Identification of bioactive anti-angiogenic components targeting tumor endothelial cells in Shenmai injection using multidimensional pharmacokinetics

Zhong, Chongjin; Jiang, Chao; Ni, Suiying; Wang, Qizhi; Cheng, Lan; Wang, Huan; Zhang, Qixiang; Liu, Wenyue; Zhang, Jingwei; Liu, Jiali; Wang, Mu-Lan; Jin, Min; Shen, Pei-Qiang; Yao, Xuequan; Wang, Guangji; Zhou, Fang

doi:10.1016/j.apsb.2019.12.011

Cited by 29 publications

(15 citation statements)

References 55 publications

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“…In addition, mild hyperthermia can increase blood perfusion and oxygen supply, which also promotes blood vessel normalization 34 . The abnormal structure of tumor vessels, characterized by the high density of vessels and poor pericyte coverage, leads to various malignant outcomes in the tumor microenvironment, such as tumor metastasis and immunosuppression 35 , 36 . Tumor vessel normalization can enhance the delivery of drugs and the infiltration of lymphocytes to improve the treatment efficacy 37 , 38 .…”

Section: Resultsmentioning

confidence: 99%

Magnetism-mediated targeting hyperthermia-immunotherapy in “cold” tumor with CSF1R inhibitor

Fang

et al. 2021

Theranostics

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Background: Immunotherapy has profoundly changed the landscape of cancer management and represented the most significant breakthrough. Yet, it is a formidable challenge that the majority of cancers - the so-called “cold” tumors - poorly respond to immunotherapy. To find a general immunoregulatory modality that can be applied to a broad spectrum of cancers is an urgent need. Methods: Magnetic hyperthermia (MHT) possesses promise in cancer therapy. We develop a safe and effective therapeutic strategy by using magnetism-mediated targeting MHT-immunotherapy in “cold” colon cancer. A magnetic liposomal system modified with cell-penetrating TAT peptide was developed for targeted delivery of a CSF1R inhibitor (BLZ945), which can block the CSF1-CSF1R pathway and reduce M2 macrophages. The targeted delivery strategy is characterized by its magnetic navigation and TAT-promoting intratumoral penetration. Results: The liposomes (termed TAT-BLZmlips) can induce ICD and cause excessive CRT exposure on the cell surface, which transmits an “eat-me” signal to DCs to elicit immunity. The combination of MHT and BLZ945 can repolarize M2 macrophages in the tumor microenvironment to relieve immunosuppression, normalize the tumor blood vessels, and promote T-lymphocyte infiltration. The antitumor effector CD8 + T cells were increased after treatment. Conclusion: This work demonstrated that TAT-BLZmlips with magnetic navigation and MHT can remodel tumor microenvironment and activate immune responses and memory, thus inhibiting tumor growth and recurrence.

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Section: Resultsmentioning

confidence: 99%

Magnetism-mediated targeting hyperthermia-immunotherapy in “cold” tumor with CSF1R inhibitor

Fang

et al. 2021

Theranostics

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“…Delicaflavone was widely distributed, with a large apparent distribution volume (585.74, 697.10, and 761.09 L/kg) and extensive clearance (127.99, 173.34, and 201.91 L/h/kg) at three oral doses, respectively. It was inferred that the rapid and extensive biotransformation of DF in rats might be the main cause of the low bioavailability of DF after oral administration ( Wang et al, 2014 ; Zhong et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Tissue Distribution, and Human Serum Albumin Binding Properties of Delicaflavone, a Novel Anti-Tumor Candidate

et al. 2021

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Delicaflavone (DF), a natural active ingredient from Selaginella doederleinii Hieron, has been reported to have favorable anticancer effects and is thus considered a potential anticancer agent. However, its pharmacokinetics and plasma protein binding properties remain unknown. Here, we investigated the pharmacokinetic profile of DF in rats using a validated HPLC-MS/MS methods, as well as its human serum albumin (HSA) binding properties through multi-spectroscopic and in silico methods. The results showed that DF was rapidly eliminated and had a widespread tissue distribution after intravenous administration. DF showed linear dynamics in the dose range of 30–60 mg/kg and poor oral bioavailability. The major distribution tissues of DF were the liver, lungs, and kidneys. Ultraviolet and fluorescence spectroscopy and molecular docking demonstrated that DF had a static quenching effect on HSA, with one binding site, and relatively strong binding constants. Thermodynamic analysis of the binding data revealed that hydrogen bonding and van der Waals interactions played major roles in binding. The results of this study further our understanding of the pharmacokinetic and plasma protein binding properties of the potential anticancer agent DF and shed light on pharmacological strategies that may be useful for the development of novel cancer therapeutics.

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“…Xenograft tumor tissues were collected and fixed overnight in 4% paraformaldehyde and then dehydration with 20% and 30% sucrose, respectively. Tumor tissues were cut into 10 μm sections (free-floating) in a cryostat and processed for immunofluorescence as previously described [ 27 ]. To determine the vessel branches and calculate the tumor microvascular density, the sections were incubated with anti-CD31 (1:100, BD Biosciences, Franklin Lakes, NJ, USA) and α-SMA (1:100, BD Biosciences, Franklin Lakes, NJ, USA) at 4 ℃ overnight and then incubated with Cy5- or Cy2-conjugated secondary antibody (1:200, Jackson ImmunoResearch, West Grove, PA, USA) for 1 h at 37 ℃.…”

Section: Methodsmentioning

confidence: 99%

Sequence-dependent synergistic effect of aumolertinib-pemetrexed combined therapy on EGFR-mutant non-small-cell lung carcinoma with pre-clinical and clinical evidence

Fang

Zhang

et al. 2022

J Exp Clin Cancer Res

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Background Inevitably developed resistance of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) limited its clinical benefit on non-small cell lung cancer (NSCLC). Upfront combination therapy is promising to prevent this resistance. Compelling clinical evidence indicated the failure of third-generation EGFR TKIs combined with either immunotherapy or antiangiogenic agents. In comparison, combined treatment of third-generation EGFR TKIs and chemotherapy might be a favorable choice. Herein, we systematically analyzed and compared the effects of pemetrexed and a novel third-generation EGFR TKI aumolertinib combined in different sequences, subsequently revealed the potential mechanisms and proved the optimal combination schedule with clinical retrospective study. Methods Three combination schedules involving pemetrexed and aumolertinib in different sequences were developed. Their inhibition effects on cell proliferation and metastasis were firstly compared upon three human NSCLC cell lines in vitro, by cell counting kit-8, colony formation, wound healing and transwell assays respectively. Further evaluation in vivo was proceeded upon H1975 and HCC827 xenograft model. Gene and protein expression were detected by Q-PCR and western blot. Drug concentration was determined by LC–MS/MS. VEGF secretion was determined by ELISA. Tumor vessel was visualized by immunofluorescence. Lastly, a clinical retrospective study was raised with 65 patients’ data. Results The combination of pemetrexed and aumolertinib exhibited a sequence-dependent and EGFR mutant-dependent synergistic effect in vitro and in vivo. Only treatment with aumolertinib following pemetrexed (P-A) exhibited synergistic effect with stronger anti-tumor growth and anti-metastasis ability than monotherapy and also other combination sequences. This synergism could exclusively be observed in H1975 and HCC827 but not A549. Pathway analysis showed that P-A significantly enhanced the suppression of EGFR pathway. In addition, our results intriguingly found an obvious reduction of VEGF secretion and the accompanying normalization of the intratumor vessel, consequently increasing intratumoral accumulation of pemetrexed in P-A group. Finally, the clinical retrospective study verified the synergistic effect of P-A combination by significantly superior tumor response than aumolertinib monotherapy. Conclusion Aumolertinib-pemetrexed combined therapy is promising for EGFR mutant NSCLC but only in right administration sequence. P-A could become an advantageous combination strategy in clinical with synergistic inhibition of tumor growth and metastasis.

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Identification of bioactive anti-angiogenic components targeting tumor endothelial cells in Shenmai injection using multidimensional pharmacokinetics

Cited by 29 publications

References 55 publications

Magnetism-mediated targeting hyperthermia-immunotherapy in “cold” tumor with CSF1R inhibitor

Magnetism-mediated targeting hyperthermia-immunotherapy in “cold” tumor with CSF1R inhibitor

Pharmacokinetics, Tissue Distribution, and Human Serum Albumin Binding Properties of Delicaflavone, a Novel Anti-Tumor Candidate

Sequence-dependent synergistic effect of aumolertinib-pemetrexed combined therapy on EGFR-mutant non-small-cell lung carcinoma with pre-clinical and clinical evidence

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