber can protect against colorectal cancer (CRC). Survival in CRC patients is significantly reduced due to metastasis. However, little is known regarding the impact of dietary fiber on the CRC metastasis. In this study, we analyzed the effects of inulin, cellulose, and their mixture on CRC metastasis in a murine orthotopic transplantation model. BALB/C male mice were divided into the normal control (NC) (AIN-93M diet), MOD (AIN-93M diet), INU (10% w/w inulin), CEL (10% w/w cellulose), and MIX (5% w/w inulin+5% w/w cellulose) groups. Dietary fiber intake inhibited the weights of the orthotopic tumors, liver weights, and liver metastasis area (p<0.05) and improved the survival rate of tumor-bearing mice. Compared to the NC, the expression of β-catenin and the epithelial marker E-cadherin were lower, and that of mesenchymal markers, such as N-cadherin, MMP-9, and VEGF, were higher in the MOD group. All inulin, cellulose, and their mixture restored the gut microbiota diversity, and they, respectively, increased the relative abundance of Bifidobacteriales, Lactobacillus, and Lachnospiraceae. Inulin restored the levels of acetic acid, propionic acid, isobutyric acid, and butyric acid. Spearman correlation analysis results showed that there was a positive correlation between five genera and six short-chain fatty acids (SCFAs) (adjusted p<0.05). In conclusion, all inulin, cellulose, and their mixture have inhibitory effects on CRC metastasis, which may be achieved by the regulation of gut microbiota, the production of SCFAs, and the inhibition of the epithelial-to-mesenchymal transition process. Among the three dietary fiber intervention groups, the inhibitory effect of inulin is more significant.

Intelligent gold nanoparticles for malignant tumor treatment via spontaneous copper manipulation and on-demand photothermal therapy based on copper induced click chemistry.

The excessive copper in tumor cells is crucial for the growth and metastasis of malignant tumor. Herein, we fabricated a nanohybrid to capture, convert and utilize the overexpressed copper in tumor cells, which was expected to achieve copper dependent photothermal damage of primary tumor and copper-deficiency induced metastasis inhibition, generating accurate and effective tumor treatment. The nanohybrid consistsed of 3-azidopropylamine, 4-ethynylaniline and N-aminoethyl-N'-benzoylthiourea (BTU) co-modified gold nanoparticles (AuNPs). During therapy, the BTU segment would specifically chelate with copper in tumor cells after endocytosis to reduce the intracellular copper content, causing copper-deficiency to inhibit the vascularization and tumor migration. Meanwhile, the copper was also rapidly converted to be cuprous by BTU, which further catalyzed the click reaction between azido and alkynyl on the surface of AuNPs, resulting in on-demand aggregation of these AuNPs. This process not only in situ generated the photothermal agent in tumor cells to achieve accurate therapy avoiding unexpected damage, but also enhanced its retention time for sustained photothermal therapy. Both in vitro and in vivo results exhibited the strong tumor inhibition and high survival rate of tumor-bearing mice after application of our nanohybrid, indicating that this synergistic therapy could offer a promising approach for malignant tumor treatment. STATEMENT OF SIGNIFICANCE: The distinctive excessive copper in tumor cells is crucial for the growth and metastasis of tumor. Therefore, we fabricated intelligent gold nanoparticles to simultaneously response and reverse this tumorigenic physiological microenvironment for the synergistic therapy of malignant tumor. In this study, for the first time we converted and utilized the overexpressed Cu2+ in tumor cells to trigger intracellular click chemistry for tumor-specific photothermal therapy, resulting in accurate damage of primary tumor. Moreover, we effectively manipulated the content of Cu2+ in tumor cells to suppress the migration and vascularization of malignant tumor, resulting in effective metastasis inhibition.

Medicarpin suppresses proliferation and triggeres apoptosis by upregulation of BID, BAX, CASP3, CASP8, and CYCS in glioblastoma.

Glioblastoma (GBM) is the most malignant brain tumor and incurable. Medicarpin (MED), a flavonoid compound from the legume family, has multiple targets and anticancer properties. However, the role of MED in GBM remains unclear. The objective of this study was to explore the effects of MED on the apoptosis of GBM and to explain the potential molecular mechanisms. We found that the IC50 values of U251 and U-87 MG cells treated with MED for 24 h were 271 μg/mL and 175 μg/mL, and the IC50 values for 48 h were 154 μg/mL and 161 μg/mL, respectively. Additionally, the cell cycle of U251 and U-87 MG cells were arrested at the G2/M phase. Furthermore, the apoptosis rate of U251 and U-87 MG cells increased from 6.26% to 18.36% and 12.46% to 31.33% for 48 h, respectively. The migration rate of U251 and U-87 MG decreased from 20% to 5% and 25% to 15% for 12 h and these of U251 and U-87 MG decreased from 50% to 28% and 60% to 25% for 24 h. MED suppressed GBM tumorigenesis, and improved survival rate of tumor-bearing mice. Taken together, MED triggered GBM apoptosis through upregulation of pro-apoptotic proteins (BID, BAX, CASP3, CASP8, and CYCS), showed strong inhibitory effects on cell proliferation and cell migration, and displayed anti-tumor activity in nude mice.

Blue Light Inhibits Proliferation of Metastatic Cancer Cells by Regulating Translational Initiation: A Synergistic Property with Anticancer Drugs.

The aim of this study was to examine the inhibitory effect of blue light (BL) on the proliferation of metastatic cancer cells and synergistic properties with chemo-drugs. BL significantly inhibited the proliferation of B cell lymphoma (A20 and RAMOS) cells in a dose-dependent manner. Anti-proliferative effect of BL irradiation was identified to be associated with the inhibition of proliferating-cell nuclear antigen expression and cell cycle by decreasing S-phase cells. Consistent with its inhibitory effects, BL irradiation at 20 J/cm2 daily for 10 days inhibited metastasis of cancer cells which were distributed and invaded to other organs including bone marrow, liver, kidney, etc., and induced paraplegia, thereby leading to an increased survival rate of tumor-bearing mice. Anti-proliferative activity of BL was expanded in solid tumor cells including pancreatic carcinoma (Mia PaCa-2, PANC-1), lung carcinoma A549 and colorectal carcinoma HCT116 cells. Additionally, combination with chemo-drugs such as 5-FU and gemcitabine resulted in an increase in the anti-proliferative activity after BL irradiation accompanied by regulating mRNA translational process via inhibition of p70S6K, 4EBP-1 and eIF4E phosphorylation during cellular proliferation. These results indicate the anti-metastatic and photo-biogoverning abilities of BL irradiation as a potent therapeutic potential for repressing the progression of tumor cells.

Exploring the Phytochemical Profile and Biological Activities of Clerodendrum infortunatum.

Clerodendrum infortunatum (C. infortunatum), the hill glory bower, is reputed as the prodigious treasure for Indian folk medicine. The study has focused on exploring the phytochemistry and antitumor potential of the C. infortunatum root extract in vitro and in vivo. The ethyl acetate root extract has demonstrated the highest cytotoxicity in a series of nine human tumor cell lines. Further fractionation of the same has yielded seven compounds. The structures of these compounds were confirmed with spectroscopic techniques. Considering the toxicity observed with the crude extract, cytotoxicity of these compounds was further assessed in two breast carcinoma cell lines (MCF-7[ER/PR-positive HER2-negative] and MDA-MB-231 [ER/PR/HER2-negative]) and in two cervical cancer [human papilloma virus (HPV)-negative C33A and HPV-positive SiHa] cell lines. Betulinic acid (BA) was found as the active principle contributing the cytotoxic activity, and cervical cancer cell lines documented the minimum IC50 value in 24 h. In order to validate the in vitro experimental data, we have established a xenograft model of HPV-positive cervical cancer in female NOD/SCID mice treated with BA using doxorubicin as the positive control. BA treatment gradually reduced the tumor size, maintaining healthy hematological and biochemical parameters, and improved the survival rate of tumor-bearing mice considerably. Thus, our findings suggest that the C. infortunatum root extract has a promising anticancer property against HPV-positive cervical cancer and supports its usage by traditional healers for treating cervical cancer.

SREKA-targeted liposomes for highly metastatic breast cancer therapy

Chemotherapy is still a leading therapeutic approach in various tumor types that is often accompanied by a poor prognosis because of metastases. PEGylated liposomes with CREKA targeting moiety are well-known therapeutic agents, especially in highly metastatic experimental models. CREKA specifically targets tumor-associated ECM, which is present at the primary, as well as metastatic tumor sites. To better understand the function of the targeting moieties, we decided to design various liposome formulations with different amounts of targeting moiety attached to their DSPE-PEG molecules. Moreover, a new tumor-homing pentapeptide (SREKA) was designed, and a novel conjugation strategy between SREKA and DSPE-PEGs. First, the in vitro proliferation inhibition of drug-loaded liposomes and the cellular uptake of their cargo were investigated. Afterward, liposome stability in murine blood and drug accumulation in different tissues were measured. Furthermore, in vivo tumor growth, and metastasis inhibition potencies of the different liposome formulations were examined. According to our comparative studies, SREKA-liposomes have a uniform phenotype after formulation and have similar characteristics and tumor-homing capabilities to CREKA-liposomes. However, the exchange of the N-terminal cysteine to serine during conjugation results in a higher production yield and better stability upon conjugation to DSPE-PEGs. We also showed that SREKA-liposomes have significant inhibition on primary tumor growth and metastasis incidence; furthermore, increase the survival rate of tumor-bearing mice. Besides, we provide evidence that the amount of targeting moiety attached to DSPE-PEGs is largely responsible for the stability of liposomes, therefore it plays an important role in toxicity and targeting.

Cyclic diguanylate analogues: Facile synthesis, STING binding mode and anti-tumor immunity delivered by cytidinyl/cationic lipid

Herein 2-cyanoethoxy-N,N,N′,N′-tetraisopropyl-phosphorodiamidite(10, PIII, 3.5 eq.) could synergistically react with 3′,5′-dihydroxyl groups in a dinucleotide(PV) at the cyclization step for the synthesis of cyclic dinucleotides (CDNs) (c-di-GMP, cGAMP etc.) and their phosphorothioated analogues. A dynamic PIII-PV coordination mechanism has been proposed for the cyclization procedure which is confirmed by the variant 31P NMR data and molecular simulation. Among the mono-phosphorothioated CDNs, two stereoisomers showed different capacity for STING activation and the reason was predicted by molecular modeling. While compound 12b1 showed most potent ability to elicit cytokines (IFNβ, IL-6, Cxcl9 and Cxcl10) induction compared to another stereoisomer. Also, 12b1 significantly inhibited the tumor growth in the EO771 model with both 0.1 μg (i.t.) and 2 μg (i.v.) administration through the aid of a Mix delivery system developed by our group, and achieved a 31% long-term survival rate of tumor-bearing mice. 12b1/Mix significantly improved the percentage of CD8+ or CD4+ effector memory T (Tem, CD44highCD62Llow) cells and CD8+ central memory T (Tcm, CD44highCD62Lhigh) cells in the blood of EO771 mice, inducing the immune memory against EO771 tumor cells. Relatively lower dose regimens of 12b1(0.1 μg)/Mix displayed better tumor suppression by more potent STING pathway activation and higher levels of cytokines induction in the tumor.

Optimized Therapeutic 177Lu-Labeled PSMA-Targeted Ligands with Improved Pharmacokinetic Characteristics for Prostate Cancer.

Clinical trials have shown the significant efficacy of [177Lu]Lu-PSMA-617 for treating prostate cancer. However, the pharmacokinetic characteristics and therapeutic performance of [177Lu]Lu-PSMA-617 still need further improvement to meet clinical expectations. The aim of this study was to evaluate the feasibility and therapeutic potential of three novel 177Lu-labeled ligands for the treatment of prostate cancer. The novel ligands were efficiently synthesized and radiolabeled with non-carrier added 177Lu; the radiochemical purity of the final products was determined by Radio-HPLC. The specific cell-binding affinity to PSMA was evaluated in vitro using prostate cancer cell lines 22Rv1and PC-3. Blood pharmacokinetic analysis, biodistribution experiments, small animal SPCET imaging and treatment experiments were performed on normal and tumor-bearing mice. Among all the novel ligands developed in this study, [177Lu]Lu-PSMA-Q showed the highest uptake in 22Rv1 cells, while there was almost no uptake in PC-3 cells. As the SPECT imaging tracer, [177Lu]Lu-PSMA-Q is highly specific in delineating PSMA-positive tumors, with a shorter clearance half-life and higher tumor-to-background ratio than [177Lu]Lu-PSMA-617. Biodistribution studies verified the SPECT imaging results. Furthermore, [177Lu]Lu-PSMA-Q serves well as an effective therapeutic ligand to suppress tumor growth and improve the survival rate of tumor-bearing mice. All the results strongly demonstrate that [177Lu]Lu-PSMA-Q is a PSMA-specific ligand with significant anti-tumor effect in preclinical models, and further clinical evaluation is worth conducting.

DMA, a Small Molecule, Increases Median Survival and Reduces Radiation-Induced Xerostomia via the Activation of the ERK1/2 Pathway in Oral Squamous Cell Carcinoma.

Simple SummaryRadiotherapy is commonly used to treat the majority of patients with head and neck cancers. Salivary glands in the radiation field are affected by this procedure. The purpose of this study was to investigate the role of DMA as a radiomodulator to evaluate the real possibilities of reducing the incidence and severity of xerostomia in head and neck squamous cell carcinoma (HNSCC) patients. The effect of DMA on the response of head and neck cell lines in the presence of radiation was analyzed using clonogenic survival and xenograft tumor assays for cell line-derived xenografts as well as patient-derived xenografts. The combinatorial treatment of DMA along with radiation influenced the migration of cells. The changes associated with migration were observed through a microscope and wound healing assay. In addition, the stimulated saliva was measured. Tissue sections were analyzed using immunohistochemistry to stain for molecular markers of cell proliferation and porin channels.Survival, recurrence, and xerostomia are considerable problems in the treatment of oral squamous carcinoma patients. In this study, we investigated the role of DMA (5-(4-methylpiperazin-1-yl)-2-[2′-(3,4-dimethoxyphenyl)5″benzimidazoyl]benzimidazole) as a salivary gland cytoprotectant in a patient-derived xenograft mouse model. A significant increase in saliva secretion was observed in the DMA-treated xenograft compared to radiation alone. Repeated doses of DMA with a high dose of radiation showed a synergistic effect on mice survival and reduced tumor growth. The mean survival rate of tumor-bearing mice was significantly enhanced. The increased number of Ki-67-stained cells in the spleen, intestine, and lungs compared to the tumor suggests DMA ablates the tumor but protects other organs. The expression of aquaporin-5 was restored in tumor-bearing mice injected with DMA before irradiation. The reduced expression of αvβ3 integrin and CD44 in DMA alone and DMA with radiation-treated mice suggests a reduced migration of cells and stemness of cancer cells. DMA along with radiation treatment results in the activation of the Ras/Raf/MEK/ERK pathway in the tumor, leading to apoptosis through caspase upregulation. In conclusion, DMA has strong potential for use as an adjuvant in radiotherapy in OSCC patients.

Combinatorial therapeutic approaches of photodynamic therapy and immune checkpoint blockade for colon cancer treatment

Photodynamic therapy (PDT) has shown impressive therapeutic effects on various types of cancers by reactive oxygen species (ROS) generation and induction of immune responses. However, under certain conditions, the immune responses induced by PDT are not always sufficient to eradicate the remaining tumor cells. On the other hand, the photosensitizer indocyanine green (ICG) can mediate PDT under near-infrared (NIR) illumination, thereby enhancing the penetration depth of the excitation light into the tumor. We found that ICG is rapidly taken up in vitro by colorectal MC38 and CT26 tumor cells and it promotes PDT-mediated cell-killing effects. Our results furthermore revealed that ICG induces immunogenic cell death (ICD), as dendritic cells (DCs) were found to engulf ICG-PDT-treated tumor cells and undergo phenotypic maturation. ICG accumulated in tumors 2 h after administration, as measured by fluorescence and photoacoustic imaging. Considering the advantages of ICG as a photosensitizer, we sought to design a therapy that combines PDT and immune checkpoint blockade to maximize tumor control. To this end, a 25% thermosensitive polymer 407 hydrogel was included as a co-delivery platform for this treatment scheme. NIR-PDT under 808 nm irradiation in combination with cytotoxic T-lymphocyte-associated protein 4 (CTLA4)/programmed death-ligand 1 (PD-L1) checkpoint blockade prolonged survival rate of colorectal tumor-bearing mice by inducing a series of immune responses, like the phagocytosis of tumor debris by macrophages and DCs, and induction of acute inflammation, leukocyte infiltration, maturation and activation of DCs. Altogether, our work presents a NIR-triggered PDT strategy in combination with immune checkpoint blockade. Compared to a single treatment, the combination treatment increased efficiency to inhibit solid tumor growth and improved the survival rate of tumor-bearing mice.

Oncolytic and protective effects of strain 100 of a new group of non-classified rotavirus of reoviridae family on B16/F10 melanoma growth in experiment.

e21587 Background: The purpose of this study was to assess the effect of a strain 100 of a new group of rotavirus of Reoviridae family on the growth of transplantable B16/F10 melanoma in mice and the survival of the animals. Methods: We studied the strain 100 of a new group of rotavirus of Reoviridae family (RVK) ( http://jbks.ru/archive/issue-10/article-6 ). RVK 100 is a live attenuated non-pathogenic virus growing on pig embryo kidney cell culture with concentration 5·109 per 1 ml. The dynamics of melanoma growth and the survival of tumor-bearing animals receiving RVK were studied in 25 male mice divided into 5 equal groups, each n = 5. RVK was administered intramuscularly and orally once a week 0.3 mL and 25 µL, respectively: to groups 1-2 21 days prior to the tumor inoculation, a total of 4 injections (“vaccination” regimen); to groups 3-4 – 7 days after tumor inoculation with the onset of tumor nodes, a total of 3 injections (“treatment” regimen); group 5 included controls receiving 0.85% NaCl solution. Groups 1 and 3 received live RVK, groups 2 and 4 - RVK inactivated by UV radiation. Results: Survival of mice in groups 1-2 receiving both live and inactivated RVK in the “vaccination” regimen was increased statistically significantly: in group 1, Me = 25 days after melanoma transplantation (LQ 24; UQ 30), in group 2 Me = 26 days (LQ 25; UQ 30), in controls Me = 14 days (LQ 10; UQ 22); p = 0.032 and p = 0.0079, respectively. RVK administration in the “treatment” regimen did not cause such changes. While mice of group 3 receiving the live strain 100 showed a tendency to higher survival, compared to controls (Me = 23 days, LQ 22; UQ 24, p = 0.056), the administration of inactivated RVK (group 4) did not significantly improve the survival of animals, compared to controls (Me = 22 days (LQ 21; UQ 33, p = 0.151). Conclusions: Improved survival of animals with B16/F10 melanoma after the RVK administration indicates the virus ability to slow down tumor growth and confirms our previously published data on the RVK strain 228, although, in contrast to it, the strain 100 is able to increase the survival rate of tumor-bearing mice only when used in the “vaccination” regimen, which refers mainly to the inactivated virus. Since the inactivation of the RVK strain 100 eliminates its effect when used in the “treatment”, but not “vaccination” regimen, it seems to be associated with an immunostimulatory effect but not with an oncolytic one.

Chrysin enhances antitumour immunity response through the IL-12-STAT4 signal pathway in the B16F10 melanoma mouse model.

Chrysin (CHR) is a flavonoid with extensive pharmacological activity. The molecular formula of CHR is C15 H10 O4 . CHR is reported to have antioxidative, antitumour and antiviral functions. To evaluate its potential function as a vaccine adjuvant, we prepared a melanoma vaccine using a soluble protein extract of B16F10 melanoma cells as antigen and CHR as an adjuvant. The melanoma model was developed after two immunizations, and it was discovered that combining B16F10 soluble protein antigen-mixed CHR vaccine could inhibit tumour growth in the mouse model, and the overall survival rate was higher than that of the B16F10 antigen vaccine alone. In vivo and in vitro experiments were conducted to determine whether CHR functioned as an adjuvant by activating antigen-presenting cells (APCs). We discovered that CHR activated APCs both in vivo and in vitro and may enhance Th1 cell function by activating the IL12-STAT4 signal pathway, thereby enhancing the antitumour response of cytotoxic T lymphocytes (CTLs) in vivo. Next, to verify the critical role of CD8+ T cells in suppressing melanoma development, we transplanted CD8+ T cells from immunized mice to B16F10 tumour-bearing mice and discovered that the survival rate of tumour-bearing mice was significantly prolonged. In summary, our experimental results indicate that CHR can be used as a potential adjuvant to enhance antigen immunogenicity, inhibit B16F10 tumour growth in mice and improve tumour immune response.

Mycobacterial surface characters remodeled by growth conditions drive different tumor-infiltrating cells and systemic IFN-γ/IL-17 release in bladder cancer treatment

ABSTRACT The mechanism of action of intravesical Mycobacterium bovis BCG immunotherapy treatment for bladder cancer is not completely known, leading to misinterpretation of BCG-unresponsive patients, who have scarce further therapeutic options. BCG is grown under diverse culture conditions worldwide, which can impact the antitumor effect of BCG strains and could be a key parameter of treatment success. Here, BCG and the nonpathogenic Mycobacterium brumae were grown in four culture media currently used by research laboratories and BCG manufacturers: Sauton-A60, -G15 and -G60 and Middlebrook 7H10, and used as therapies in the orthotopic murine BC model. Our data reveal that each mycobacterium requires specific culture conditions to induce an effective antitumor response. since higher survival rates of tumor-bearing mice were achieved using M. brumae-A60 and BCG-G15 than the rest of the treatments. M. brumae-A60 was the most efficacious among all tested treatments in terms of mouse survival, cytotoxic activity of splenocytes against tumor cells, higher systemic production of IL-17 and IFN-ɣ, and bladder infiltration of selected immune cells such as ILCs and CD4TEM. BCG-G15 triggered an antitumor activity based on a massive infiltration of immune cells, mainly CD3+ (CD4+ and CD8+) T cells, together with high systemic IFN-ɣ release. Finally, a reduced variety of lipids was strikingly observed in the outermost layer of M. brumae-A60 and BCG-G15 compared to the rest of the cultures, suggesting an influence on the antitumor immune response triggered. These findings contribute to understand how mycobacteria create an adequate niche to help the host subvert immunosuppressive tumor actions.

Intelligent Gold Nanoparticles with Oncogenic MicroRNA-Dependent Activities to Manipulate Tumorigenic Environments for Synergistic Tumor Therapy.

Tumorigenic environments, especially aberrantly overexpressed oncogenic microRNAs, play a critical role in various activities of tumor progression. However, developing strategies to effectively utilize and manipulate these oncogenic microRNAs for tumor therapy is still a challenge. To address this challenge, spherical nucleic acids (SNAs) consisting of gold nanoparticles in the core and antisense oligonucleotides as the shell are fabricated. Hybridized to the oligonucleotide shell is a DNA sequence to which doxorubicin is conjugated (DNA-DOX). The oligonucleotides shell is designed to capture overexpressed miR-21/miR-155 and inhibit the expression of these oncogenic miRNAs in tumor cells after tumor accumulation to manipulate genetic environment for accurate gene therapy. This process further induces the aggregation of these SNAs, which not only generates photothermal agents to achieve on-demand photothermal therapy in situ, but also enlarges the size of SNAs to enhance the retention time in the tumor for sustained therapy. The capture of the relevant miRNAs simultaneously triggers the intracellular release of the DNA-DOX from the SNAs to deliver tumor-specific chemotherapy. Both in vivo and in vitro results indicate that this combination strategy has excellent tumor inhibition properties with high survival rate of tumor-bearing mice, and can thus be a promising candidate for effective tumor treatment.

Therapeutic nucleus-access BNCT drug combined CD47-targeting gene editing in glioblastoma

Glioblastoma is the most common brain primary malignant tumor with the highest mortality. Boron neutron capture therapy (BNCT) can efficiently kill cancer cells on the cellular scale, with high accuracy, short course and low side-effects, which is regarded as the most promising therapy for malignant brain tumors like glioma. As the keypoint of BNCT, all boron delivery agents currently in clinical use are beset by insufficient tumor uptake, especially in the tumor nucleus, which limits the clinical application of BNCT. In this study, nuclear targeting of boron is achieved by DOX-CB, consisting of doxorubicin (DOX) and carborane (CB) utilizing the nuclear translocation property of DOX. The nucleus of GL261 cells takes up almost three times the concentration of boron required for BNCT. To further kill glioma and inhibit recurrence, a new multifunctional nanoliposome delivery system DOX-CB@lipo-pDNA-iRGD is constructed. It combines DOX-CB with immunotherapy strategy of blocking macrophage immune checkpoint pathway CD47-SIRPα by CRISPR-Cas9 system, coupling BNCT with immunotherapy simultaneously. Compared with clinical drug Borocaptate Sodium (BSH), DOX-CB@lipo-pDNA-iRGD significantly enhances the survival rate of tumor-bearing mice, reduces tumor stemness, and improves the prognosis. The excellent curative effect of this nanoliposome delivery system provides an insight into the combined treatment of BNCT.Graphical

Membrane-camouflaged supramolecular nanoparticles for co-delivery of chemotherapeutic and molecular-targeted drugs with siRNA against patient-derived pancreatic carcinoma

Pancreatic cancer remains one of the most lethal malignancies worldwide. The combination of the first-line standard agent gemcitabine (GEM) with the molecular-targeted drug erlotinib (Er) has emerged as a promising strategy for pancreatic cancer treatment. However, the clinical benefit from this combination is still far from satisfactory due to the unfavorable drug antagonism and the fibrotic tumor microenvironment. Herein, we propose a membrane-camouflaged dual stimuli-responsive delivery system for the co-delivery of GEM and Er into pancreatic cancer cells and tissues to block the antagonism, as well as reshapes profibrotic tumor microenvironment via simultaneous delivery of small interference RNA (siRNA) for synergistic pancreatic cancer treatment. This “all-in-one” delivery system exhibits sensitive GSH and pH-dependent drug release profiles and enhances the inhibitory effects on the proliferation and migration of tumor cells in vitro. Excitingly, the systemic injection of such a biomimetic drug co-delivery system not only resulted in superior inhibitory effects against orthotopic pancreatic tumor and patient-derived tumor (PDX), but also greatly extended the survival rate of tumor-bearing mice. Our findings provide a promising therapeutic strategy against pancreatic cancer through the enhanced synergistic effect of target therapy, chemotherapy and anti-fibrotic therapy, which represents an appealing way for pancreatic cancer treatment.

Fabrication of pH/Redox Dual-Responsive Mixed Polyprodrug Micelles for Improving Cancer Chemotherapy.

In this work, we prepared pH/redox dual-responsive mixed polyprodrug micelles (MPPMs), which were co-assembled from two polyprodrugs, namely, poly(ethylene glycol) methyl ether-b-poly (β-amino esters) conjugated with doxorubicin (DOX) via redox-sensitive disulfide bonds (mPEG-b-PAE-ss-DOX) and poly(ethylene glycol) methyl ether-b-poly (β-amino esters) conjugated with DOX via pH-sensitive cis-aconityl bonds (mPEG-b-PAE-cis-DOX) for effective anticancer drug delivery with enhanced therapeutic efficacy. The particle size of MPPMs was about 125 nm with low polydispersity index, indicating the reasonable size and uniform dispersion. The particle size, zeta-potential, and critical micelle concentration (CMC) of MPPMs at different mass ratios of the two kinds of polyprodrugs were dependent on pH value and glutathione (GSH) level, suggesting the pH and redox responsiveness. The drug release profiles in vitro of MPPMs at different conditions were further studied, showing the pH—and redox-triggered drug release mechanism. Confocal microscopy study demonstrated that MPPMs can effectively deliver doxorubicin molecules into MDA-MB-231 cells. Cytotoxicity assay in vitro proved that MPPMs possessed high toxic effect against tumor cells including A549 and MDA-MB-231. The results of in vivo experiments demonstrated that MPPMs were able to effectively inhibit the tumor growth with reduced side effect, leading to enhanced survival rate of tumor-bearing mice. Taken together, these findings revealed that this pH/redox dual-responsive MPPMs could be a potential nanomedicine for cancer chemotherapy. Furthermore, it could be a straightforward way to fabricate the multifunctional system basing on single stimuli-responsive polyprodrugs.

Intelligent gold nanoparticles for synergistic tumor treatment via intracellular Ca2+ regulation and resulting on-demand photothermal therapy

Designing therapeutics to utilize and manipulate the aberrant high concentration of Ca2+ in tumor cells would be a promising approach for effective tumor therapy. Herein, we fabricated a nanohybrid to significantly reduce the intracellular Ca2+ of tumor cells meanwhile to perform Ca2+ triggered photothermal therapy under 660 nm irradiation for synergistic tumor treatment. This nanohybrid contains gold nanoparticle as core, ethylene glycol bis (2-aminoethyl ether)-N, N, N', N'-tetraacetic acid (EGTA, Ca2+ chelating agent) as shell and folic acid (FA, tumor targeting agent) conjugated polyethylene glycol 4000 (PEG) as corona, where the EGTA shell and PEG-FA corona was connected by esterase-cleavable ester bonds. After injection, the nanohybrid maintained a stable “off state” during blood circulation due to the anti-fouling property and EGTA-blocking performed by PEG section. The PEG-FA would be removed by over-expressed esterase in tumor cells after FA mediated tumor accumulation and endocytosis, which activated EGTA to capture Ca2+ in tumor cells, resulting in the truncation of Ca2+ signaling for tumor inhibition. Moreover, the specific chelation between Ca2+ and the nanohybrid would further cause the intracellular assembly of these nanoparticles in tumor cells, which in situ generated an excellent photothermal agent for enhanced tumor therapy under 660 nm irradiation. Both in vitro and in vivo results showed excellent tumor inhibition and high survival rate of tumor-bearing mice after treatment by our AEPF nanohybrid, indicating this synergistic therapy via on-demand Ca2+ manipulation and Ca2+ triggered photothermal therapy could be a green approach for tumor treatment with high efficiency and minimum side effects.