Synthesis of tumor-selective bradykinin enhancing tumor accumulation of nanomedicine

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06704
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Sojo University
• Principal Investigator: Hideaki Nakamura 崇城大学, 薬学部, 准教授 (30435151)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ブラジキニン / 腫瘍 / pH応答性 / ポリマー

Outline of Final Research Achievements

The pH-responsive HPMA-polymer conjugates of bradykinin (P-BK), which have different pH-responsiveness, were synthesized to investigate their effect on tumor accumulation of high molecular weight anticancer agents. The pH-responsiveness of the HPMA-polymer conjugate, P-BK, could be modulated by changing the substituent adjacent to the hydrazone linkage without loss of BK activity. Although P-BK had higher plasma stability and low BK-like activity, release of BK in response to an acidic environment resulted in restoration of its vascular permeability-increasing activity. Administration of P-BK increased blood flow to the tumor and enhanced tumor accumulation of anticancer drugs, leading to improved anti-tumor effects of the anticancer drugs. These effects were more pronounced with the more pH-sensitive P-BK.

Free Research Field

医療薬学

Academic Significance and Societal Importance of the Research Achievements

高分子性抗がん剤（抗体医薬品やリポソーム製剤）は腫瘍などの内皮細胞間隙が広い血管を有する臓器に選択的に分布する特徴を持ち、腫瘍を標的とした多くの高分子性抗がん剤が研究・開発されてきた。しかし難治性がんでは流入血液量が乏しく血管透過性が高くないため、抗がん剤が送達されにくく、がん治療を行う上での難点の一つとなっている。ブラジキニンなどの血管作動性因子を腫瘍選択的に作用させるP-BKを用いた、腫瘍への流入血液量ならびに腫瘍血管の血管透過性を制御し、高分子性抗がん剤の腫瘍集積性を増強しようとする研究は、高分子性抗がん剤を用いたがん治療を行う上で、重要な基礎研究になると思われる。