Tumor Growth Inhibition Rate Research Articles

Shenling Baizhu Decoction (SLBZD) may play a synergistic role of tirelizumab in the treatment of colorectal cancer by influencing the imbalance of colon flora and Tumor microenvironment.

Objective: To explore whether SLBZD can play a synergistic role in promoting the efficacy of PD-1 inhibitors in the treatment of colorectal cancer by influencing the intestinal microenvironment and Tumor microenvironment. Method: Shenling Baizhu Decoction (SLBZD) and tirelizumab (TLzmab) treated the colorectal mouse model. The tumor growth rate, tumor weight, and tumor growth inhibition rate were evaluated. Fecal microbiota was detected by 16S rDNA sequencing and immune cell was detected by the flow cytometry analysis. Result: Compared to tumor weight, there exist significant differences between each group among the three groups. Compared to tumor volume, there was no statistically significant difference in tumor size between the control group and the TLzmab group at 7 days. However, there was a statistical difference in tumor size among the three groups at 18 days. By analyzing the diversity of the Gut microbiota, the diversity decreased after TLzmab treatment with a statistically significant difference. Compared with the control group, the diversity of the TLzmab+SLBZD group increased. The proportion of lymphocytes in the blood was analyzed by flow cytometry. Compared with the control group, Myeloid-derived suppressor cells (MDSCs) decreased and T regulatory cells (Treg) increased significantly in the TLzmab group. Compared with the control group and TLzmab group, the TLzmab+SLBZD group showed a significant increase in M1 type macrophages, while the M2 type macrophages, MDSCs, and Treg showed a significant decrease. Conclusion: An imbalance of Gut microbiota and imbalance of tumor immune microenvironment will occur during TLzmab treatment, which will lead to poor therapeutic effect of TLzmab or drug resistance. SLBZD will increase the abundance of Gut microbiota, which will lead to the increase of M1 macrophages in the tumor immune microenvironment and the decrease of M2 macrophages and Treg cells, thus exerting the synergistic effect of TLzmab. This study provides a new way to explore the improvement of ICIs through traditional Chinese medicine.

Homologous polydopamine ameliorates haemolysis of melittin for enhancing its anticancer efficacy.

Despite exhibiting potent anticancer activity, the strong hemolytic properties of melittin (MEL) significantly restrict its delivery efficiency and clinical applications. To address this issue, we have devised a strategy wherein homologous dopamine (DA), an essential component of bee venom, is harnessed as a vehicle for the synthesis of MEL-polydopamine (PDA) nanoparticles (MP NPs). The ingenious approach lies in the fact that MEL is a basic polypeptide, and the polymerization of DA is also conducted under alkaline conditions, indicating the distinctive advantages of PDA in MEL encapsulation. Furthermore, MP NPs are modified with folic acid to fabricate tumor-targeted nanomedicine (MPF NPs). MPF NPs can ameliorate the hemolysis of MEL in drug delivery and undergo degradation triggered by high levels of reactive oxygen species (ROS) within solid tumors, thereby facilitating MEL release and subsequent restoration of anticancer activity. After cellular uptake, MPF NPs induce cell apoptosis through the PI3K/Akt-mediated p53 signaling pathway. The tumor growth inhibitory rate of MPF NPs in FA receptor-positive 4T1 and CT26 xenograft mice reached 78.04% and 81.66%, which was significantly higher compared to that in FA receptor-negative HepG2 xenograft mice (45.79%). Homologous vehicles provide a new perspective for nanomedicine design.

Hyaluronic acid-modified liposomes Potentiated in-vivo anti-hepatocellular carcinoma of icaritin.

Introduction: Icaritin (ICT), a promising anti-hepatocellular carcinoma (HCC) prenylated flavonoid, is hindered from being applied due to its low water solubility and high lipophilicity in poorly differentiated HCC which is associated with upregulation of CD44 isoforms. Thus, hyaluronic acid (HA), a natural polysaccharide with high binding ability to CD44 receptors, was used to formulate a modified liposome as a novel targeted ICT-delivery system for HCC treatment. Methods: The ICT-Liposomes (Lip-ICT) with and without HA were prepared by a combined method of thin-film dispersion and post-insertion. The particle size, polydispersity (PDI), zeta potential, encapsulation efficacy (%EE), drug loading content (%DLC), and in vitro drug release profiles were investigated for physicochemical properties, whereas MTT assay was used to assess cytotoxic effects on HCC cells, HepG2, and Huh7 cells. Tumor bearing nude mice were used to evaluate the inhibitory effect of HA-Lip-ICT and Lip-ICT in vivo. Results: Lip-ICT and HA-Lip-ICT had an average particle size of 171.2 ± 1.2nm and 208.0 ± 3.2 nm, with a zeta potential of -13.9 ± 0.83 and -24.8 ± 0.36, respectively. The PDI resulted from Lip-ICT and HA-Lip-ICT was 0.28 ± 0.02 and 0.26 ± 0.02, respectively. HA-Lip-ICT demonstrated higher in vitro drug release when pH was dropped from 7.4 to 5.5, The 12-h release rate of ICT from liposomes increased from 30% at pH7.4 to more than 60% at pH5.5. HA-Lip-ICT displayed higher toxicity than Lip-ICT in both HCC cells, especially Huh7with an IC50 of 34.15 ± 2.11μM. The in vivo tissue distribution and anti-tumor experiments carried on tumor bearing nude mice indicated that HA-Lip- ICT exhibited higher tumor accumulation and achieved a tumor growth inhibition rate of 63.4%. Discussion: The nano-sized Lip-ICT was able to prolong the drug release time and showed long-term killing HCC cells ability. Following conjugation with HA, HA-Lip-ICT exhibited higher cytotoxicity, stronger tumor targeting, and tumor suppression abilities than Lip-ICT attributed to HA-CD44 ligand-receptor interaction, increasing the potential of ICT to treat HCC.

Dual-purposing disulfiram for enhanced chemotherapy and afterglow imaging using chlorin e6 and semiconducting polymer combined strategy.

Rationale: One of the main challenges in chemotherapy is achieving high treatment efficacy while minimizing adverse events. Fully exploiting the therapeutic potential of an old drug and monitoring its effects in vivo is highly valuable, but often difficult to achieve. Methods: In this study, by encapsulating disulfiram (DSF) approved by US Food and Drug Administration, semiconducting polymer nanocomplex (MEHPPV), and Chlorin e6 into a polymeric matrix F127 via nanoprecipitation method, a nanosystem (FCMC) was developed for afterglow imaging guided cancer treatment. The characteristics, stability as well as the ability of singlet oxygen (1O2) production of FCMC were first carefully examined. Then, we studied the mechanism for enhanced anti-cancer efficiency and afterglow luminescence in vitro. For experiments in vivo, 4T1 subcutaneous xenograft tumor mice were injected with FCMC via the tail vein every three days and the antitumor effect of FCMC was evaluated by monitoring tumor volume and body weight every three day. Results: The nanosystem, which combines DSF with Ce6, can generates abundant 1O2 that enhances the antitumor activity of DSF. The in vivo results show that FCMC-treated group exhibits an obviously higher tumor-growth inhibition rate of 67.89% after 15 days of treatment, compared to the control group of F127@MEHPPV-CuET. Moreover, Ce6 also greatly enhances the afterglow luminescence intensity of MEHPPV and promotes the redshift of the afterglow emission towards the ideal near-infrared imaging window, thereby enabling efficient afterglow tumor imaging in vivo. Conclusions: This multifunctional nanoplatform not only improves the anticancer efficacy of DSF, but also enables monitoring tumor via robust afterglow imaging, thus exhibiting great potential for cancer therapy and early therapeutic outcome prediction.

Design and synthesis of luotonin A-derived topoisomerase targeting scaffold with potent antitumor effect and low genotoxicity

Conventional topoisomerase (Topo) inhibitors typically usually exert their cytotoxicity by damaging the DNAs, which exhibit high toxicity and tend to result in secondary carcinogenesis risk. Molecules that have potent topoisomerase inhibitory activity but involve less DNA damage provide more desirable scaffolds for developing novel chemotherapeutic agents. In this work, we broke the rigid pentacyclic system of luotonin A and synthesized thirty-three compounds as potential Topo inhibitors based on the devised molecular motif. Further investigation disclose that two compounds with the highest antiproliferation activity against cancer cells, 5aA and 5dD, had a distinct Topo I inhibitory mechanism different from those of the classic Topo I inhibitors CPT or luteolin, and were able to obviate the obvious cellular DNA damage typically associated with clinically available Topo inhibitors. The animal model experiments demonstrated that even in mice treated with a high dosage of 50 mg/kg 5aA, there were no obvious signs of toxicity or loss of body weight. The tumor growth inhibition (TGI) rate was 54.3 % when 20 mg/kg 5aA was given to the T24 xenograft mouse model, and 5aA targeted the cancer tissue precisely without causing damage to the liver and other major organs.

Abstract B049: Lipid nanoparticle-delivered toll-like receptor agonists are highly effective in cancer immunotherapy

Abstract Background: Tumor immunotherapy has shown promising efficacy in various types of cancer. However, the effectiveness of immunotherapy is often limited by the immune-suppressive microenvironment within tumors. To address this challenge, we developed a method of intratumoral injection using lipid nanoparticles (LNPs) to deliver Toll-like receptor 7, 8, and 9 agonists. LNPs effectively enhance immune activation while reducing systemic responses by increasing drug retention within the tumor. Methods: We encapsulated 30nt-CpG and Resiquimod into LNPs (QTsomeTM). Subcutaneous inoculation of 2 × 106 MC38 cells was performed in mice. Once the average tumor volume reached approximately 100mm3, we divided 15 mice into 3 groups based on tumor volume. Intratumoral injections began on the same day of grouping, with a dosage of 1mg/kg (5 injections every 3 days). Tumor volume and body weight were measured twice a week. We conducted two parallel experiments, each with 7 mice for the MC38 model and 8 mice for the B16 melanoma model in each group, to compare the efficacy of 26nt-CpG and 30nt-CpG. Results: On the 15th day post-dosing, the tumor growth inhibition rate (TGI) was 79.9% (P<0.001), resulting in a 73.7% increase in survival rate. LNP-delivered 26nt-CpG demonstrated a TGI rate of 75.4% (P<0.001), while 30nt-CpG showed a TGI of 81.9% (P<0.001). Interestingly, the 26nt-CpG group exhibited faster weight gain, indicating better safety. In the mouse B16 melanoma model, LNP-delivered 26nt-CpG achieved a TGI rate of 75.2% (P<0.001), slightly higher than 30nt-CpG (71.0%, P<0.001), and also resulted in faster weight gain. Conclusion: In conclusion, the use of LNP-delivered Toll-like receptor agonists demonstrated excellent tumor therapeutic effects and good safety in mouse models. Activation of Toll-like receptors effectively stimulated immune cells such as CD8+ T cells and NK cells, enhancing their ability to kill tumor cells. Direct injection of LNPs into the tumor improved this effect while reducing systemic side effects. This drug holds promise as a broad-spectrum anti-tumor treatment and may have potential for expanding the indications of existing tumor immunotherapies. Citation Format: Jun Bai, Fei Su, Chen Li, Yujing Wu, Jing Li, Xiaobin Zhao, Yongsheng Yang, Robert J Lee. Lipid nanoparticle-delivered toll-like receptor agonists are highly effective in cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B049.

Abstract C146: VIC-1911, a selective Aurora kinase A inhibitor, synergizes with sacituzumab govitecan in triple-negative breast cancer

Abstract BACKGROUND: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases and 30-40% of U.S. breast cancer deaths. Although current precision treatments improve TNBC patient outcomes, TNBC heterogeneity has led to therapeutic targeting challenges. Also, the resistance of TNBC to conventional treatment remains a significant clinical problem. Therefore, informed evaluation of new targets can improve the treatment of TNBC, representing an unmet need. Dysregulation of the cell cycle is a hallmark of cancer for unlimited proliferation. Abnormal mitosis and cell-cycle checkpoints are crucial in leading to aneuploidy and genetic instability. Aurora kinase A (AURKA), a serine/threonine kinase, regulates mitosis in the early stages (G2/M phase) by regulating centrosome maturation and disjunction, thereby establishing a bipolar mitotic spindle. VIC-1911 (previously known as TAS-119), a novel, orally active, highly selective inhibitor of AURKA with a low toxicity profile, suppresses the growth of various cancer cell lines in vitro and in vivo. As AURKA can modulate DNA damage response, we hypothesized that VIC-1911 combined with sacituzumab govitecan (SG), which has a topoisomerase 1 inhibitor as a payload, has a synergistic antitumor effect on TNBC. MATERIALS AND METHODS: To evaluate the short-term in vitro efficacy of VIC-1911 alone and combination with SG, a sulforhodamine B cell proliferation assay was performed using 10 TNBC cell lines. For long-term treatment conditions, a colony formation assay was conducted. Western blot and immunofluorescent analyses were conducted to confirm treatment-mediated DNA damage and apoptosis. Human TNBC cell line–derived mammary fat pad xenograft models were used to evaluate the antitumor effect of VIC-1911 and SG. RESULTS: In vitro proliferation, data demonstrated that single-agent VIC-1911 had a nanomolar to micromolar range of half-maximal inhibitory concentrations (2.69 nM to 10.6 mM) in the tested TNBC cell lines. The half-maximal inhibitory concentration was correlated with c-Myc expression (R2=0.4876, p=0.0247). Exposure to the combination of VIC-1911 and SG led to significant death of VIC-1911–sensitive TNBC cell lines (p<0.05). Western blot and immunofluorescent analysis revealed that VIC-1911 and SG combination caused TNBC cell death by inducing expression of phosphorylated histone H2AX (DNA damage marker) and cleaved poly (ADP-ribose) polymerase (apoptosis marker). Furthermore, the combination of VIC-1911 and SG had significantly greater antitumor efficacy than did either agent alone in SUM149 TNBC xenograft models (tumor growth inhibition rate (TGI): VIC-1911, 61.4%; SG, 68.3%; combination, 82.9%; p<0.01) and HCC1806 TNBC xenograft models (TGI: VIC-1911, 49.3%; SG, 66.3%; combination, 85.9%; p<0.01). CONCLUSION: The AURKA inhibitor VIC-1911 has a synergistic antitumor effect with SG by inducing DNA damage in TNBC cells. PDX and additional mechanistic studies are planned to further evaluate VIC-1911 and SG as novel combination therapy for TNBC. Citation Format: Jangsoon Lee, YoungJin Gi, Thomas Myers, Linda Paradiso, Debu Tripathy, Naoto T. Ueno. VIC-1911, a selective Aurora kinase A inhibitor, synergizes with sacituzumab govitecan in triple-negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C146.

Abstract A174: Antitumor activity of lipid nanoparticle-delivered anti-miR-21

Abstract Background: MicroRNAs (miRNAs) are small non-coding RNA molecules that play crucial roles in various biological processes, such as growth, development, aging, and apoptosis. Several studies have shown that miRNAs, including miR-21, can function as either oncogenes or tumor suppressor genes, influencing tumor initiation and progression. Aberrant expression of miR-21 has been observed in different cancer cells, indicating its significant involvement as an oncogenic miRNA in the development of various types of tumors. Antisense oligonucleotides (ASOs) have been identified as effective tools for downregulating target genes by either triggering RNase H endonuclease activity to cleave the ASO-target gene heteroduplex or by interfering with splicing and translation regulation of the target RNA sequence. ASOs have the potential to target not only mRNA but also oligonucleotides like miRNAs or small interfering RNAs (siRNAs), making them a promising approach for miRNA inhibition. However, the efficient delivery of freely circulating ASOs to the tumor microenvironment poses a challenge due to their high density of negative charges, impeding cell uptake. To address this issue, a novel lipid nanoparticle (LNP) platform called QTsome has been developed, which combines quaternary amine cationic lipids and tertiary amine ionizable lipids to enhance drug delivery. The utilization of a mixture of cationic and ionizable lipids in QTsome allows for optimal pH-dependent drug loading and release characteristics. In this study, our objective was to employ the QTsome system to deliver an ASO targeting miR-21 (AM-21) for potential tumor therapy. Methods: A total of 8E6 A549 cells were inoculated into mice, and when the tumor volume reached 100mm3, the mice were randomly divided into seven groups based on tumor volume, with each group consisting of five mice.On the day of grouping, drug administration was initiated with the following doses: 1mg/kg, every 3 days (Q3D); 2mg/kg, Q3D; 3mg/kg, Q3D; 4mg/kg, Q3D; 4mg/kg, every 4 days (Q4D); 4mg/kg, every 5 days (Q5D); 4mg/kg, every 7 days (Q7D). The drugs were administered a total of 5 times. Additionally, the A549/MC38 model was constructed using the same method. The antitumor activity of the drug and its therapeutic effect in combination with Erlotinib were evaluated in both the A549 CDX and MC38 syngeneic mouse models through intravenous injection, with a dose of 4mg/kg, Q3D. Results: The study revealed that the optimal dose for achieving the maximum antitumor effect was 4mg/kg, administered 3 times per day. In the A549 model, the tumor growth inhibition rates were 71.91%, 60.93%, and 80.44% for the AM-21/QTsome group, Erlotinib group, and the combination of AM-21/QTsome and Erlotinib group, respectively. In the MC38 mouse model, the tumor inhibition rate of AM-21/QTsome was 33.29%. Conclusion: These results emphasize the potential of miR-21 as a therapeutic target for cancer treatment, demonstrating that AM-21/QTsome holds great promise as a groundbreaking drug in this field. Citation Format: Jing Li, Qiaofang Ma, Xinyue Zhang, Xiaojie Chen, Jialiang Lin, Jun Bai, Fei Su, Xiaobin Zhao, Robert J. Lee, Yongsheng Yang. Antitumor activity of lipid nanoparticle-delivered anti-miR-21 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A174.

Discovery and bioassay of disubstituted β-elemene-NO donor conjugates: synergistic enhancement in the treatment of leukemia

Natural products are essential sources of antitumor drugs. One such molecule, β-elemene, is a potent antitumor compound extracted from Curcuma wenyujin. In the present investigation, a series of novel 13,14-disubstituted nitric oxide (NO)-donor β-elemene derivatives were designed, with β-elemene as the foundational compound, and subsequently synthesized to evaluate their therapeutic potential against leukemia. Notably, the derivative labeled as compound 13d demonstrated a potent anti-proliferative activity against the K562 cell line, with a high NO release. In vivo studies indicated that compound 13d could effectively inhibit tumor growth, exhibiting no discernible toxic manifestations. Specifically, a significant tumor growth inhibition rate of 62.9% was observed in the K562 xenograft tumor mouse model. The accumulated data propound the potential therapeutic application of compound 13d in the management of leukemia.

The triple-drug combination DBDx enhances the antitumor efficacy of PD-1 antibody associated with Treg modulation.

This study investigated the antitumor efficacy of programmed cell death protein-1 (PD-1) antibody and DBDx, a triple-drug combination of dipyridamole, bestatin, and dexamethasone, and their related immunomodulation. Mouse melanoma B16, mouse Lewis lung carcinoma, and mouse breast carcinoma 4T1 were used for evaluating the in vivo therapeutic efficacy of DBDx, PD-1 antibody, and their combination. The peripheral blood and tumor tissues of 4T1 tumor-bearing mice were collected to analyze regulatory T cells and measured using flow cytometry. The combination of PD-1 antibody and DBDx enhanced the therapeutic efficacy against B16 melanoma. The suppression of tumor growth by PD-1 antibody and DBDx was more significant than that by anti-PD-1 monotherapy. The tumor growth inhibition rates of PD-1 antibody, DBDx, and their combination were 54.0%, 72.4%, and 83.1%, respectively, suggesting a synergistic effect as determined by the coefficient of drug interaction. No significant changes were found in the body weights in all the above groups, indicating that the treated mice tolerated the applied drug doses. Similarly, enhanced therapeutic efficacy of the PD-1 antibody and DBDx combination was observed in murine Lewis lung carcinoma and 4T1 breast cancer models. In 4T1 breast cancer-bearing mice, the immunotherapy-related changes in lymphocytes in peripheral blood and tumor microenvironment were evaluated with flow cytometry. Compared with anti-PD-1 monotherapy, peripheral blood and tumor-infiltrating lymphocytes were found a lower ratio of regulatory T cell (Treg) subset cells and a higher ratio of CD8+/Treg cells. The combination of PD-1 antibody and DBDx could achieve enhanced therapeutic antitumor efficacy than anti-PD-1 monotherapy, suggesting potential for using the triple-drug combination DBDx in cancer immunotherapy.

Design, synthesis, and biological evaluation of 4-(2-fluorophenoxy)-7-methoxyquinazoline derivatives as dual EGFR/c-Met inhibitors for the treatment of NSCLC

In non-small cell lung cancer (NSCLC) treatment, aberrant expression of c-mesenchymal-epithelial transition factor (c-Met) has been identified as a driving factor in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. Unfortunately, none of the EGFR/c-Met dual-target inhibitors have successfully passed clinical trials. Hence, based on molecular docking analysis and combination principles of EGFR and c-Met inhibitors, three series of 4-(2-fluorophenoxy)-7-methoxyquinazoline derivatives as new EGFR/c-Met inhibitors were designed, synthesized, and evaluated for their biological activities. Among these compounds, TS-41 displayed the best inhibitory activity against EGFRL858R and c-Met kinases, with an IC50 value of 68.1 nM and 0.26 nM respectively. Moreover, it also showed excellent inhibitory activity on three NSCLC cell lines A549−P, H1975 and PC-9 with IC50 values ranging from 1.48 to 2.76 μM. Flow cytometry assays demonstrated that TS-41 induced apoptosis and cell cycle arrest of A549−P cells in a concentration-dependent manner, corresponding to JC-1 staining assay results. Western blot analysis revealed that TS-41 significantly downregulated the phosphorylation of EGFR, c-Met, and downstream AKT at molecular level. Importantly, TS-41 exhibited potent in vivo anticancer efficacy in an A549−P-bearing allograft nude mouse model at a dose of 60 mg/kg with a tumor growth inhibition rate of 55.3 % compared with Afatinib (46.4 %), as well as low hemolytic toxicity and organ toxicity. Molecular docking results showed that TS-41 was well embedded into the cavity of EGFR (PDB: 5GMP) and c-Met (PDB: 3LQ8) proteins, respectively. In summary, TS-41 is a high-efficiency and low-toxicity EGFR/c-Met inhibitor for the treatment of NSCLC and is worthy of further exploration.

Light dose effect of photodynamic therapy on growth inhibition and apoptosis induction in non-small cell lung cancer: A study in nude mouse model

BackgroundPhotodynamic therapy (PDT) is receiving increasing attention in treating non-small cell lung cancer (NSCLC) worldwide, but in clinical practice, the relationship between treatment effect and PDT light dose in NSCLC remains unclear. Therefore, we aimed to determine the optimal light dose for PDT by exploring molecular biomarkers and evaluating tumor growth data. MethodsWe applied bioinformatics to identify promising genes and pathways in NSCLC and PDT. Then, the human lung adenocarcinoma cell line A549-bearing BALB/c nude mice were treated with hematoporphyrin derivative (HPD, 3 mg/kg) that is currently used widely for lung cancer treatment in the world even with photosensitization issues. After 48 h, tumor-bearing mice were irradiated superficially at doses of 100, 200, 300, 400, and 500 J/cm2. The tumor growth data and apoptotic molecules were assessed and calculated. ResultsBioinformatics results indicated that the apoptosis pathway was significantly enriched and caspase 3 was the most promising biomarker on prognosis in NSCLC-PDT. Compared to the untreated group, there was no difference in the relative tumor volume (RTV) of the 100 J/cm2 group, while the RTV of the other treatment groups (200–500 J/cm2) was significantly lower. In the 100 J/cm2 group, there were significant differences in the complete remission (CR, 0 %) and the percentage of tumor growth inhibition rate (TGI%) over 75 % (20 %) compared with the other treatment groups, especially the 300 and 400 J/cm2 groups (CR 70 %; TGI% 90 %). In the 300 and 400 J/cm2 groups, the expression of caspase 3, cleaved-caspase 3, PARP1, and Bax was increased significantly, while Bcl-2 expression was significantly lower. ConclusionsModerate doses of PDT (300 or 400 J/cm2) are more effective than low (100 or 200 J/cm2) or high doses (500 J/cm2) in the A549 tumor-bearing mice model. Since the A549 tumor is more akin to human tumors in pathological behavior, these experimental data may contribute to improving HPD-PDT illumination protocols for favorable clinical outcomes.

Safety assessment, radioiodination and preclinical evaluation of antinuclear antibody as novel medication for prostate cancer in mouse xenograft model

This study aims to provide in vitro and in vivo data to support the utilization of antinuclear antibodies (ANAs) as novel tools for the diagnosis and treatment of prostate cancers. The hematological, biochemical, and histological toxicities of ANAs were assessed at the doses of 5 and 50 μg per mouse. Radiolabeling study was then conducted with ANA and 131I using the chloramine T method, and the biodistribution and treatment efficacy were subsequently investigated in a PC3 xenograft model. No changes in clinical behavior or signs of intoxication, necrosis, or malignancy were observed in ANA-treated mice. 131I-ANA was obtained in very high yield and radiochemical purity, at 94.97 ± 0.98% and 98.56 ± 0.29%, respectively. They achieved immunoreactivity fraction of 0.841 ± 0.17% with PC-3 cells. Levels of radiolabeled ANAs were 1.15–10.14 times higher in tumor tissues than in other examined organs at 24 h post-injection. The tumor growth inhibition rates were 28.33 ± 5.01% in PC3 xenografts mice treated with 131I-ANAs compared with controls and a nearly twofold improvement in median survival was observed. These results demonstrate that radioimmunotherapy of radiolabeled natural ANAs may be an effective treatment for prostate tumors.

Design, synthesis and biological evaluation of novel dihydroquinolin-4(1H)-one derivatives as novel tubulin polymerization inhibitors

A series of novel dihydroquinolin-4(1H)-one derivatives targeting colchicine binding site on tubulin were designed, synthesized and evaluated as anticancer agents. The most potent compound 6t showed remarkable antiproliferative activities against four cancer cell lines with IC50 values among 0.003–0.024 μM and tubulin polymerization inhibitory activity (IC50 = 3.06 μM). Further mechanism studies revealed that compound 6t could induce K562 cells apoptosis and arrest at the G2/M phase. Meanwhile, 6t significantly inhibited migration and invasion of MDA-MB-231 cells, and disrupted the angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro. In addition, compound 6t inhibited tumor growth in H22 allograft tumor model with a tumor growth inhibition (TGI) rate of 63.3 % (i.v., 20 mg/kg per day) without obvious toxicity. Collectively, these results indicated that compound 6t was a novel tubulin polymerization inhibitor with potent anticancer properties in vitro and in vivo.

Modification of osimertinib to discover new potent EGFRC797S-TK inhibitors

The EGFRC797S mutation is a dominant mechanism of acquired resistance after the treatment of non-small cell lung cancer (NSCLC) with osimertinib in clinic. To date, there is no inhibitor approved to overcome the resistance caused by osimertinib. In this study, a series of compounds with phenylamino-pyrimidine scaffold deriving from osimertinib were designed, synthesized and evaluated as fourth-generation EGFRC797S-TK inhibitors. Consequently, compound Os30 exhibited potent inhibitory activities against both EGFRDel19/T790M/C797S TK and EGFRL858R/T790M/C797S TK with IC50 values of 18 nM and 113 nM, respectively. Moreover, Os30 can powerfully inhibit the proliferation of KC-0116 (BaF3-EGFRDel19/T790M/C797S) and KC-0122 (BaF3-EGFRL858R/T790M/C797S) cells. In addition, Os30 can suppress EGFR phosphorylation in a concentration-dependent manner in KC-0116 cells, arrest KC-0116 cells at G1 phase and induce the apoptosis of KC-0116 cells. More importantly, Os30 showed potent antitumor efficacy in the KC-0116 cells xenograft nude mice tumor model with the tumor growth inhibitory rate of 77.6% at a dosage of 40 mg/kg. These findings demonstrate that modification of osimertinib can discover new potent EGFRC797S-TK inhibitors, and compound Os30 is a potent fourth-generation EGFR inhibitor to treat NSCLC with EGFmRC797S mutation.

Discovery of highly potent and selective KRASG12C degraders by VHL-recruiting PROTACs for the treatment of tumors with KRASG12C-Mutation

Although several covalent KRASG12C inhibitors have made great progress in the treatment of KRASG12C-mutant cancer, their clinical applications are limited by adaptive resistance, motivating novel therapeutic strategies. Through drug design and structure optimization, a series of highly potent and selective KRASG12C Proteolysis Targeting Chimeras (PROTACs) were developed by incorporating AMG510 and VHL ligand VH032. Among them, degrader YN14 significantly inhibited KRASG12C-dependent cancer cells growth with nanomolar IC50 and DC50 values, and ＞ 95 % maximum degradation (Dmax). Molecular dynamics (MD) simulation showed that YN14 induced a stable KRASG12C: YN14: VHL ternary complex with low binding free energy (ΔG). Notably, YN14 led to tumor regression with tumor growth inhibition (TGI%) rates more than 100 % in the MIA PaCa-2 xenograft model with well-tolerated dose-schedules. We also found that KRASG12C degradation exhibited advantages in overcoming adaptive KRASG12C feedback resistance over KRASG12C inhibition. Furthermore, combination of RTKs, SHP2, or CDK9 inhibitors with YN14 exhibited synergetic efficacy in KRASG12C-mutant cancer cells. Overall, these results demonstrated that YN14 holds exciting prospects for the treatment of tumors with KRASG12C-mutation and boosted efficacy could be achieved for greater clinical applications via drug combination.

Asymmetric A‐DA′D‐A′′ Molecular Configuration Type‐I Photosensitizer with Two Complementary Reactive Oxygen Species for Efficient Imaging and Photodynamic Therapy

AbstractType‐I photosensitizers (PSs) can efficiently generate reactive oxygen species (ROS) in the hypoxia condition of tumors, which show less oxygen dependence and are considered better candidates for photodynamic therapy (PDT). However, relatively few efficient type‐I organic PSs simultaneously generating two or more type‐I ROS under irradiation are reported. Herein, new alternate donor (D)‐acceptor (A) type molecules containing ladder‐type core (DA′D) fused with an electron‐deficient benzothiadiazole core are reported, which show symmetrical A‐DA′D‐A (QY1) and asymmetrical A‐DA′D‐A′′ (QY2) configurations, respectively. As these ROSs possess complementary properties of strong oxidizing ability (•OH) and long radical lifetime (O2•−), in vitro and in vivo experiments demonstrate that QY1 and QY2 show excellent PDT effects for tumor cells under normoxia or hypoxia, and can achieve remarkable tumor growth inhibition (TGI) rate of 90% for the QY2. More importantly, the generation of •OH in these PSs is revealed by experiments both in aqueous and in vitro, including the well‐known transformation of O2•− and direct electron transition from water to excited triplet PS. It thus provides a comprehensive understanding of the O2 dependence property of •OH radical and deep insights into the mechanism of type‐I PS.

Proteasome inhibitors reduce CD73 expression partly via decreasing p-ERK in NSCLC cells

Ecto-5'-nucleotidase (CD73), encoded by the NT5E gene, mediates tumor immunosuppression and has been targeted for the development of new anticancer drugs. Proteasome inhibitors impair protein degradation by inhibiting proteasome and have been used in the clinic for cancer therapy. Here we report that proteasome inhibitors reduce the protein and mRNA levels of CD73. Among 127 tested small-molecule drugs, proteasome inhibitors were found to consistently decrease the protein and mRNA levels of CD73 in NSCLC NCI-H1299 cells. This effect was further confirmed in different NSCLC cells exposed to different proteasome inhibitors. In those treated cells, the protein levels of ERK and its active form p-ERK, the vital components in the MAPK pathway, were reduced. Consistently, inhibitors of MEK and ERK, another two members of the MAPK pathway, also lowered the protein and mRNA levels of CD73. Correspondingly, treatments with fibroblast growth factor 2 (FGF2), an activator of the MAPK pathway, enhanced the levels of p-ERK and partly rescued the proteasome inhibitor-driven reduction of CD73 mRNA and protein in NSCLC cells. However, exogenous CD73 overexpression in murine Lewis lung carcinoma (LLC) cells was not lowered either in vitro or in vivo, by the treatments with proteasome inhibitors and basically, did not affect their in vitro proliferative inhibition either. In contrast, CD73 overexpression dramatically reduced the in vivo anticancer activity of Bortezomib in immunocompetent mice, with tumor growth inhibition rates from 52.18 % for LLC/vector down to 8.75 % for LLC/NT5E homografts. These findings give new insights into the anticancer mechanisms of proteasome inhibitors.

Rational design of β-carboline as an efficient type I/II photosensitizer to enable hypoxia-tolerant chemo-photodynamic therapy

Photodynamic therapy (PDT) is a clinically approved treatment for cancer due to its high spatiotemporal selectivity and non-invasive modality. However, its therapeutic outcomes are always limited to the severe hypoxia environment of the solid tumor. Herein, two novel photosensitizers HY and HYM based on naturally antitumor alkaloids β-carboline were designed and synthesized. Through a series of experiments, we found HY and HYM can produce type II ROS (singlet oxygen) after light irradiation. HYM had higher singlet oxygen quantum yield and molar extinction coefficient than HY, as well as type I PDT behavior, which further let us find that HYM could exhibit robust phototoxicity activities in both normoxia and hypoxia. Meanwhile, HYM showed tumor-selective cytotoxicity with minimal toxicity toward normal cells. Notably, thanks to HYM's hypoxia-tolerant type I/II PDT and tumor selective chemotherapy, HYM showed synergistic inhibitory effect on tumor growth (inhibition rate > 91%). Our research provides a promising photosensitizer for hypoxia-tolerant chemo-photodynamic therapy, and may also give a novel molecular skeleton for photosensitizer design.

Positive Chemotaxis of CREKA-Modified Ceria@Polydopamine Biomimetic Nanoswimmers for Enhanced Penetration and Chemo-photothermal Tumor Therapy.

Tumor interstitial pressure represents the greatest barrier against drug diffusion into the depth of the tumor. Biometric nanomotors highlight the possibility of enhanced deep penetration and improve cellular uptake. However, control of their directionality remains difficult to achieve. Herein, we report cysteine-arginine-glutamic acid-lysine-alanine (CREKA)-modified ceria@polydopamine nanobowls as tumor microenvironment-fueled nanoscale motors for positive chemotaxis into the tumor depth or toward tumor cells. Upon laser irradiation, this nanoswimmer rapidly depletes the tumor microenvironment-specific hydrogen peroxide (H2O2) in the nanobowl, contributing to a self-generated gradient and subsequently propulsion (9.5 μm/s at 46 °C). Moreover, the asymmetrical modification of CREKA on nanobowls could automatically reconfigure the motion direction toward tumor depth or tumor cells in response to receptor-ligand interaction, leading to a deep penetration (70 μm in multicellular spheroids) and enhanced antitumor effects over conventional nanomedicine-induced chemo-photothermal therapy (tumor growth inhibition rate: 84.2% versus 56.9%). Thus, controlling the direction of nanomotors holds considerable potential for improved antitumor responses, especially in solid tumors with high tumor interstitial pressure.