Chemical modification of bradykinin-polymer conjugates for optimum delivery of nanomedicines to tumors

• Published in: Nanomedicine Vol. 57; p. 102744
• Main Authors: Appiah, Enoch, Nakamura, Hideaki, Assumang, Anthony, Etrych, Tomáš, Haratake, Mamoru
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2024
• Subjects: Bradykinin; Controlled release; HPMA polymer; Hydrazone; Tumor; Tumor; HPMA polymer; Hydrazone; Bradykinin; Controlled release
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2024.102744

We recently prepared pH-responsive HPMA copolymer conjugates of bradykinin (P-BK), which release BK in response to the acidic tumor microenvironment, and found that administration of P-BK increased the tumor accumulation and therapeutic efficacy of nanomedicine. Because the release of BK from P-BK determines its onset of action, P-BKs with different release rates were prepared, and their properties were evaluated. The release kinetics were significantly altered by substitution proximal to hydrazone bond, release constant of methyl-substituted P-BK (P-MeBK) was approximately 4- and 80-fold higher than that of cyclopropyl-substituted P-BK (P-CPBK) and phenyl-substituted P-BK (P-PhBK). None of the P-BKs were active, but the release of BK restored their BK-like activity. Pre-administration of the P-BKs increased the tumor accumulation of nanomedicine in C26 tumor-bearing mice by 2- and 1.4-fold for P-MeBK and P-PhBK at 3 and 6 h. Altogether, this study provides insights into the design of pH-responsive nanodrugs with the desired release properties to target acidic lesions such as cancer and inflammation.
HPMA copolymer conjugates of Bradykinin (P-BKs) with different pH responsiveness were successfully prepared. The release kinetics of P-BKs were significantly altered by substitution proximal to hydrazone bond. The release of BK restored their activity, despite of lack of activity in P-BKs. Pretreatment of P-BKs enhanced tumor accumulation of nanomedicine, although each P-BK showed different onset times. [Display omitted]