br The effect of PEBCA
The effect of PEBCA-CBZ and free CBZ was also examined in or-thotopically growing MDA-MB-231 tumors without showing the same efficacy as in the MAS98.12 PDX model. Since the influence of these NPs are based on the so-called EPR effect , the tumor vasculature is supposed to be a critical factor. We have earlier shown that the basal-like MAS98.12 tumor has a higher vascularization than the luminal-like MAS98.06 tumor [37,38]. Although angiogenesis also has been visua-lized in MDA-MB-231 tumors in mice , the difference in vascular-ization of the MAS98.12 and MDA-MB-231 tumors is less well char-acterized. However, in two previously published studies, the blood volume constituted 2.4% of the tumor volume 5 weeks after inoculation of MDA-MB-231  and 5.9% at 5 weeks after transplantation of MAS98.12 , suggesting more efficient vascularization in the latter model.
Both the fluorescence in vivo imaging data and the quantification of CBZ in tissue samples clearly demonstrate accumulation of the PEBCA NPs in DZNep nodes (Fig. 3B,C and Fig. 4B). Accumulation of drugs or imaging agents in lymph nodes was recently reviewed [41,42], sug-gesting a benefit of injecting very small NP [43,44]. A study reported accumulation into lymph nodes of particles similar to those used in the present study, i.e. poly(butylcyanoacrylate) modified with Pluronic F127 and loaded with vincristine . As these NPs were shown to rapidly release vincristine and vincristine also accumulated in lymph nodes following injection of the non-encapsulated drug , it is dif-ficult to evaluate to which extent these NPs actually accumulated in the
lymph nodes. Delivery of drug to lymph nodes has been discussed for treatment of metastasizing tumors [41,46]. Since local lymph nodes are the first site of breast cancer metastasis, and also a significant distant metastatic site, in particular in the aggressive triple negative basal like breast cancer , accumulation of PEBCA-CBZ in lymphatic tissue may be an important feature of such treatment. In summary, the PEBCA-CBZ NPs seem promising for treatment of breast cancer, but further preclinical studies are necessary to show a beneficial effect of PEBCA-CBZ in metastatic cancer models. Furthermore, the observation that PEBCA seems to enhance in-tratumoral infiltration of anti-tumorigenic macrophages might be of general value and should be further investigated, either by using such NPs as an immune modulator or a vehicle able to enhance the ther-apeutic effect of encapsulated drugs.
Transparency declaration section
The authors declare potential conflict of interest through two pending patent applications.
Funding and acknowledgements
The two groups at Institute for Cancer Research and the group at SINTEF were all supported by the Research Council of Norway through its funding scheme NANO2021, project number 228200/O70 (Biodegradable nanoparticles in cancer diagnosis and therapy). The excellent technical assistance of Geir Frode Øy (animal studies), Tonje Sønstevold and Ane Sager Longva (cell studies), Anne Rein Hatletveit (particle synthesis) and Cathrine Løvmo (MS analyses) are greatly ac-knowledged. We thank the Department for Comparative Medicine for the services they provided and the other members of the NANOCAN project for valuable discussions.
Appendix A. Supplementary data
A. Bofin, G.M. Maelandsmo, L.A. Akslen, O. Engebraaten, I.S. Gribbestad, In vivo MRI and histopathological assessment of tumor microenvironment in luminal-like and basal-like breast cancer xenografts, J. Magn. Reson. Imaging 35 (5) (2012) 1098–1107.
O. Engebraten, G.M. Maelandsmo, B. Johansen, S.A. Moestue, Anti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer model, BMC Cancer 16 (2016) 191.
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Caged-xanthone from Cratoxylum formosum ssp. pruniflorum inhibits malignant cancer phenotypes in multidrug-resistant human A549 lung cancer cells through down-regulation of NF-κB
Chutima Kaewpiboona, , Nawong Boonnakb, Natpaphan Yawutc, Sirichat Kaowinnc, Young-Hwa Chungc, a Department of Biology, Faculty of Science, Thaksin University, Patthalung 93210, Thailand b Department of Basic Science and Mathematics, Faculty of Science, Thaksin University, Songkhla 90000, Thailand c Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 46241, Republic of Korea