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Vascular disrupting agent induced aggregation of gold nanoparticles for photothermally enhanced tumor vascular disruption.

ABSTRACT: Although vascular disrupting agents (VDAs) have been extensively implemented in current clinical tumor therapy, the notable adverse events caused by long-term dosing severely limit the therapeutic efficacy. To improve this therapy, we report a strategy for VDA-induced aggregation of gold nanoparticles to further destroy tumor vascular by photothermal effect. This strategy could effectively disrupt tumor vascular and cut off the nutrition supply after just one treatment. In the murine tumor model, this strategy results in notable tumor growth inhibition and gives rise to a 92.7% suppression of tumor growth. Besides, enhanced vascular damage could also prevent cancer cells from distant metastasis. Moreover, compared with clinical therapies, this strategy still exhibits preferable tumor suppression and metastasis inhibition ability. These results indicate that this strategy has great potential in tumor treatment and could effectively enhance tumor vascular damage and avoid the side effects caused by frequent administration.

SUBMITTER: Hong S

PROVIDER: S-EPMC7274768 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Vascular disrupting agent induced aggregation of gold nanoparticles for photothermally enhanced tumor vascular disruption.

Hong Sheng S Zheng Di-Wei DW Zhang Cheng C Huang Qian-Xiao QX Cheng Si-Xue SX Zhang Xian-Zheng XZ

Science advances 20200605 23

Although vascular disrupting agents (VDAs) have been extensively implemented in current clinical tumor therapy, the notable adverse events caused by long-term dosing severely limit the therapeutic efficacy. To improve this therapy, we report a strategy for VDA-induced aggregation of gold nanoparticles to further destroy tumor vascular by photothermal effect. This strategy could effectively disrupt tumor vascular and cut off the nutrition supply after just one treatment. In the murine tumor model ...[more]

PMID: 32548273

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Project description:Surgery, radiation and chemotherapy remain the mainstay of current cancer therapy. However, treatment failure persists due to the inability to achieve complete local control of the tumor and curtail metastatic spread. Vascular disrupting agents (VDAs) are a class of promising systemic agents that are known to synergistically enhance radiation, chemotherapy or thermal treatments of solid tumors. Unfortunately, there is still an unmet need for VDAs with more favorable safety profiles and fewer side effects. Recent work has demonstrated that conjugating VDAs to other molecules (polyethylene glycol, CNGRCG peptide) or nanoparticles (liposomes, gold) can reduce toxicity of one prominent VDA (tumor necrosis factor alpha, TNF-?). In this report, we show the potential of a gold conjugated TNF-? nanoparticle (NP-TNF) to improve multimodal cancer therapies with VDAs. In a dorsal skin fold and hindlimb murine xenograft model of prostate cancer, we found that NP-TNF disrupts endothelial barrier function and induces a significant increase in vascular permeability within the first 1-2 h followed by a dramatic 80% drop in perfusion 2-6 h after systemic administration. We also demonstrate that the tumor response to the nanoparticle can be verified using dynamic contrast-enhanced magnetic resonance imaging (MRI), a technique in clinical use. Additionally, multimodal treatment with thermal therapies at the perfusion nadir in the sub- and supraphysiological temperature regimes increases tumor volumetric destruction by over 60% and leads to significant tumor growth delays compared to thermal therapy alone. Lastly, NP-TNF was found to enhance thermal therapy in the absence of neutrophil recruitment, suggesting that immune/inflammatory regulation is not central to its power as part of a multimodal approach. Our data demonstrate the potential of nanoparticle-conjugated VDAs to significantly improve cancer therapy by preconditioning tumor vasculature to a secondary insult in a targeted manner. We anticipate our work to direct investigations into more potent tumor vasculature specific combinations of VDAs and nanoparticles with the goal of transitioning optimal regimens into clinical trials.

Project description:Anti-programmed cell death protein 1 (PD-1) therapy has shown promising efficacy in hepatocellular carcinoma (HCC), but its response rates in advanced HCC are lower than 20%. A critical reason for this is the imbalance between CD8+ T cells and tumor burden. Here, a novel concept of vascular disruption and normalization dependent on a polymeric vascular disrupting agent (VDA) poly (L-glutamic acid)-graft-methoxy poly (ethylene glycol)/combretastatin A4 (CA4-NPs) + a vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) inhibitor DC101 is applied to improve anti-PD-1 therapy, wherein CA4-NPs reduce tumor burden and DC101 simultaneously increases the number of intratumoral CD8+ T cells, successfully regulating the abovementioned imbalance in an H22 tumor model. Methods: Blood vessel density, tumor cell proliferation, and necrosis were evaluated to reveal the effects on reducing tumor burden by CA4-NP treatment. Pericyte coverage of blood vessels, tumor blood vessel perfusion, tumor hypoxia, and intratumoral immune cells were examined to verify their role in vascular normalization and immune cell homing of DC101. Furthermore, the effects of CA4-NPs + DC101 on reducing tumor burden and increasing the number of immune cells were studied. Finally, tumor suppression, intratumoral CD8+ T cell activation, and the synergistic effects of anti-PD-1 combined with CA4-NPs + DC101 were verified. Results: The tumor inhibition rate of anti-PD-1 antibody combined with CA4-NPs + DC101 reached 86.4%, which was significantly higher than that of anti-PD-1 (16.8%) alone. Importantly, the Q value reflecting the synergy between CA4-NPs + DC101 and anti-PD-1 was 1.24, demonstrating a strong synergistic effect. Furthermore, CA4-NPs + DC101 improved anti-PD-1 therapy by increasing the number of intratumoral CD8+ T cells (anti-PD-1, 0.31% vs triple drug combination, 1.18%). Conclusion: These results reveal a novel approach to enhance anti-PD-1 therapy with VDAs + VEGF/VEGFR2 inhibitors in HCC.

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Vascular disrupting agent induced aggregation of gold nanoparticles for photothermally enhanced tumor vascular disruption.

Publications

Vascular disrupting agent induced aggregation of gold nanoparticles for photothermally enhanced tumor vascular disruption.

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