PMID- 33278478 OWN - NLM STAT- MEDLINE DCOM- 20210705 LR - 20210705 IS - 1873-4995 (Electronic) IS - 0168-3659 (Linking) VI - 329 DP - 2021 Jan 10 TI - Manipulating dynamic tumor vessel permeability to enhance polymeric micelle accumulation. PG - 63-75 LID - S0168-3659(20)30720-3 [pii] LID - 10.1016/j.jconrel.2020.11.063 [doi] AB - Selectively delivering anticancer drugs to solid tumors while avoiding their accumulation in healthy tissues is a major goal in polymeric micelle research. We have recently discovered that the extravasation and permeation of polymeric micelles occur in a dynamic manner characterized by vascular bursts followed by a brief and vigorous outward flow of fluid (called "nano-eruptions"). Nano-eruptions allow delivery of polymeric micelle-associated drugs, though delivery can be heterogeneous both among tumors and within an individual tumor, leading to suboptimal intratumoral distribution. Manipulation of nano-eruptions is expected to improve the efficiency of drug delivery systems (DDSs). By using compounds that affect the intratumoral environment, i.e. a TGF-beta inhibitor and chloroquine, the possibility of manipulating nano-eruptions to improve delivery efficiency was investigated. Both compounds were tested in a mouse xenograft model of GFP-labeled pancreatic tumor cells by tracing nano-eruption events and extravasation of size-modulated polymeric micelles in real-time through intravital confocal laser scanning microscopy. The TGF-beta inhibitor increased the number of dynamic vents, extended duration time, and generated dynamic vents with a wide range of sizes. Chloroquine did not affect the frequency of nano-eruptions, but it increased tumor vessel diameter, maximum nano-eruption area, and maximum radial increase. Both the TGF-beta inhibitor and chloroquine augmented nano-eruptions to diffuse polymeric micelles through tumor stroma, and these medications had a greater effect on the polymeric micelles with larger size, i.e. 70-nm, than on the smaller polymeric micelles having a 30-nm diameter. The results indicate that TGF-beta inhibition and chloroquine refashion the intratumoral distribution of DDSs by different mechanisms. CI - Copyright (c) 2020 Elsevier B.V. All rights reserved. FAU - Inoue, Yuta AU - Inoue Y AD - Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Innovation Center of NanoMedicine, Kawasaki Institute of Industry Promotion, 3-25-14 Tono-machi, Kawasaki-ku, Kawasaki City, Kanagawa 210-0821, Japan. FAU - Matsumoto, Yu AU - Matsumoto Y AD - Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Innovation Center of NanoMedicine, Kawasaki Institute of Industry Promotion, 3-25-14 Tono-machi, Kawasaki-ku, Kawasaki City, Kanagawa 210-0821, Japan. Electronic address: yumatsumoto-ent@umin.ac.jp. FAU - Toh, Kazuko AU - Toh K AD - Innovation Center of NanoMedicine, Kawasaki Institute of Industry Promotion, 3-25-14 Tono-machi, Kawasaki-ku, Kawasaki City, Kanagawa 210-0821, Japan. FAU - Miyano, Kazuki AU - Miyano K AD - Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Innovation Center of NanoMedicine, Kawasaki Institute of Industry Promotion, 3-25-14 Tono-machi, Kawasaki-ku, Kawasaki City, Kanagawa 210-0821, Japan. FAU - Cabral, Horacio AU - Cabral H AD - Innovation Center of NanoMedicine, Kawasaki Institute of Industry Promotion, 3-25-14 Tono-machi, Kawasaki-ku, Kawasaki City, Kanagawa 210-0821, Japan; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. FAU - Igarashi, Kazunori AU - Igarashi K AD - Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Innovation Center of NanoMedicine, Kawasaki Institute of Industry Promotion, 3-25-14 Tono-machi, Kawasaki-ku, Kawasaki City, Kanagawa 210-0821, Japan. FAU - Iwasaki, Shinichi AU - Iwasaki S AD - Department of Otolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. FAU - Kataoka, Kazunori AU - Kataoka K AD - Innovation Center of NanoMedicine, Kawasaki Institute of Industry Promotion, 3-25-14 Tono-machi, Kawasaki-ku, Kawasaki City, Kanagawa 210-0821, Japan; Institute for Future Initiatives, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. FAU - Yamasoba, Tatsuya AU - Yamasoba T AD - Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201202 PL - Netherlands TA - J Control Release JT - Journal of controlled release : official journal of the Controlled Release Society JID - 8607908 RN - 0 (Drug Carriers) RN - 0 (Micelles) RN - 0 (Polymers) SB - IM MH - Animals MH - Drug Carriers/therapeutic use MH - Drug Delivery Systems MH - Mice MH - *Micelles MH - *Neoplasms/drug therapy MH - Permeability MH - Polymers/therapeutic use OTO - NOTNLM OT - Chloroquine OT - EPR effect OT - Intravital microscopy OT - Nano-eruption OT - Polymeric micelle OT - TGF-beta inhibitor EDAT- 2020/12/06 06:00 MHDA- 2021/07/06 06:00 CRDT- 2020/12/05 20:09 PHST- 2020/04/30 00:00 [received] PHST- 2020/11/21 00:00 [revised] PHST- 2020/11/30 00:00 [accepted] PHST- 2020/12/06 06:00 [pubmed] PHST- 2021/07/06 06:00 [medline] PHST- 2020/12/05 20:09 [entrez] AID - S0168-3659(20)30720-3 [pii] AID - 10.1016/j.jconrel.2020.11.063 [doi] PST - ppublish SO - J Control Release. 2021 Jan 10;329:63-75. doi: 10.1016/j.jconrel.2020.11.063. Epub 2020 Dec 2.