Author + information
- Juan Cheng, MS,
- Chenwen Li, MS and
- Jianxiang Zhang, PhD∗ ()
- ↵∗Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China
We appreciate Dr. Tian and colleagues for their comments on our study “A Targeting Nanotherapy for Abdominal Aortic Aneurysms” (1). First, they had a concern about off-target effects of our targeting nanotherapies. This is true that nonspecific accumulation remains a critical issue for all nanotherapies, regardless of surface engineering with different biophysicochemical strategies (2). In addition, for nanotherapies containing physically entrapped drugs, their premature release can lead to absorption and distribution of drug molecules in other nontarget tissues or organs, at least to a certain degree. Both effects might result in adverse reactions. Consequently, we agree with Dr. Tian and colleagues that long-term safety needs to be carefully examined by comprehensive studies.
As for their second comment about the measurement of matrix metalloproteinases (MMPs) by Western blot, we cannot totally agree with them. Whereas gelatin zymography has been a commonly used method for detecting activity of MMPs, calcium buffer is required in this experiment. However, the aortic tissues with abdominal aortic aneurysms (AAAs) induced by CaCl2 contain a considerable amount of calcium ions, due to significant calcification, which may influence the outcome of gelatin zymography. Actually, we had tried this assay in our initial experiments, but no desirable results were obtained. Accordingly, the relative contents of MMP-2 and MMP-9 were analyzed by Western blot, because this method has also been extensively used by other researchers (3). Definitely, it should be more convincing if the active forms of MMPs can be detected by other available and reliable methods. As suggested by Dr. Tian and colleagues, the plasma levels of MMPs can be tested in the future studies to provide more information.
Finally, we agree with the issue that the pathogenesis of different animal models of AAAs is different. However, CaCl2-mediated AAA in rats and human subrenal AAA share many similar pathological characteristics (4), and therefore, it has been extensively used in mechanistic studies and drug discovery. Meanwhile, independent of animal models, similar pathological features, such as of inflammatory cell infiltration, elevated MMPs, overproduced reactive oxygen species, artery calcification, and degradation of elastic lamellae aorta, are all involved in AAAs. Consequently, we can expect beneficial therapeutic outcomes for our reactive oxygen species–responsive nanotherapies in other AAA models, although further studies are necessary.
In conclusion, we believe that our results can provide a new perspective to the development of targeting AAA therapies. Nevertheless, more comprehensive preclinical experiments are required before clinical trials of these new nanotherapies, with respect to both efficacy and safety.
Please note: This study was supported by the National Natural Science Foundation of China (Nos. 81471774), the Science and Technology Innovation Program in Military Medicine of Southwest Hospital (No. SWH2016LHYS-05), and the Program for Distinguished Young Scholars of TMMU. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2019 American College of Cardiology Foundation