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Updated: May 29, 2026
Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice
Published on: January 19, 2018
Effects of the novel vascular targeting agent MDS-11P on tumor vascularity and its antitumor activity
Zhi-Ting Deng1, Teng Feng, Peng Wang
1Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Abstract:
Vascular disrupting agents show selective effects on tumor established vasculature, and achieve encouraging results in both pre-clinical and clinical experiments. In the present study, we investigated the effects of a new CA4 derivative MDS-11 and its prodrug MDS-11P on vascular disrupting activity in vitro and in vivo. Surface plasmon resonance (SPR) and tubulin polymerization assay showed that MDS-11 interacted with tubulin directly and inhibited tubulin polymerization in a cell free system, and western blot assay further confirmed the action in the cellular level. MDS-11 was found to significantly disrupt the microtubulin skeleton in proliferating HUVECs than quiescent ones determined by confocal microscopy. Furthermore, MDS-11 was found to damage the HUVEC-formed tube quickly, but did not influence structures of microvessels from aortic ring possessing pericytes and smooth muscle cells until 3 h treatment. In A549 xenograft mice, immunohistochemistry staining of tumor sections revealed that a single dose of MDS-11P led to large areas of necrosis within tumor and reduced the number of tumor vessels, which was consolidated by perfused vascular volume assay. Pharmacokinetic studies of MDS-11P indicated that MDS-11P rapidly converted to the active form, MDS-11, and exhibited a much faster elimination in mice. The antitumor analysis using H22 and A549 mice xenograft models revealed that the growth inhibition rates of MDS-11P at 50 mg/kg (twice a day for three weeks) reached 59.4%, 60.5% respectively without obvious weight loss. Taken together, these results suggest that MDS-11 is a potential vascular disrupting agent for further development of antitumor drug.
Insights
A new vascular disrupting agent, MDS-11, and its prodrug MDS-11P, show promise for cancer treatment. They target tumor vasculature, inhibit tubulin polymerization, and effectively reduce tumor growth in preclinical models without significant toxicity.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Vascular disrupting agents (VDAs) selectively target tumor vasculature.
- CA4 derivatives have shown potential in preclinical and clinical settings.
Purpose of the Study:
- To investigate the in vitro and in vivo vascular disrupting activity of a novel CA4 derivative, MDS-11, and its prodrug, MDS-11P.
- To evaluate the potential of MDS-11 and MDS-11P as antitumor agents.
Main Methods:
- Surface plasmon resonance (SPR) and tubulin polymerization assays to assess tubulin interaction.
- Western blot and confocal microscopy to evaluate effects on HUVECs (human umbilical vein endothelial cells).
- A549 xenograft mouse models for in vivo efficacy, necrosis, and vascularization assessment; pharmacokinetic studies.
Main Results:
- MDS-11 directly interacts with tubulin, inhibiting polymerization in vitro and disrupting microtubule structure in proliferating HUVECs.
- MDS-11P rapidly converts to MDS-11 in vivo, causing tumor necrosis and reducing tumor vascularization in A549 xenografts.
- MDS-11P demonstrated significant antitumor activity in H22 and A549 models with high growth inhibition rates and no obvious weight loss.
Conclusions:
- MDS-11 exhibits potent vascular disrupting and antitumor properties by targeting tubulin.
- MDS-11P is a promising prodrug that effectively delivers MDS-11 for cancer therapy.
- MDS-11 represents a potential VDA candidate for further preclinical and clinical development.
