Abstract
Tumor requires tumor vasculature to supply oxygen and nutrients so as to support its continued growth, as well as provide a main route for metastatic spread. In this study, a TF-cascade-targeted strategy aiming to disrupt tumor blood vessels was developed by combination of TF-targeted HMME-loaded drug delivery system and PDT. PDT is a promising new modality in the treatment of cancers, which employs the interaction between a tumor-localizing photosensitizer and light of an appropriate wavelength to bring about ROS-induced cell death. In vitro results showed that protein EGFP-EGF1modification could significantly contribute to the uptake of nanoparticles by TF over-expressed BCECs. In vivo multispectral fluorescent imaging, the EGFP-EGF1 conjugated nanoparticles showed significantly higher accumulation in tumor tissues than non-conjugated ones. Tumor tissue slides further presented that EGFP-EGF1 conjugated nanoparticles showed significantly higher accumulation in tumor vasculature than non-conjugated ones. In vitro study demonstrated that PDT increased TF expression of BCECs. In vivo imaging, ex vivo imaging and tumor tissue slides showed that PDT further contribute EGFP-EGF1-NP accumulation in tumor. These promising results indicated that PDT enhanced EGFP-EGF1modified PEG-PLGA nanoparticle accumulation in tumor vaculature. Considering that EGFP-EGF1 conjugation enhanced nanoparticles uptake by TF over-expressed endothelium and PDT increased endothelium TF expression. We conclude that PDT triggered a TF cascade targeted effect. A combination of both EGFP-EGF1 modification and PDT provided a positive feed-back target effect to tumor vessels and might have a great potential for tumor therapy.
Highlights
Tumor angiogenesis and vasculature is the pathological basis of their proliferation and metastasis.Targeting vascular network is an attractive approach for the treatment of human malignancies [1, 2]
The Hematoporphyrin monomethyl ether (HMME) loaded PEG-PLGA nanoparticle ENP (NP) had an average diameter of about 103.2 nm and the diameter was increased to approximately 116.4 nm after EGFP-EGF1 conjugation
There was no significant difference in particle size between EGFP-EGF1-conjugated nanoparticles and non-conjugated ones and between loaded coumarin-6/ Dir and its non-loaded counterpart
Summary
Tumor angiogenesis and vasculature is the pathological basis of their proliferation and metastasis. Target therapy involved PDT which gives “a second location” appeared with more accurate target efficacy. It only effects by strictly tumor-focused exposure to laser light, which may be highly specific because of largely improving tumor imaging modalities [17, 18]. Anti-vasculature PDT which aims to target tumour vessels rather than its parenchyma may served as a alternative therapeutic approach. TF-cascade-targeted efficacy was made in the strategy, and TF-targeted nanoparticles would precisely direct the tumor vasculature because of PDT. We established a TF-cascade-targeted drug delivery system——EGFP-EGF1-NP loaded HMME (ENP-HMME) for tumor therapy. We hypothesized that ROS was intentionally produced during PDT and caused vascular endothelial injury, inducing TF expression on the endothelium of tumor vasculature. Targeting property of fluorescencelabeled ENP and the forming ability of TF by BCECs were investigated both in vitro and in vivo and compared with those of unmodified NP-HMME
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