Prof. Wanwan Li’s Research Group Reports A Novel and Efficient Treatment Against Deep-Seated Cancers
Recently, the research group led by Prof. Wanwan Li from School of Materials Science and Engineering, SJTU and State Key Lab of Metal Matrix Composites made important progress in the field of nanobiotechnology. Their research article titled “Antiangiogenesis Combined with Inhibition of the Hypoxia Pathway Facilitates Low-Dose, X-ray-Induced Photodynamic Therapy” has been published in ACS Nano. This study reported an efficient dual-core-satellite architecture, which enabled the separated and controllable loading of nanoscintillator, photosensitizer and angiogenic inhibitor, and ultimately promoted the synergistic therapy of X-Ray-induced photodynamic therapy (XPDT) and antiangiogenic therapy. Due to the advantages of this unique structure in improving energy transfer efficiency, increasing drug loading and achieving controlled drug release, it can achieve efficient removal of deep-seated tumors with ultralow radiation dose.
Due to the high penetration depth of X-rays, XPDT has unique advantages in the noninvasive treatment of deep-seated tumors. However, this emerging technology is currently facing some limitations, such as the performance degradation of scintillators in the nanoscale; The unreasonable structure design between scintillator and photosensitizer leads to low energy transfer efficiency; As well as tumor hypoxia induced angiogenesis, metastasis, metabolic changes.
Figure 1. Schematic Illustrations of Nanoplatform Construction and Combined Therapy.
Given these circumstances, Li wanwan's research team had made breakthroughs from these three aspects. They first synthesized ultrasmall nanoscintillators (14 nm) with high scintillation efficiency by codoping strategy. Under X-ray irradiation, the nanoscintillator emited strong green fluorescence visible to the naked eye. At the same time, the nanoscintillator had high photo and chemical stability in physiological environment. Secondly, they constructed a dual-core-satellite architecture by introducing dendrimers as the fundamental framework. Dendrimers had double loading characteristics, i.e., both the internal cavity and surface functional groups could be used as loading platforms, which greatly improved the type and capacity of drug loading. Besides, the dendrimer size was about 3.6 nm, which significantly improved the energy transfer efficiency from nanoscintillator to photosensitizer. Finally, to block the tumor hypoxia mediated angiogenesis pathway, they adopted sunitinib, an FDA approved receptor tyrosine kinase inhibitor, to achieve the synergistic treatment of XPDT and antiangiogenesis.
Figure 2. Characterizations of nanoscintillator and constructions of nanoplatform.In vitro studies showed that the nanoplatform had significant antiangiogenic effect and XPDT effect at low treatment dose. The XPDT resulted from singlet oxygen under X-ray irradiation; WB test showed that the antiangiogenic effect was related to the downregulation of VEGFA, HIF-1a and p-STAT3. The in vivo experiments showed that at the dose of 1 Gy, the synergetic treatment could lead to a large area of apoptosis of tumor cells, and the tumor vascular density decreased significantly. These results indicated that the combination therapy enabled good complementarity between XPDT and anti-angiogenesis, which could attack tumor from different aspects and prevented tumor from escaping. This combined combat strategy could effectively remove deep-seated tumors.
Finally, toxicological evaluations showed that the nanoplatform had no significant short-term or long-term toxicity. This was because the elements Ca and F in scintillator were widely existed in human body; Rose Bengal was an ophthalmic diagnostic reagent widely used in clinic; Sunitinib was a drug approved by the US FDA. In other words, the nanoplatform had high biosafety, and had broad application prospects in the treatment of deep-seated tumors.
Figure 3. In vivo combined XPDT and anti-angiogenic therapy.Doctoral candidate Zhao Jiang is the first author of this paper; Prof. Wanwan Li and Prof. Daxiang Cui are co-corresponding authors of this paper. This work is supported by Prof. Daxiang Cui from School of Electronic Information and Electrical Engineering and Prof. Xiaoyuan Chen from National University of Singapore. This work is ﬁnancially supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, and the Science and Technology Committee of Shanghai.