High Antitumor Activity Research Articles

Lava-051, a Novel Bispecific Gamma-Delta T-Cell Engager (Gammabody), in Relapsed/Refractory MM and CLL: Pharmacodynamic and Early Clinical Data

Background: LAVA-051 is a Vγ9Vδ2-T cell engaging bispecific antibody of 27 kDa that directly engages tumor expressed CD1d and the Vδ2-TCR chain of Vγ9Vδ2-T cells to kill tumor cells in a tumor target-dependent manner. Binding between LAVA-051 and CD1d also causes the activation of a second effector cell type: invariant natural killer T (iNKT) (Nature Cancer 2020;1:1054-1065). By dual engagement of these unique innate-like T cell subsets with inherent antitumor activity, LAVA-051 has the potential to exhibit high potency antitumor activity. Based on clinical experience with systemic activation of Vγ9Vδ2-T cells through aminobisphosphonates and in vivo studies in non-human primates (NHP) with a surrogate CD1d-γδ T cell engager, a low risk for cytokine release syndrome (CRS) is expected. CD1d is expressed by tumor cells in the majority of patients with CLL (chronic lymphocytic leukemia) and MM (multiple myeloma), while expression in AML (acute myeloid leukemia) is most pronounced on (myelo)monocytic subtypes. The local tolerance of subcutaneous (SC) administration of LAVA-051 was studied in a NHP model with no signs of local intolerance or histopathological abnormalities observed. Methods: An open label, accelerated titration design, phase 1/2a study in patients with relapsed/ refractory CLL and MM (NCT04887259) is ongoing to determine the safety of LAVA-051 and its recommended Phase 2a dose (RP2D). Adverse Events (AEs) are graded per CTCAE V5.0 criteria and CRS is graded per ASTCT criteria. IMWG criteria (MM) and iwCLL guidelines (CLL) are used for disease evaluation. The RP2D will be the optimal biological active dose, supported by a panel of specific pharmacodynamic assays to determine the pattern of change in the binding of LAVA-051 to peripheral blood Vγ9Vδ2-T cells (i.e. Vγ9Vδ2-TCR occupancy), and in the frequency and activation status of Vγ9Vδ2-T and iNKT cells in circulation. LAVA-051 is administered by IV infusion over 2 hours twice a week or by SC administration; observation of changes in PD parameters following SC administration as compared to IV infusion will enhance selection of RP2D administration and schedule. Results: As of July 25, 2022, a dose level of 100 µg has been reached (starting dose 0.45 µg) with no reports of CRS or dose limiting toxicities (DLTs). Eight patients in total have been treated with LAVA-051; 4 patients with MM and 4 patients with CLL with treatment duration range of 1.6 to 18.1 weeks. Treatment emergent AEs (TEAEs) were predominantly of grade 1 and 2 severity, with a minority of AEs observed across more than one dose level: lymphadenopathy, pyrexia (underlying causes different from CRS), epistaxis, dyspnea, and leukopenia. Severity of TEAEs did not increase with escalating doses and no patient discontinued treatment due to an AE. Disease stabilization has been observed in two patients. Despite no observation of formal response, lymph node shrinkage was observed in one CLL patient and decreasing M-protein levels in one MM patient. Pharmacodynamic data reflect changes as expected per LAVA-051 mechanism of action (MoA): Vγ9Vδ2-T cell activation markers (CD25 and CD69) were consistently upregulated in each dose cohort where this could be assessed, maximum measured Vγ9Vδ2-T cell receptor occupancy increased with higher dose cohorts, and iNKT cell activation was observed. Furthermore, no significant increases in IL-6 or other CRS-related cytokines have been observed. Pharmacokinetic data indicate predictable and linear pharmacokinetics. Updated safety, PD, and PK results following IV and SC administration will be presented at the congress. Conclusions: LAVA-051 has been well tolerated early in dose escalation with pharmacodynamics and early clinical signs reflective of its intended MoA. The differentiating importance of these pharmacodynamic parameters with any correlating preliminary antitumor activity will be further elucidated with continued dose escalation by the IV and SC route and in the determination of the RP2D and schedule.

Dihydroartemisinin synergistically enhances the cytotoxic effects of oxaliplatin in colon cancer by targeting the PHB2-RCHY1 mediated signaling pathway.

Dihydroartemisinin (DHA) has recently attracted increasing attention for its low toxicity and high antitumor activity. DHA has been reported to have synergistic anticancer effects with a variety of drugs in the clinic; however, the molecular mechanism by which DHA inhibits tumorigenesis and improves oxaliplatin cytotoxicity in colon cancer cells is still not well understood. In this study, we found that DHA can inhibit cell proliferation and colony formation in a dose-dependent manner. Prohibitin 2 (PHB2) is a potential target by which DHA exerts its antitumor and cytotoxic effects. The function and molecular mechanism of PHB2 in colon cancer tumorigenesis were fully studied to determine the regulatory mechanism between DHA and PHB2. We found that PHB2, a mitochondrial inner membrane scaffold protein, has a higher expression level in colon cancer tissues than in adjacent nontumor tissues and is mainly localized in mitochondria. Overexpression of PHB2 can promote cell proliferation and colony formation in vitro and accelerate tumor growth in vivo. We also found that the expression level of PHB2 was inversely related to the cytotoxicity of DHA and oxaliplatin in colon cancer cells. The molecular mechanism of PHB2 in tumorigenesis and cancer therapy was further studied. The results showed that 20 μM DHA can downregulate PHB2 expression in a ubiquitylation-dependent manner and subsequently block PHB2-induced RCHY1 upregulation and p53 and p21 downregulation. In this process, RCHY1 is necessary for PHB2 to play a tumor-promoting role. Thus, PHB2 and RCHY1 are effective targets for colon cancer therapy, and DHA has synergistic anticancer effects with oxaliplatin via promoting PHB2 degradation in colon cancer cells.

Antitumor effects of polysaccharides from Tetrastigma hemsleyanum Diels et Gilg via regulation of intestinal flora and enhancing immunomodulatory effects in vivo.

Tetrastigma hemsleyanum Diels et Gilg is a traditional Chinese herbal medicine with high medicinal value, and antitumor, antioxidant and anti-inflammatory biological activities. However, while several studies have focused on flavonoids in Tetrastigma hemsleyanum tubers, there are few studies on the enhanced immune effect of Tetrastigma hemsleyanum polysaccharides (THP). In this study, we evaluated the antitumor effect of THP in a lung tumor model and explored the mechanism of antitumor activity through intestinal flora. In addition, a cyclophosphamide (CTX)-induced immunosuppression model was used to declare the immunomodulatory effect of THP in the immunosuppressive state induced by antitumor drugs. The results showed that THP increased the content of ileum secreted immunoglobulin A (SIgA) and cecum short-chain fatty acids (SCFAs) and improved microbial community diversity, regulating the relative abundance of dominant microbiota flora from the phylum level to the genus level, and recovering the intestinal microflora disorder caused by tumors. Additionally, THP can increase the organ indices and improve immune organ atrophy. THP can upregulate routine blood counts and stimulate the production of the serum cytokines. THP also promoted the macrophage phagocytic index, NK-cell activation, and complement and immunoglobulin (IgG, IgA, IgM) levels. The detection of Splenic lymphocyte proliferation and T lymphocyte subsets also sideways reflects that THP can restore CTX-induced immune inhibition in mice. In conclusion, this study suggests that THP can effectively achieve the enhanced antitumor effects, regulate gut microbiota and improve the immunosuppression induced by antitumor drugs. Therefore, THP can enhance the immune capacity and provide novel immunomodulatory and antineoplastic adjuvant agents.

Single-Site Fe-N-C Atom Based Carbon Nanotubes for Mutually Promoted and Synergistic Oncotherapy.

A carbon nanotube (CNT) supported single-site Fe-N-C catalyst (CNTs/Fe-N-C) exhibited attractive properties in peroxidase (POD)-like activity and photothermal effect. Herein, we designed a therapeutic platform by wrapping doxorubicin (DOX) in mesoporous CNTs/Fe-N-C with the cell membrane (CM) of breast cancer. The ultimate nanoagent (CNTs/Fe-N-C/DOX/CM) exhibited high antitumor activity on account of its efficient catalytic ability, increased drug release rates, and significant photothermal effect. Due to the POD-like activity, CNTs/Fe-N-C could effectively catalyze hydrogen peroxide (H2O2) into cytotoxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT) of the tumor. Besides, the released DOX not only merely induced the diagnosis of the tumor cells for chemotherapy (CT) but also generated H2O2 to promote CDT. Moreover, the photothermal effect of the nanoagent could use for photothermal therapy (PTT). The increasing temperature was conducive to the release of DOX from micropore into the cell, which indirectly enhanced CT and CDT effects. As an intelligent and multifunctional drug delivery platform, the present CNTs/Fe-N-C/DOX/CM nanoagent could be engineered with synergistic treatments and favorable biosafety, which provides a promising paradigm in site-specific antitumor treatment and biomedicine.

Anti-tumor effects and mechanism of a novel camptothecin derivative YCJ100

AimsIn this study, we synthesized a 10-fluorine-substitution derivative of CPT (Camptothecin) YCJ100 and evaluated its antitumor activity and systemic toxicity. Materials and methodsDetermination of in vitro antitumor activity and mechanism of YCJ100 by the MTT assay, Molecular docking, EdU staining, Cell cycle and apoptosis determination, Western blot analysis and Topoisomerase I activity assay. The antitumor effects of YCJ100 were evaluated in primary HCC (hepatocellular carcinoma), ICC (intrahepatic cholangiocarcinoma) mouse models, and pancreatic cancer xenograft models. Key findingsYCJ100 showed superior cytotoxic activity compared to Topotecan in SW480, SW1990, Hep3B, HepG2, A549, A2780, HeLa, and QBC cells. YCJ100 blocked the cell cycle in the G2/M phase, inhibited cell proliferation and induced apoptosis in HepG2 and SW1990 cells. Mechanistically, YCJ100 inhibited topoisomerase I activity in both a cell-free system and a cellular system, similar to the mechanism of Topotecan. YCJ100 showed significant antitumor activity and was more potent than Topotecan in primary HCC and ICC mouse models, as well as a xenograft mouse model. Additionally, YCJ100 showed only minor toxicity to the mouse hematopoietic system, liver, and kidney. These findings indicate that YCJ100 has high antitumor activity and low systemic toxicity. SignificanceOur findings demonstrate that YCJ100, as a Topoisomerase I inhibitor, has in vitro and in vitro antitumor activity. This study provides a new lead compound worthy of further preclinical evaluation and potential clinical development.

Development of a nitroreductase-dependent theranostic payload for antibody-drug conjugate

Antibody-drug conjugates are gradually revolutionizing anticancer therapy. Payload is one of the most crucial components of ADC for high antitumor activity. However, there is no direct and real-time monitoring method for the intracellular release mechanism of the payload. Herein, we developed a theranostic payload that possessed dual functions of therapy and imaging. This payload consisted of the classic payload MMAE and the novel nitro-coumarin probe reported for the first time, which has the dual characteristics of electron transfer ability and the on–off fluorescence property. In this paper, the theranostic property of the novel payload has been preliminarily demonstrated. The fluorescence intensity of the payload in target cells greatly increased approximately 9 times in 120 min through the high content analysis, and the intracellular distribution of the payload could be directly monitored by a confocal microscope. In in vitro cytotoxicity assays, the payload showed broad-spectrum and high antitumor activity (0.09 nM to 1.2 nM), which was equivalent to the MMAE (0.06 nM to 1.1 nM). Moreover, the ADC loaded with L-233 maintained the theranositc property. In conclusion, our work developed a theranostic payload for the first time and provides a new direct and real-time monitoring method for intracellular studies of ADC payloads.

Gold Nanoparticle-Incorporated Chitosan Nanogels as a Theranostic Nanoplatform for CT Imaging and Tumour Chemotherapy.

PurposeThe translation of nanocarrier-based theranostics into cancer treatment is limited by their poor cellular uptake, low drug-loading capacity, uncontrolled drug release, and insufficient imaging ability.MethodsIn this study, novel hybrid nanogels were fabricated as theranostic nanocarriers by modifying chitosan (CTS)/tripolyphosphate (TPP) nanoparticles (NPs) with polyacrylic acid (PAA) and further conjugating cysteine-functionalized gold nanoparticles (AuNPs).ResultsThe resultant nanogels, referred to as CTS/TPP/PAA@AuNPs (CTPA), exhibited excellent colloidal stability and a high encapsulation rate of 87% for the cationic drug doxorubicin (DOX). In the tumour microenvironment, the acidic pH and overexpression of lysozyme triggered CTPA@DOX to degrade and emit smaller nanoblocks (30–40 nm), which sequentially released the drug in a tumour-responsive manner. Cellular uptake experiments demonstrated that CTPA facilitates the entry of DOX into the cytoplasm. Furthermore, as visualised through AuNP-mediated computed tomography (CT) imaging, CTPA@DOX enabled favourable accumulation in the tumour. Our in vitro and in vivo data demonstrated that CTPA enabled advanced tumour cell-targeting delivery of DOX, which showed greater anti-tumour activity and biosafety than free DOX.ConclusionThe natural polymer CTS was developed for degradable nanogels, which can precisely track drugs with high antitumour activity. Additionally, the surface adjustment strategy can be assembled to achieve cationic drug loading and high drug-loading capacity, controlled drug release, and sufficient imaging ability. Therefore, multifunctional CTPA enables efficient drug delivery and CT imaging, which is expected to provide a valuable strategy for designing advanced theranostic systems.

253 (PB033) - The Trop-2-targeting antibody drug conjugate DB-1305 has higher antitumor activity and a potentially better safety profile compared with DS-1062

Background: Trop-2 is a well validated oncology therapeutic target. DB-1305 is an antibody drug conjugate designed by conjugating an anti-Trop-2 antibody with a novel topoisomerase I inhibitor P1021 via an enzymatically cleavable tetrapeptide linker. Material and Methods: To characterize DB-1305 and the payload P1021, thorough studies were performed including in vitro functional assays, in vivo efficacy and PK/PD studies with murine CDX models, as well as PK/TK and GLP toxicity studies in monkeys and rats. Results: The results show that in vitro, DB-1305 selectively bound to Trop-2-positive cells and was endocytosed into their lysosomes. DB-1305 led to Trop-2-dependent cytotoxicity in Trop-2-expressing cells but not Trop-2-negative cells in a concentration-dependent manner. DB-1305 demonstrated tumor cell proliferation inhibition activities comparable to or stronger than DS-1062 produced in-house, as well as intriguingly displayed a stronger bystander killing effect. in vivo, DB-1305 showed strong anti-tumor activity in mouse models of MDA-MB-468, COLO205 and DMS-53, with significantly higher efficacy compared with DS-1062. In Trop-2 negative SHP77 model, DB-1305 did not suppress tumor growth, indicating the dependence of DB-1305 activity on Trop-2 expression. The PK/PD study performed by treatment of DB-1305 in the MDA-MB-468 model demonstrated substantially increased ratios of P1021 exposure (AUC) to the exposure of DB-1305-total antibody or DB-1305-ADC in the tumor than in serum, suggesting that P1021 is effectively released in the tumor. The pharmacokinetics parameters of DB-1305 (total antibody, ADC, and released payload) were obtained from the PK/TK studies in monkeys. The PK/TK profile of P1021 was assessed in rats in addition to the PK/TK study of DB-1305 in monkeys. The exposure levels of DB-1305 and P1021 had no obvious gender difference and no apparent accumulation in monkeys and rats. The systemic exposure AUC0-last and Cmax of ADC showed similar values to those of total antibody, and both parameters were increased approximately dose proportionally from 1 mg/kg to 10 mg/kg. Particularly, in monkeys, the peak concentration of P1021 in the DB-1305 10 mg/kg group was reduced to 1/171 compared with the P1021 0.14 mg/kg (equivalent to the molar mass of P1021 in 10 mg/kg DB-1305), while the t1/2 was prolonged from 0.651 h to 194 h. DB-1305 was well tolerated in the GLP toxicity studies in Cynomolgus monkeys with the highest non-severely toxic dose (HNSTD) of 80 mg/kg, which is significantly higher than HNSTD of 30 mg/kg for DS-1062. Conclusions: Taken together, this study has demonstrated higher efficacy and a potentially better safety profile of DB-1305 compared with DS-1062, supporting further clinical development of DB-1305 and indicating the great potential of DB-1305 in the treatment of Trop-2-positive cancers. No conflict of interest.

Symmetry dual functional pyrimidine-BODIPY probes for imaging targeting and activity study.

Nondestructive diagnosis of tumor has always been the goal of scientists. Fluorescent dyes have become the rising star in the field of cancer diagnosis because of their excellent characteristics. Therefore, in this work, fluorescence probes d-Y-B and dO-Y-B with anti-tumor activity were constructed by introducing pyrimidine groups with high anti-tumor activity using fluorescence dye BODIPY as parent nucleus. The modified BODIPY group in the structure had the advantage of fluorescent dye, ensuring the strong fluorescence and photosensitivity of the target compound. That ethylenediamine acts as a bridge with two -NH- groups to increase molecular hydrogen bonding, and can bind firmly to multiple proteins. Co-localization of the target compounds d-Y-B and dO-Y-B with the hoechst dye for labeling living cells showed that these compounds had high biocompatibility and photostability for localization to HeLa cells. In vivo imaging in mice can realize specific localization and real-time visualization of tumor cells. The results of cytotoxicity experiments in vitro and computer software simulating molecular docking confirmed the potential of the target compounds as an anticancer agents. The bifunctional probe realized visualization of cancer cells in mice, and can kill cancer cells by anti-proliferation, which may provide a direction for future anticancer drug development.

γδ T cells: The potential role in liver disease and implications for cancer immunotherapy.

The γδ T cell subset was discovered over 30 years ago, yet continues to be an exciting and challenging component of the adaptive immune response. While γδ T cells represent a very small fraction of all T cells in humans, γδ T cells have a vital effect on human immunity, serving as a bridge between the innate and adaptive immune systems. The characteristics of γδ T cells include recognition of non-MHC restrictive antigens, as well as the ability to secrete an abundance of cytokines, suggesting that γδ T cells have high antitumor activity. As such, they have gained ample attention with respect to tumor immunotherapy in the last decade. The γδ T cell subset comprises up to ∼15-20% of the T-lymphocyte population in the liver, although the liver is recognized as an immune organ with primary immune functions, the role of γδ T cells in liver disease has not been established. Herein, we present a comprehensive overview of molecular mechanisms underlying immune γδ T cell activity in liver disease, including immune liver injury, viral hepatitis, cirrhosis, and hepatocellular carcinoma, and review γδ T cell-based clinical immunotherapeutic approaches.

Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma

BackgroundAnti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy showed remarkable efficacy in patients with relapsed or refractory multiple myeloma (RRMM). This phase 1 dose-escalation and expansion study...

Characterization of the immune related lncRNAs in bladder cancer to aid immunotherapy.

Bladder cancer (BLCA) is the 10th most common form of cancer worldwide. Currently, the response rate of BLCA patients to novel immunotherapy and immune checkpoint inhibitor (ICI) treatment is around 30% or less. Therefore, there is an urgent clinical demand to understand the regulation of immune function in BLCA patients. LncRNAs are known to play fundamental roles in the regulation of the immune system in the tumor microenvironment. In this report, we performed a comprehensive analysis to identify immune-related lncRNAs (IRLs) in BLCA patients using The Cancer Genome Atlas (TCGA) databases. BLCA patients were divided into five TME subtypes. Subtype HMIE was strongly related to survival and high anti-tumor activity of patients. Through a four-step analysis, we identified 34 IRLs as subtype HMIE related lncRNAs (HMIE-lncs).The correlation analysis with immune cell infiltration and target gene pathway enrichment showed that 34 HMIE-lncs were correlated with immune cell activation and tumor cell killing. Among them, 24 lncRNAs were related to good prognosis. We constructed a risk model to predict BLCA. Cross tumor validation was performed, and the results showed that the 34 HMIE-lncs identified in the BLCA patients in this study were highly expressed in the immune-favorable TME subtype (IE) in most of the other cancer types.

The antitumor effect induced by an IL-2 'no-alpha' mutein depends on changes in the CD8+ T lymphocyte/Treg cell balance.

High doses of interleukin-2 (IL-2) have been used for the treatment of melanoma and renal cell carcinoma, but this therapy has limited efficacy, with a ~15% response rate. Remarkably, 7%–9% of patients achieve complete or long-lasting responses. Many patients treated with IL-2 experienced an expansion of regulatory T cells (Tregs), specifically the expansion of ICOS+ highly suppressive Tregs, which correlate with worse clinical outcomes. This partial efficacy together with the high toxicity associated with the therapy has limited the use of IL-2-based therapy. Taking into account the understanding of IL-2 structure, signaling, and in vivo functions, some efforts to improve the cytokine properties are currently under study. In previous work, we described an IL-2 mutein with higher antitumor activity and less toxicity than wtIL-2. Mutein was in silico designed for losing the binding capacity to CD25 and for preferential stimulation of effector cells CD8+ and NK cells but not Tregs. Mutein induces a higher anti-metastatic effect than wtIL-2, but the extent of the in vivo antitumor activity was still unexplored. In this work, it is shown that mutein induces a strong antitumor effect on four primary tumor models, being effective even in those models where wtIL-2 does not work. Furthermore, mutein can change the in vivo balance between Tregs and T CD8+ memory/activated cells toward immune activation, in both healthy and tumor-bearing mice. This change reaches the tumor microenvironment and seems to be the major explanation for mutein efficacy in vivo.

Design, Synthesis, Molecular Docking, and Biological Studies of New Heterocyclic Compounds Derived from β-Diketones as Novel EGFR and Pim-1 Inhibitors Endowed with Antitumor Activity

Cancer is a disease illustrated by a shift in the controlled mechanisms that control both cell proliferation and differentiation. It is regarded as a prime health problem worldwide and a leading cause of human death rate exceeded only by cardiovascular diseases. Many reported works are concerned with discovering new antitumor compounds, encouraging us to synthesize new anticancer agents. In this work, we aimed to synthesize target molecules from 1,3-dicarbonyl compounds through heterocyclization reactions. The reaction of either 4-methylaniline (1a) or 1-naphthylamine (1b) with diethyl malonate (2) gave the anilide derivatives 3a and 3b, respectively. The latter underwent a series of heterocyclization reactions to give the pyridine, pyran, and thiazole derivatives confirmed by the required spectral data. The in-vitro antitumor evaluation of the newly synthesized products against three cancer cell lines, MCF-7, NCI-H460, SF-268, and WI 38, which were used as the normal cell lines, was conducted, and the data revealed that compounds 11a, 18b, 18c, and 20d showed high antitumor activity and 20d individualized with potential antitumor activity towards cell lines with lowest cytotoxicity effect. Both EGFR and PIM-1 enzymes inhibition were investigated for the compound 20d, and it was found that the inhibition effect of compound 20d was promising for each enzyme, showing IC50 = 45.67 ng and 553.3 ng for EGFR and PIM-1, respectively. Molecular docking results of compound 20d showed strong binding interactions with both the enzymes, where good binding modes were obtained in the case of EGFR, which was closely similar to the binding mode of standard Erlotinib.While 20d showed complete superimposition binding interactions with VRV-cocrystallized ligand of PIM-1 that may expound the in-vitro antitumor activity.

Preparation of polydopamine-modified celastrol nanosuspension and its anti-liver cancer activity in vitro

Celastrol (CEL) is one of the main effective components of traditional Chinese medicine Tripterygium wilfordii Hook.f, which has high antitumor activity. However, its low solubility and low bioavailability limit its clinical use. In this study, a CEL nanosuspension (PDA@CEL-NS) with near-infrared photothermal properties was prepared. PDA@CEL-NS contained spherical nanoparticles with an average particle size of 189.67 nm, zeta potential of −30.23 mV, and 60.33% drug loading. X-ray diffraction showed that PDA@CEL-NS had an amorphous structure. PDA@CEL-NS had good stability after storage at 4 °C and 37 °C for 30 days, and there was no aggregation or sedimentation in a 5% glucose solution or culture medium. The highly dispersed nanoparticles greatly improved dissolution in vitro, and the cumulative release rate of PDA@CEL-NS over 72 h was as high as 60.10%. It demonstrated both high release and a good sustained-release effect. Cell experiments showed that PDA@CEL-NS had stronger efficacy than CEL-NS or CEL, and the efficacy was further enhanced after laser application. Nuclear rupture and deformation and the induction of apoptosis were potential toxic mechanisms, and they also inhibited cell migration. In conclusion, PDA@CEL-NS is expected to become a nano-drug delivery system for the treatment of cancer.

Cover Feature: Guanosine‐based Hydrogel Integrating Photothermal Effect of PDA‐AuNPs through Dynamic Borate Bond for Photothermal Therapy of Cancer (Chem. Asian J. 15/2022)

A dual-functional guanosine-based hydrogel (GBPA) integrating the photothermal property of PDA-AuNPs and the self-assembly ability of G by introducing dynamic borate ester was developed. Both in vitro and in vivo results confirmed that the GBPA hydrogel not only exhibited excellent photothermal toxicity, stability, injectability, andbiocompatibility, but also possessed high photothermal antitumor activity. These results provide a paradigm for the future design of anticancer hydrogels integrating multiple functions. More information can be found in the Research Article by Jiang Liu et al.

Chiral RuII -PtII Complexes Inducing Telomere Dysfunction against Cisplatin-Resistant Cancer Cells.

The application of G-quadruplex stabilizers presents a promising anticancer strategy. However, the molecular crowding conditions within cells diminish the potency of current G-quadruplex stabilizers. Herein, chiral RuII -PtII dinuclear complexes were developed as highly potent G-quadruplex stabilizers even under challenging molecular crowding conditions. The compounds were encapsulated with biotin-functionalized DNA cages to enhance sub-cellular localization and provide cancer selectivity. The nanoparticles were able to efficiently inhibit the endogenous activities of telomerase in cisplatin-resistant cancer cells and cause cell death by apoptosis. The nanomaterials demonstrated high antitumor activity towards cisplatin-resistant tumor cells as well as tumor-bearing mice. To the best of our knowledge, this study presents the first example of a RuII -PtII dinuclear complex as a G-quadruplex stabilizer with an anti-cancer effect towards drug-resistant tumors inside an animal model.

Chiral Ru II ‐Pt II Complexes Inducing Telomere Dysfunction against Cisplatin‐Resistant Cancer Cells

The application of G-quadruplex stabilizers presents a promising anticancer strategy. However, the molecular crowding conditions within cells diminish the potency of current G-quadruplex stabilizers. Herein, chiral RuII-PtII dinuclear complexes were developed as highly potent G-quadruplex stabilizers even under challenging molecular crowding conditions. The compounds were encapsulated with biotin-functionalized DNA cages to enhance sub-cellular localization and provide cancer selectivity. The nanoparticles were able to efficiently inhibit the endogenous activities of telomerase in cisplatin-resistant cancer cells and cause cell death by apoptosis. The nanomaterials demonstrated high antitumor activity towards cisplatin-resistant tumor cells as well as tumor-bearing mice. To the best of our knowledge, this study presents the first example of a RuII-PtII dinuclear complex as a G-quadruplex stabilizer with an anti-cancer effect towards drug-resistant tumors inside an animal model.

Acid-Base Equilibrium and Self-Association in Relation to High Antitumor Activity of Selected Unsymmetrical Bisacridines Established by Extensive Chemometric Analysis.

Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents previously synthesized by our group. Our recent studies have demonstrated their high antitumor potential against multiple cancer cell lines and human tumor xenografts in nude mice. At the cellular level, these compounds affected 3D cancer spheroid growth and their cellular uptake was selectively modulated by quantum dots. UAs were shown to undergo metabolic transformations in vitro and in tumor cells. However, the physicochemical properties of UAs, which could possibly affect their interactions with molecular targets, remain unknown. Therefore, we selected four highly active UAs for the assessment of physicochemical parameters under various pH conditions. We determined the compounds’ pKa dissociation constants as well as their potential to self-associate. Both parameters were determined by detailed and complex chemometric analysis of UV-Vis spectra supported by nuclear magnetic resonance (NMR) spectroscopy. The obtained results indicate that general molecular properties of UAs in aqueous media, including their protonation state, self-association ratio, and solubility, are strongly pH-dependent, particularly in the physiological pH range of 6 to 8. In conclusion, we describe the detailed physicochemical characteristics of UAs, which might contribute to their selectivity towards tumour cells as opposed to their effect on normal cells.

Molecular-docking-guided design, palladium-catalyzed synthesis and anticancer activity of paclitaxel-benzoxazoles hybrids

A series of new paclitaxel-benzoxazoles hybrids were designed based on both the molecular docking mode of beta-tubulin with paclitaxel derivatives (7a and 7g), and the activity-structure relationship of C-13 side chain in paclitaxel. Palladium-catalyzed direct Csp2–H arylation of benzoxazoles with different aryl-bromides was used as the key synthetic strategy for the aryl-benzoxazoles moieties in the hybrids. Twenty-six newly synthesized hybrids were screened for their antiproliferative activity against human cancer cell lines such as human breast cancer cells (MDA-MB-231) and liver hepatocellular cells (HepG2) by the MTT assay and results were compared with paclitaxel. Interestingly, most hybrids (7a–7e, 7i, 7k, 7l, 7A, 7B, 7D and 7E) showed significantly active against both cell lines at concentration of 50 µM, which indicated that the hybrid strategy is effective to get structural simplified paclitaxel analogues with high anti-tumor activity.