Intratumoral platelet deletion offers an alternative approach to enhancing the EPR effect
Nanoparticles locally deplete tumour-associated platelets and increase drug accumulation in tumours
Platelets are shown to be loyal guardians of tumor vessels, wherein they secret their granule contents or directly adhere to neutrophil-induced vascular breaches to protect vascular integrity and prevent tumor hemorrhage1-3. With these previous findings in mind, we hypothesized that targeting platelets may represent a new method to specifically destabilize tumor vasculature and increase its leakage, thus augmenting the EPR effect. The enhancement of EPR effect is able to promote the extravasation of nanoparticles from tumor blood vessels, which is crucial for nanomedicine development in cancer therapy.
To test our hypothesis, we have formulated hybrid nanoparticles comprising lipids and polymers coloaded with doxorubicin and R300, an antiplatelet antibody. At the same time, we coated the nanoparticles with a shell layer composing of matrix metalloproteinase 2 (MMP2)-cleavable peptides, conferring the particles an active targeting ability to tumor sites (Figure 1). After intravenous administration, these nanoconjugates tissue-specifically deleted intratumoral platelets in tumor-bearing mouse model and increased the size of fenestrations of tumor vasculatures, and thus enhanced doxorubicin-loaded core nanoparticle accumulation in tumors. The results also showed clear evidence that compared with free-drug control and chemotherapeutic nanoparticles without R300, the doxorubicin /R300 formulations had the highest efficacy against tumor growth and metastasis in vivo.
Figure1. Design features and proposed mechanism of action of PLP-D-R in tumor blood vessels in vivo. (a) Schematic illustration of the MMP2-responsive nanoparticles. (b) The shell layer of the resulting PLP-D-R is cleaved within tumors by MMP2 which is overexpressed on the surface of tumor endothelial and stroma cells, leading to R300 release. R300 binds to platelet-surface receptors, and facilitates the formation of platelet microaggregates and subsequent depletion. The absence of platelets in tumors induces openings in the vessel walls, enhancing the EPR effect, which provides ready access for core nanoparticles to enter the tumor.
The general strategy of increasing the permeability of tumor blood vessels to augment the EPR effect may benefit not only nanomedicines, but all drugs. We have successfully developed a nanoparticle-based approach to achieve local depletion of tumor-associated platelets and enhance vessel permeability. In addition, the synergistic effect of antiplatelet treatment and doxorubicin dramatically improves chemotherapeutic efficacy and decreases unwanted side effects. We believe that this therapeutic strategy has great potential for the treatment of a wide range of solid tumors through the disruption of vascular barriers to augment the EFR effect, and that is a great push in the field enhancing EPR effect for nanotherapeutics application as caner-fighters. We also believe that the study is extremely important to introduce antiplatelet therapy for improving traditional chemotherapeutic efficacy in the clinical setting.
Our paper: Li, S. et al. Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours. Nat. Biomed. Eng. 1, 0115 (2017).
- Gros, A., et al. Single platelets seal neutrophil-induced vascular breaches via GPVI during immune-complex–mediated inflammation in mice. Blood 126, 1017-1026 (2015).
- Boulaftali, Y., et al. Platelet ITAM signaling is critical for vascular integrity in inflammation. J. Clin. Invest. 123, 908-916 (2013).
- Ho-Tin-Noé, B., et al. Platelet granule secretion continuously prevents intratumor hemorrhage. Cancer Res. 68, 6851-6858 (2008).