Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis

Mikada, Mamoru; Sukhbaatar, Ariunbuyan; Miura, Yoshinobu; Horie, Seichi; Sakamoto, Maya; Mori, Shiro; Kodama, Tetsuya

doi:10.1111/cas.13206

Cited by 53 publications

(48 citation statements)

References 19 publications

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“…Since LNs have a rich vascular network, 13 tumor cells can develop in them without tumor angiogenesis. 14,15 Thus, hematogenous delivery of macromolecular drugs based on the enhanced permeability and retention effect 16 and normalization of the circulation (ie, improvement of the flow and functions of the vasculature) 17 would not be effective in the treatment of metastatic LNs. In addition, the lymphatic system preferentially takes up large-sized particles and high molecular weight substances.…”

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confidence: 99%

Treatment of false‐negative metastatic lymph nodes by a lymphatic drug delivery system with 5‐fluorouracil

et al. 2019

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Metastatic lymph nodes ( LN s) may be the origin of systemic metastases. It will be important to develop a strategy that prevents systemic metastasis by treating these LN s at an early stage. False‐negative metastatic LN s, which are found during the early stage of metastasis development, are those that contain tumor cells but have a size and shape similar to LN s that do not host tumor cells. Here, we show that 5‐fluorouracil (5‐ FU ), delivered by means of a novel lymphatic drug delivery system ( LDDS ), can treat LN s with false‐negative metastases in a mouse model. The effects of 5‐ FU on four cell lines were investigated using in vitro cytotoxicity and cell survival assays. The therapeutic effects of LDDS ‐administered 5‐ FU on false‐negative metastatic LN s were evaluated using bioluminescence imaging, high‐frequency ultrasound ( US ), and histology in MHX 10/Mo‐ lpr / lpr mice. These experimental animals develop LN s that are similar in size to human LN s. We found that all cell lines showed sensitivity to 5‐ FU in the in vitro assays. Furthermore, a concentration‐dependent effect of 5‐ FU to inhibit tumor growth was observed in tumor cells with low invasive growth characteristics, although a significant reduction in metastatic LN volume was not detected in MHX 10/Mo‐ lpr / lpr mice. Adverse effects of 5‐ FU were not detected. 5‐Fluorouracil administration with a LDDS is an effective treatment method for false‐negative metastatic LN s. We anticipate that the delivery of anticancer drugs by a LDDS will be of great benefit in the prevention and treatment of cancer metastasis via LN s.

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Treatment of false‐negative metastatic lymph nodes by a lymphatic drug delivery system with 5‐fluorouracil

et al. 2019

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“…Two hundred milliliters of ICG liposomes was administered intravenously. The fluorescence intensity of leaked ICG was measured at 0, 5, 30, 60, 120 and 180 minutes after injection using an IVIS; Xenogen, Alameda, CA, USA), as previously described in the literature [25,26].…”

Section: Methodsmentioning

confidence: 99%

The effect of anti-IL-6 receptor antibody for the treatment of McH-lpr/lpr-RA1 mice that spontaneously developed ankylosing arthritis

Izumiyama

Mori

Takeda³

et al. 2018

Preprint

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Abstract[Background]McH-lpr/lpr-RA1 mice are a new strain of mice which spontaneously develop arthritis in the ankle, leading finally to ankylosis. There is no published data that drug treatment has been trialed on these mice.[Objectives]This study examined the effect of the mouse anti-IL-6 receptor antibody, MR16-1, for the treatment of ankylosis in McH-lpr/lpr-RA1 mice.[Methods]Male McH-lpr/lpr-RA1 mice were randomly divided into control and treatment groups. MR16-1 was administered from 10 weeks of age for the treatment group. Saline was applied for the control group. The drug was administered once a week, at an initial dose of 2 mg, then maintained at 0.5 mg once per week thereafter. The effects were evaluated by the histopathological synovitis score, in vivo imaging using indocyanine green liposomes, and analysis of the gene expression of inflammatory cytokines.[Results]Tissue analyses were carried out at 14, 17 and 20 weeks of age. The synovitis scores of treated groups were significantly lower compared with those of the control group at every age. The kappa coefficient was 0.77. However, progression of ankylosis persisted in the MR16-1 treated group. In vivo imaging using indocyanine green liposomes showed significant decreases in signal intensities of treated groups at week 14, but no significant differences were observed at week 18. Blood serum amyloid A levels in treated groups were significantly lower at 17 weeks of age. The gene expression levels of Tnf and Il17 were also significantly lower in MR16-1 treated groups.[Conclusions]Administration of the anti-IL-6 receptor antibody is effective for the treatment of synovitis and bone destruction of McH-lpr/lpr-RA1 mice. McH-lpr/lpr-RA1 mice may be a suitable experimental model for the development of new treatments for spondyloarthritis. IL6 signal blockade could contribute to the treatment of spondyloarthritis, and further studies should be carried out to confirm its potential in the prevention of deformity associated with ankylosis.

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“…In secondary lesions, the EPR effect will likely only be present in nodules that exceed the size threshold above which vascularization becomes a necessity, and will probably be equally heterogeneous. Although the physiological processes of abnormal vessel development underlying the EPR effect could be observed even in the initial phases of tumorigenesis (Hagendoorn et al, 2006), early and small lymphogenic metastases were not efficiently targeted by >150 nm liposomes (Mikada et al, 2017). However, 30 nm polymeric micelles loaded with a platinum complex suppressed lymph node metastases in a melanoma model, suggesting only a low grade EPR effect in these nodules (Cabral et al, 2015).…”

Section: Magnitude and Heterogeneity Of The Epr Effectmentioning

confidence: 99%

Overcoming Physiological Barriers to Nanoparticle Delivery—Are We There Yet?

Thomas

Weber

2019

Front. Bioeng. Biotechnol.

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The exploitation of nanosized materials for the delivery of therapeutic agents is already a clinical reality and still holds unrealized potential for the treatment of a variety of diseases. This review discusses physiological barriers a nanocarrier must overcome in order to reach its target, with an emphasis on cancer nanomedicine. Stages of delivery include residence in the blood stream, passive accumulation by virtue of the enhanced permeability and retention effect, diffusion within the tumor lesion, cellular uptake, and arrival at the site of action. We also briefly outline strategies for engineering nanoparticles to more efficiently overcome these challenges: Increasing circulation half-life by shielding with hydrophilic polymers, such as PEG, the limitations of PEG and potential alternatives, targeting and controlled activation approaches. Future developments in these areas will allow us to harness the full potential of nanomedicine.

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Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis

Cited by 53 publications

References 19 publications

Treatment of false‐negative metastatic lymph nodes by a lymphatic drug delivery system with 5‐fluorouracil

Treatment of false‐negative metastatic lymph nodes by a lymphatic drug delivery system with 5‐fluorouracil

The effect of anti-IL-6 receptor antibody for the treatment of McH-lpr/lpr-RA1 mice that spontaneously developed ankylosing arthritis

Overcoming Physiological Barriers to Nanoparticle Delivery—Are We There Yet?

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