{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:13:06Z","timestamp":1788221586996,"version":"build-2803163510"},"reference-count":30,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015386","name":"Japan Society for Aeronautical and Space Sciences","doi-asserted-by":"publisher","award":["21K06704"],"award-info":[{"award-number":["21K06704"]}],"id":[{"id":"10.13039\/100015386","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K09931"],"award-info":[{"award-number":["24K09931"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Enhancing the tumor accumulation of nanomedicines through vascular modulation represents a promising strategy to improve anticancer drug delivery. Bradykinin (BK), a potent vasoactive peptide, can enhance intratumoral blood flow and vascular permeability; however, its clinical application is hampered by rapid proteolytic degradation and systemic side effects, including hypotension. To address these limitations, we developed P-RIBKs, N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates of retro-inverso bradykinin, in which a proteolysis-resistant retro-inverso analog of BK (RIBK) was conjugated via an acid-cleavable hydrazone linkage. RIBK retained vascular permeability-enhancing activity comparable to native BK while exhibiting resistance to proteolytic degradation in plasma. RIBK activated G protein-dependent calcium signaling while failing to induce B2 receptor internalization. Conjugation of RIBK to HPMA copolymer via hydrazone linkage attenuated its vasoactive activity under physiological conditions while enabling tumor-selective release within the acidic microenvironment. The release kinetics of RIBK from P-RIBKs were modulable by varying the substituent adjacent to the hydrazone linkage, and sustained release, as achieved with the phenyl-substituted conjugate (P-PhRIBK), was found to enhance tumor accumulation of a model nanomedicine. Furthermore, pretreatment with P-PhRIBK augmented the antitumor efficacy of liposomal doxorubicin (DOXIL) in a murine colon tumor model. These results demonstrate that P-PhRIBK provides a tumor vascular modulator for improving the delivery and therapeutic efficacy of anticancer nanomedicines.<\/jats:p>","DOI":"10.1021\/acsomega.6c04991","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T04:01:44Z","timestamp":1786161704000},"page":"49965-49976","source":"Crossref","is-referenced-by-count":0,"title":["Tumor-Selective\nVascular Modulation by Acid-Cleavable\nRetro-Inverso Bradykinin Conjugates Enhances the Antitumor Efficacy\nof Nanomedicine"],"prefix":"10.1021","volume":"11","author":[{"given":"Anthony","family":"Assumang","sequence":"first","affiliation":[{"name":"Sojo University , , Ikeda 4-22-1 , Nishi-Ku, ,","place":["Kumamoto, Japan, 860-0082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4857-2529","authenticated-orcid":true,"given":"Hideaki","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Sojo University , , Ikeda 4-22-1 , Nishi-Ku, ,","place":["Kumamoto, Japan, 860-0082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enoch","family":"Appiah","sequence":"additional","affiliation":[{"name":"Sojo University , , Ikeda 4-22-1 , Nishi-Ku, ,","place":["Kumamoto, Japan, 860-0082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Kotali\u0301k","sequence":"additional","affiliation":[{"name":"Czech Academy of Sciences , , Heyrovsky Sq. 2 , ,","place":["Prague 6, Czech Republic, 162 06"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Morimitsu","sequence":"additional","affiliation":[{"name":"Sojo University , , Ikeda 4-22-1 , Nishi-Ku, ,","place":["Kumamoto, Japan, 860-0082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5908-5182","authenticated-orcid":true,"given":"Toma\u0301s\u030c","family":"Etrych","sequence":"additional","affiliation":[{"name":"Czech Academy of Sciences , , Heyrovsky Sq. 2 , ,","place":["Prague 6, Czech Republic, 162 06"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0805-4532","authenticated-orcid":true,"given":"Mamoru","family":"Haratake","sequence":"additional","affiliation":[{"name":"Sojo University , , Ikeda 4-22-1 , Nishi-Ku, ,","place":["Kumamoto, Japan, 860-0082"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"issue":"12 Pt 1","key":"2026083119150728000_cit1","first-page":"6387","article-title":"A new concept for macromolecular therapeutics in cancer chemotherapy:\nmechanism of tumoritropic accumulation of proteins and the antitumor\nagent smancs","volume":"46","author":"Matsumura","year":"1986","journal-title":"Cancer Res."},{"issue":"3","key":"2026083119150728000_cit2","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.addr.2010.04.009","article-title":"The EPR effect:\nUnique features of\ntumor blood vessels for drug delivery, factors involved, and limitations\nand augmentation of the effect","volume":"63","author":"Fang","year":"2011","journal-title":"Adv. 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