Antitumor Ability Research Articles

Nano-hydroxyapatite-evoked immune response synchronized with controllable immune adjuvant release for strengthening melanoma-specific growth inhibition

Concerns about the potential systematic toxicity limit the extensive application of traditional therapeutic drugs for melanoma therapy, nano-hydroxyapatite (nHA) with good biocompatibility and anti-tumor ability could be an alternative choice. In this study, nHA was employed as an anti-tumor biomaterial due to its tumor-specific toxicity. Meanwhile, granulocyte-macrophage colony-stimulating factor (GM-CSF) served as the immune adjuvant to activate the immune response. The delivery platform was fabricated by co-encapsulation of both nHA and GM-CSF into a biocompatible thermosensitive PLGA-PEG-PLGA hydrogel. The results showed that the bio-activities of nHA and GM-CSF could be well-maintained within the hydrogel. Interestingly, the addition of nHA could attenuate the burst release of GM-CSF due to possible protein absorption capacity of nHA, which is beneficial for GM-CSF sustainable release at the tumor site, achieving boosted and prolonged anti-tumor immunity. The in vitro and in vivo data demonstrated that nHA/GM-CSF hydrogel exhibited greater potency to inhibit tumor growth via enhanced CD8+ T-cell response compared with hydrogel and nHA hydrogel groups, contributed by the synergistic effects of nHA and GM-CSF. Overall, the strategy combining nHA and immune adjuvant shows great promise, which largely broadens the choice of combinational therapies for melanoma. Statement of significanceNano-hydroxyapatite (nHA) has been confirmed to specifically inhibit melanoma tumor growth and induce immune response. However, its antitumor efficiency and immunity-evoking capacity are limited. In this study, granulocyte-macrophage colony-stimulating factor (GM-CSF) was introduced to serve as the immune adjuvant. Both of them were encapsulated into a biocompatible thermosensitive PLGA-PEG-PLGA hydrogel. The addition of nHA could attenuate the burst release of GM-CSF due to the interaction with nHA, which is beneficial for GM-CSF sustainable release at tumor site, achieving boosted and prolonged anti-tumor immunity. Anti-tumor immune response could be activated due to the release of tumor-associated antigen and tumor debris induced by the specifically tumor inhibition effect of nHA and GM-CSF. The combination of nHA and GM-CSF could play synergistic inhibiting effect on tumor growth via boosting and prolonging anti-tumor immunity.

Al-MPS Obstructs EMT in Breast Cancer by Inhibiting Lipid Metabolism via miR-215-5p/SREBP1.

Alkali-extractable mycelial polysaccharide (Al-MPS) is a natural macromolecular polymer that has shown anti-hyperlipidemic and antitumor abilities. This study investigates the mechanism by which Al-MPS inhibits lipid metabolism and epithelial-mesenchymal transition (EMT) in breast cancer (BC). BC cells (MCF-7 and MDA-MB-231) were transfected and/or treated with Al-MPS. CCK-8, Transwell, and scratch assays were used to evaluate the tumorigenic behaviors of BC cells. The expression levels of SREBP1, E-cadherin, N-cadherin, Snail, vimentin, FASN, ACLY, and ACECS1 in BC cells were detected by Western blotting. Dual-luciferase reporter and RNA pull-down assays were performed to verify the binding between miR-215-5p and SREBP1 mRNA. Nude mice were injected with MDA-MB-231 cells and treated with Al-MPS. The changes in tumor volume and protein expression were monitored. miR-215-5p was downregulated and SREBP1 was upregulated in BC. Al-MPS increased miR-215-5p expression and inhibited SREBP1 expression, lipid metabolism, and EMT in BC. Inhibition of miR-215-5p or overexpression of SREBP1 promoted the tumorigenic behaviors of BC cells by stimulating lipid metabolism and counteracted the antitumor effect of Al-MPS. SREBP1 was a downstream target of miR-215-5p. In conclusion, Al-MPS inhibits lipid metabolism and EMT in BC via the miR-215-5p/SREBP1 axis. This study supports the application of polysaccharides in cancer treatment and the molecules regulated by Al-MPS may be used as biomarkers or therapeutic targets for BC.

IL-9/STAT3/fatty acid oxidation-mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity.

CD8+ T cell longevity regulated by metabolic activity plays important roles in cancer immunotherapy. Although in vitro–polarized, transferred IL-9–secreting CD8+ Tc9 (cytotoxic T lymphocyte subset 9) cells exert greater persistence and antitumor efficacy than Tc1 cells, the underlying mechanism remains unclear. Here, we show that tumor-infiltrating Tc9 cells display significantly lower lipid peroxidation than Tc1 cells in several mouse models, which is strongly correlated with their persistence. Using RNA-sequence and functional validation, we found that Tc9 cells exhibited unique lipid metabolic programs. Tc9 cell–derived IL-9 activated STAT3, upregulated fatty acid oxidation and mitochondrial activity, and rendered Tc9 cells with reduced lipid peroxidation and resistance to tumor- or ROS-induced ferroptosis in the tumor microenvironment. IL-9 signaling deficiency, inhibiting STAT3, or fatty acid oxidation increased lipid peroxidation and ferroptosis of Tc9 cells, resulting in impaired longevity and antitumor ability. Similarly, human Tc9 cells also exhibited lower lipid peroxidation than Tc1 cells and tumor-infiltrating CD8+ T cells expressed lower IL9 and higher lipid peroxidation– and ferroptosis-related genes than circulating CD8+ T cells in patients with melanoma. This study indicates that lipid peroxidation regulates Tc9 cell longevity and antitumor effects via the IL-9/STAT3/fatty acid oxidation pathway and regulating T cell lipid peroxidation can be used to enhance T cell–based immunotherapy in human cancer.

C-Met specific CAR-T cells as a targeted therapy for non-small cell lung cancer cell A549

ABSTRACT Non-small cell lung cancer (NSCLC) is considered to be one of the most prevalent and fatal malignancies, with a poor survival rate. Chimeric antigen receptor T cell (CAR-T) cell therapy is one of the most exciting directions in the field of Cellular immunotherapy. Therefore, CAR-T cells that target c-Met have been developed for use in NSCLC therapy and might be a potential therapeutic strategy. The anti c-Met ScFv structure was fused with the transmembrane and intracellular domains. Using a lentiviral vector to load the c-Met CAR gene, then transfected the c-Met CAR lentiviral into human T cells to obtain the second generation c-Met CAR-T expressing CARs stably. In vitro co-culture, experiments revealed that CAR-T cells have high proliferative activity and the potential to secrete cytokines (IL-2, TNF-α, and IFN-γ). c-Met CAR-T cells showed special cellular cytotoxicity in LDH release assay. A subcutaneous tumor model in nude mice was used to test the anticancer effectiveness of c-Met CAR-T cells in vivo. For c-Met positive NSCLC tissue, according to tumor volume, weight, fluorescence intensity, and immunohistochemical detection, c-Met CAR-T cells had stronger tumor growth suppression compared to untransduced T cells. HE staining revealed that c-Met CAR-T cells did not produced side effects in nude mice. Taken together, we provided useful method to generate c-Met CAR- T cells, which exhibit enhanced cytotoxicity against NSCLC cells in vitro and in vivo. Thus, providing a new therapeutic avenue for treating NSCLC clinically. Highlights (1) c-Met CAR-T capable of stably expressing c-Met CARs were constructed. (2) c-Met CAR-T have strong anti-tumor ability and proliferation ability in vitro. (3) c-Met CAR-T can effectively inhibit the growth of A549 cells subcutaneous xenografts.

Photovoltaic polymer Photosensitizer-Doped Nano-Therapeutic reagent for in vivo enhanced bioimaging guided photodynamic therapy

For tumor imaging guided photodynamic therapy process, the conundrum of achieving high fluorescence efficiency and singlet oxygen generation efficiency concurrently under the excitation condition of visible light has become a major obstacle to the integration of diagnosis and treatment. For lack of effective methods to resolve this issue, constructing a single photosensitizer with high quantum yield, efficient singlet oxygen generation, stable red emission, excellent photo-stability and low dark toxicity is challenging. In this research, the performance bottleneck is broken by designing an effective donor–acceptor system with excellent imaging and great photodynamic therapy capability through judiciously incorporating a novel polymer (J71) into a hydrophobic conjugated polymer, which is the first time of utilizing this celebrity photovoltaic material as a photosensitizer in photodynamic therapy process. Through fluorescence resonance energy transfer from conjugated polymer to J71, the singlet oxygen production rate of nanoparticles can be enhanced to 0.704. The nanoparticle also exhibits relatively high quantum yield of 0.255. The relatively strong singlet oxygen yield and relatively high fluorescence efficiency of nanoparticle was competitive with other inorganic and organic photosensitizers. Moreover, the J71 as a novel photosensitizer is a kind of 2D-conjugated polymer, which displayed promising photo-stability than traditional porphyrin photosensitizer. The prepared nanoparticles present all desired properties. A series of in vivo and in vitro results revealed the excellent fluorescence imaging capability and noteworthy anti-tumor ability, indicative of this system has great potential application in tumor imaging guided photodynamic therapy.

Special Chimeric Antigen Receptor (CAR) Modifications of T Cells: A Review.

Chimeric antigen receptor (CAR) -T cell therapy has become one of the hot topics in tumor immunity research in recent years. Although CAR-T cell therapy is highly effective in treating hematological malignancies, there are numerous obstacles that prevent CAR-T cells from having anti-tumor effects. Traditional CARs, from the first to the fourth generation, are incapable of completely overcoming these challenges. Therefore, identifying ways to boost the efficacy of CAR-T cells by utilizing the limited tumor surface antigens has become an urgent area of research. Certain special CARs that have special structures, special systems, or are greatly improved on the basis of traditional CARs, such as tandem CAR, dual-signaling CARs, AND-gate CARs, inhibitory CAR, AND-NOT CARs, CARs with three scFvs, ON/OFF-switch CARs, and universal CARs have been introduced. This study aims to use these special CARs to improve the anti-tumor ability, accuracy, and safety of CAR-T cells. In addition to summarizing various special CARs of T cells, this paper also expounds some of our own conjectures, aiming to provide reference and inspiration for CARs researchers.

Non-invasive T cells adoptive immunotherapy for solid tumor with gel anti-tumor T-cell injections

Adoptive cell therapy (ACT) is an effective immunotherapy, but there are still many challenges in treating solid tumors. Here, non-invasive T cells (NIT) adoptive therapy for solid tumors was achieved by combining isolation of T cells from tumor host blood and single cell low-differentiated rapid proliferation. T cells from the blood of tumor hosts contained CD8+ PD-1+ T cells, which had anti-tumor ability, were separated by microfluidic inertial separation techniques. Single T cell and adjuvant were encapsulated in gel droplets, which provided an excellent environment that allowed the T cells to proliferate rapidly and significantly increased the proportion of CD8+ PD-1+ T cells to total T cells. Moreover, the proliferating CD8+ PD-1+ T cells were low-differentiated, 'younger' T cell, which had an excellent anti-tumor cell capacity. Therefore, the gel anti-tumor T-cell injections (GATI), which contained cells, cytokines and adjuvants, were produced by integrated chips. In melanoma mice treatment experiment with NIT adoptive therapy, GATI inhibited tumor growth, evoked a robust cytotoxic T lymphocyte immune response and improved survival rates. Together, NIT adoptive therapy will bring a new idea to the treatment of solid tumors.

Asiatic acid from centella asiatica exert anti-invasive ability in human renal cancer cells by modulation of ERK/p38MAPK-mediated MMP15 expression

BackgroundAsiatic acid (AA) is a naturally pentacyclic triterpenoids extracted from traditional medicine Centella asiatica l. that has demonstrated possesses potential health benefits and antitumor ability. However, the precise anticancer effects and mechanisms by which AA impact RCC cells remains unclear. MethodsCell proliferation and cell cycle distribution were detected by MTT, colony formation assay and PI stain by flow cytometry, respectively. Cell mobility and invasiveness were determined by in vitro migration and invasion assay. The secretory MMP15 was detected by ELISA assay. Quantitative RT-PCR, siRNA, and immunoblot were used to determine gene expression/regulation and protein expression, respectively. Antimetastatic effect of AA were performed to lung nodule numbers in vivo metastasis mice model. MMP15, pERK1/2 and p-p38MAPK expressions were determined by immunohistochemistry. ResultsOur findings indicated cell proliferation and cell cycle distribution of RCC cells were not significantly influenced by AA treatment. AA suppressed cell migration, invasion and significantly down-regulated mRNA and protein expression of MMP-15 (Matrix Metallopeptidase-15). Activation of ERK1/2 and p38MAPK were inhibited with AA, whereas combined AA with siRNA-ERK or siRNA-p38MAPK markedly reduced the metastatic effect and decreased MMP-15 expression in 786-O and A498 cells. Finally, AA significantly reduced the lung metastasis formation and metastasis-related proteins of human 786-O cells in vivo metastasis mice model. ConclusionAA inhibits the metastatic properties of RCC cells via inhibition of the p-ERK/p-p38MAPK axis and the subsequent down-regulation of MMP-15 in vitro and in vivo. Further study of AA as a potential anti-metastatic agent for RCC is warranted.

Investigating Cancerous Exosomes' Effects on CD8+ T-Cell IL-2 Production in a 3D Unidirectional Flow Bioreactor Using 3D Printed, RGD-Functionalized PLLA Scaffolds.

Exosomes from cancer cells are implicated in cancer progression and metastasis, carrying immunosuppressive factors that limit the antitumor abilities of immune cells. The development of a real-time, 3D cell/scaffold construct flow perfusion system has been explored as a novel tool in the study of T-cells and exosomes from cancer cells. Exosomes from human lung cancer (H1299 and A549) cells were co-cultured in a unidirectional flow bioreactor with CD8+ T-cells immobilized onto 3D-printed RGD-functionalized poly(L-lactic) acid (PLLA) scaffolds and assessed for IL-2 production. The IL-2 production was investigated for a wide range of T-cell to exosome ratios. With the successful incorporation of the RGD binding motif onto the PLLA surface at controllable densities, CD8+ T-cells were successfully attached onto 2D disks and 3D printed porous PLLA scaffolds. T-cell attachment increased with increasing RGD surface density. The diameter of the attached T-cells was 7.2 ± 0.2 µm for RGD densities below 0.5 nmoles/mm2 but dropped to 5.1 ± 0.3 µm when the RGD density was 2 nmoles/mm2 due to overcrowding. The higher the number of cancer exosomes, the less the IL-2 production by the surface-attached T-cells. In 2D disks, the IL-2 production was silenced for T-cell to exosome ratios higher than 1:10 in static conditions. IL-2 production silencing in static 3D porous scaffolds required ratios higher than 1:20. The incorporation of flow resulted in moderate to significant T-cell detachment. The portions of T-cells retained on the 3D scaffolds after exposure for 4 h to 0.15 or 1.5 mL/min of perfusion flow were 89 ± 11% and 30 ± 8%, respectively. On 3D scaffolds and in the presence of flow at 0.15 ml/min, both H1299 and A549 cancerous exosomes significantly suppressed IL-2 production for T-cell to exosome ratios of 1:1000. The much higher level of exosomes needed to silence the IL-2 production from T-cells cultured under unidirectional flow, compared to static conditions, denotes the importance of the culturing conditions and the hydrodynamic environment, on the interactions between CD8+ T-cells and cancer exosomes.

A novice cocrystal nanomicelle formulation of 5-fluorouracil with proline: The design, self-assembly and in vitro/vivo biopharmaceutical characteristics

To fully play the advantages of cocrystallization and nano-preparation techniques in regulating in vitro/vivo biopharmaceutical properties of anticancer drug 5-fluorouracil (FU), and further exploit new avenues in its formulation development, a recombination strategy of cocrystallization and nano-micellar self-assembly techniques is proposed. Thereinto, the cocrystallization technique is aiming at augmenting antitumor ability by ameliorating physicochemical performances of FU, while the nano-micellar self-assembly technique is mainly employed to achieve slowed release and long-term efficacy. Guided by this strategy, a new zwitterionic cocrystal of FU with L-proline (PL), FU-PL, is successfully synthesized, and then incorporated into carriers PEG-PCL to gain cocrystal micelles. The structure of FU-PL cocrystal and morphology of the cocrystal micelles are respectively characterized via various analytical means. The comparative studies of in vivo/vitro properties are systematacially conducted by theoretical and experimental methods. The results showcase that the cocrystal's solubility and permeability are 4.60 and 3.89 folds higher than those of pristine drug FU at pH 6.8, separately; and the drug loading and entrapment efficiency of the obtained cocrystal micelles with spherical particles of 146 nm are 2.39 and 1.74 times than those of FU micelles itself, respectively. Particularly, both the cocrystal and its micelles eventually bring about the excellent antitumor activity, but the cocrystal micelles improve even more significantly in comparison with the cocrystal. These in vitro advantages have promoted the in vivo absorption with increased relative bioavailability (FREL) of 2.72 relative to FU-PL cocrystal. More particularly, the cocrystal micelles have preferable sustained-release action relative to FU micelles, thus more efficaciously prolonging the half-life and therapy duration. All these findings not only supply a novice slow-release dosage form for FU with greater efficiency, but also fill the blank of the micelle researches for antitumor pharmaceutical cocrystals.

Hollow Cuprous Oxide@Nitrogen-Doped Carbon Nanocapsules for Cascade Chemodynamic Therapy.

Cuprous-based nanozymes have demonstrated great potential for cascade chemodynamic therapy (CDT) due to their higher catalytic efficiency and simple reaction conditions. Here, hollow cuprous oxide@nitrogen-doped carbon (HCONC) dual-shell structures are designed as nanozymes for CDT oncotherapy. This HCONC with a size distribution of 130 nm is synthesized by a one-step hydrothermal method using cupric nitrate and dimethyl formamide as precursors. The thin-layer carbon (1.88 nm) of HCONC enhances the water-stability and reduces the systemic toxicity of cuprous oxide nanocrystals. The dissolved Cu+ of HCONC in acid solution induces a Fenton-like reaction and exhibits a fast reaction rate for catalyzing H2 O2 into highly toxic hydroxyl radicals (·OH). Meanwhile, the formed Cu+ consumes oversaturated glutathione (GSH) to avoid its destruction of ROS at the intracellular level. In general, both cellular and animal experiments show that HCONC demonstrates excellent antitumor ability without causing significant systemic toxicity, which may present tremendous potential for clinical cancer therapy.

Dihydromyricetin from Ampelopsis grossedentata and its derivatives: Structural characterization and anti-hepatocellular carcinoma activity

Dihydromyricetin (DMY) was efficiently extracted from Ampelopsis grossedentata and modified by esterification to obtain two derivatives, which were named as benzoylated derivative (BZ-DMY) and acetylated derivative (AC-DMY). The physicochemical characterizations of BZ-DMY and AC-DMY were investigated by TLC, SEM, HPLC, FT-IR, NMR and MS analysis. Simultaneously, the anti-hepatocellular carcinoma activity was determined by cell experiment to investigate their structure-activity relationship. The results indicated that esterification of DMY were successfully modified by benzoyl and acetyl. The substitute positions were C-3, C-5, C-7, C-3′, C-4′ and C-5′ respectively inferred from NMR analysis. In the experiment of anti-hepatocellular carcinoma activity, two novel derivatives showed better anti-tumor ability than DMY. Therefore, it can be concluded that esterified DMY could significantly induce HepG2 cells apoptosis and improve the anti-tumor activity of DMY. In summary, this research could not only enhance the development and utilization of Ampelopsis grossedentata, but also develop these two derivatives (BZ-DMY and AC-DMY) as potential anti-hepatocellular carcinoma therapeutic drugs.

Transferrin/folate dual-targeting Pluronic F127/poly(lactic acid) polymersomes for effective anticancer drug delivery

A novel dual-targeting Pluronic/poly(lactic acid) polymersome containing transferrin and folic acid ligands (Tf/FA-F127-PLA) has been designed to study its application in the targeted drug delivery system. Both biotin and folic acid conjugated Biotin/FA-F127-PLA polymersomes (Ps) were prepared as the precursor. The dual-targeting behaviors of Tf/FA-F127-PLA over C6 glioma cells were then fulfilled through connecting the precursor with biotinylated transferrin by using a three-step biotin-avidin technique. Paclitaxel (PTX) was loaded successfully into Biotin/FA-F127-PLA and showed a burst release followed by a slow-release process in vitro. It was also obtained that Tf/FA-F127-PLA had higher cytotoxicity and cellular uptake amount than non-targeted and single-targeted Ps did. These results could be because more PTX-loaded Tf/FA-F127-PLA Ps entered C6 cells through both FA-folate receptor (FR) and Tf-transferrin receptor (TfR) specific affinity and thus possessed the better anti-tumor ability. It was further proved that the uptake of Ps by C6 cells was through the endocytosis related to clathrin, caveolae, lysosome, etc. Furthermore, it was demonstrated that the uptake of dual-targeting Tf/FA-F127-PLA Ps by C6 cells was related to the endocytosis mediated by both FR and TfR. These findings indicated that dual-targeting Tf/FA-F127-PLA Ps could be a potential carrier in targeted drug delivery systems.

Multifunctional liposome for photoacoustic/ultrasound imaging-guided chemo/photothermal retinoblastoma therapy

Retinoblastoma (RB) is a malignant intraocular neoplasm that occurs in children. Diagnosis and therapy are frequently delayed, often leading to metastasis, which necessitates effective imaging and treatment. In recent years, the use of nanoplatforms allowing both imaging and targeted treatment has attracted much attention. Herein, we report a novel nanoplatform folate-receptor (FR) targeted laser-activatable liposome termed FA-DOX-ICG-PFP@Lip, which is loaded with doxorubicin (DOX)/indocyanine green (ICG) and liquid perfluoropentane (PFP) for photoacoustic/ultrasound (PA/US) dual-modal imaging-guided chemo/photothermal RB therapy. The dual-modal imaging capability, photothermal conversion under laser irradiation, biocompatibility, and antitumor ability of these liposomes were appraised. The multifunctional liposome showed a good tumor targeting ability and was efficacious as a dual-modality contrast agent both in vivo and in vitro. When laser-irradiated, the liposome converted light energy to heat. This action caused immediate destruction of tumor cells, while simultaneously initiating PFP phase transformation to release DOX, resulting in both photothermal and chemotherapeutic antitumor effects. Notably, the FA-DOX-ICG-PFP@Lip showed good biocompatibility and no systemic toxicity was observed after laser irradiation in RB tumor-bearing mice. Hence, the FA-DOX-ICG-PFP@Lip shows great promise for dual-modal imaging-guided chemo/photothermal therapy, and may have significant value for diagnosing and treating RB.

Oxygen-economizing liposomes for synergistic photodynamic and starvation therapy

Photodynamic therapy (PDT) shows great potential in cancer therapy. However, the therapeutic efficacy of PDT is limited by the hypoxic microenvironment in tumor tissue. In this research, photosensitizer chlorin e6 (Ce6) and glycolysis inhibitor 3-bromopyruvate (3BP) co-loaded liposomes are designed for synergistic photodynamic and starvation therapy. The size and morphology of the drug loaded liposomes are fully investigated by cryogenic transmission electron microscopy and dynamic light scattering. 3BP can block energy supply of cancer cells by inhibiting glycolysis for starvation therapy, which is confirmed by measuring intracellular lactate and ATP levels. Meanwhile, the intracellular oxygen consumption can be reduced by 3BP, which is able to relieve tumor hypoxic microenvironment, leading to improved therapeutic efficacy of PDT. The antitumor ability of the combined photodynamic and starvation therapy is investigated by in vitro and in vivo experiments. Such oxygen-economizing liposome provides a promising strategy for synergistic photodynamic cancer therapy.

Synthesis, solubility and antitumor activity of maslinic acid derivatives

Maslinic acid (MA), a pentacyclic triterpenoid obtained from olives that is characterized by its antiproliferative activity in tumor cells, has become a promising molecule that could be modified to improve cancer treatment. In this work we have synthesized in good yields several new MA conjugates, including glycerin, oligo(ethylene glycol), and amino acid derivatives (compounds 3a-f). The synthesis offers the possibility of recovering unreacted MA, and thus the scaling up of the process. For the tyramine-MA conjugate, compound 3f or TMA, the preparation has been optimized to a one-pot reaction. Solubility of conjugates in polar solvents has been measured, showing a marked increase of solubility with respect to MA. Moreover, we selected the tyramidyl maslinic acid conjugate (3f or TMA) to determine antitumor capacity over a wide range of cancer cell lines, including glioblastoma, melanoma, breast, lung, colorectal and pancreatic cancer. Our results clearly demonstrated that TMA induced higher cytotoxicity in all cancer cell types compared to MA. TMA was more effective than MA, especially in breast cancer cells (MCF-7) and melanoma cells (B16–F10) where IC50 reductions of 4.12 and 4.72, respectively, was detected. Interestingly, TMA showed a remarkable antitumor ability against the resistant HCT-15 colon cancer cell line. Furthermore, we demonstrated for the first time a relevant effect of a MA derivative against glioblastoma cells (A172 and SF-268). These results suggest that TMA is able to improve the antitumor characteristics of MA in a wide range of cancers and that it may be a promising compound for various tumor types, including resistant cancer.

Prodrug based on halloysite delivery systems to improve the antitumor ability of methotrexate in leukemia cell lines

The prodrug approach, as well as the development of specific systems able to deliver a chemotherapeutic agent in the target site, decreasing the side effects often associated with its administration, are still a challenging. In this context, both methotrexate drug molecules (MTX) and biotin ligand moieties, whose receptors are overexpressed on the surface of several cancer cells, were loaded on halloysite nanotubes (HNTs) to develop nanomaterial based on multifunctional and “smart” delivery systems.To highlight the crucial role played by biotin, carrier systems based on HNTs and MTX were also synthetized. In detail, several approaches were envisaged: i) a supramolecular interaction between the clay and the drug; ii) a covalent grafting of the drug onto the HNTs external surface and, iii) a combination of both approaches. The nanomaterials obtained were characterized by thermogravimetric analysis, FT-IR, and UV-vis spectroscopies, DLS and ζ−potential measurements and the morphologies were imaged by HAADF/STEM investigations. Kinetic release experiments at different pH conditions were also performed. Finally, as a proof-of-concept application of our pro-drug delivery systems based on HNTs in cancer therapy, the cytotoxic effects were evaluated on acute myeloid leukemia cell lines, HL60 and its multidrug resistance variant, HL60R. The obtained results showed that both the MTX prodrug system and the biotinylated ones played a crucial role in the biological activity and, they are promising agents for the cancer treatments.

Effective CpG Delivery Using Zwitterion-Functionalized Dendrimer-Entrapped Gold Nanoparticles to Promote T Cell-Mediated Immunotherapy of Cancer Cells.

Recently, cell-based immunotherapy has become one of the most promising ways to completely eliminate cancer. The major challenge is to effectively promote a proper immune response to kill the cancer cells by activated T cells. This study investigated the effect of T cell-mediated immunotherapy trigged by Au DENPs-MPC (zwitterion 2-methacryloyloxyethyl phosphorylcholine (MPC)-functionalized dendrimer-entrapped gold nanoparticles) loading oli-godeoxynucleotides (ODN) of unmethylated cytosine guanine dinucleotide (CPG). Here, we first synthesized Au DENPs-MPC, evaluated their capability to compress and transfect CpG-ODN to bone marrow dendritic cells (BMDCs), and investigated the potential to use T cells stimulated by matured BMDCs to inhibit the growth of tumor cells. The developed Au DENPs-MPC could apparently reduce the toxicity of Au DENPs, and enhanced transfer CpG-ODN to the BMDCs for the maturation as demonstrated by the 44.41–48.53% increase in different surface maturation markers. The transwell experiments certificated that ex vivo activated T cells display excellent anti-tumor ability, which could effectively inhibit the growth of tumor cells. These results suggest that Au DENPs-MPC can deliver CpG-ODN efficiently to enhance the antigen presentation ability of BMDCs to activate T cells, indicating that T cells-based immunotherapy mediated by Au DENPs-MPC loaded with CpG-ODN may become the most promising treatment of cancer.

Bortezomib-Encapsulated Dual Responsive Copolymeric Nanoparticles for Gallbladder Cancer Targeted Therapy.

Gallbladder cancer (GBC) is a rare but the most malignant type of biliary tract tumor. It is usually diagnosed at an advanced stage and conventional treatments are unsatisfactory. As a proteasome inhibitor, bortezomib (BTZ) exhibits excellent antitumor ability in GBC. However, the long‐term treatment efficacy is limited by its resistance, poor stability, and high toxicity. Herein, BTZ‐encapsulated pH‐responsive copolymeric nanoparticles with estrone (ES‐NP(BTZ; Ce6)) for GBC‐specific targeted therapy is reported. Due to the high estrogen receptor expression in GBC, ES‐NP(BTZ; Ce6) can rapidly enter the cells and accumulate near the nucleus via ES‐mediated endocytosis. Under acidic tumor microenvironment (TME) and 808 nm laser irradiation, BTZ is released and ROS is generated by Ce6 to destroy the “bounce‐back” response pathway proteins, such as DDI2 and p97, which can effectively inhibit proteasomes and increase apoptosis. Compared to the traditional treatment using BTZ monotherapy, ES‐NP(BTZ; Ce6) can significantly impede disease progression at lower BTZ concentrations and improve its resistance. Moreover, ES‐NP(BTZ; Ce6) demonstrates similar antitumor abilities in patient‐derived xenograft animal models and five other types of solid tumor cells, revealing its potential as a broad‐spectrum antitumor formulation.

Design, synthesis and anti-breast cancer evaluation of biaryl pyridine analogues as potent RSK inhibitors

In order to discover and develop the new RSK kinase inhibitor, 50 pyridyl biaryl derivatives were designed and synthesized with LJH685 as the lead compound and their anti-tumor ability was tested. The results showed that the ability of 7d compound to inhibit the phosphorylation of YB-1 was comparable to that of LJH685. Among them, after preliminary screening, compound 7d showed good activity in inhibiting cell proliferation. Therefore, we took 7d as an example and performed molecular docking analysis on it. Judging from the overlapping combination diagram with LJH685, the results have verified that compound 7d has a similar skeleton to LJH685 and has a similar docking effect with RSK. Therefore, compound 7d is in line with the RSK inhibitor we designed and could be developed to a promising anti-tumor drug in the future.