Kang Changyu, Kim Jaejeong, Jeong Yeonhee, Yoo Jin-Wook, Jung Yunjin
College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.
Pharmaceutics. 2024 Dec 2;16(12):1546. doi: 10.3390/pharmaceutics16121546.
In addition to oncological applications, poly(ADP-ribose) polymerase (PARP) inhibitors have potential as anti-inflammatory agents. Colon-targeted delivery of PARP inhibitors has been evaluated as a pharmaceutical strategy to enhance their safety and therapeutic efficacy against gut inflammation. Colon-targeted PARP inhibitors 5-aminoisoquinoline (5-AIQ) and 3-aminobenzamide (3-AB) were designed and synthesized by azo coupling with salicylic acid (SA), yielding 5-AIQ azo-linked with SA (AQSA) and 3-AB azo-linked with SA (ABSA). Additional conjugation of AQSA with acidic amino acids yielded glutamic acid-conjugated AQSA (AQSA-Glu) and aspartic acid-conjugated AQSA, which further increased the hydrophilicity of AQSA. The distribution coefficients of PARP inhibitors were lowered by chemical modifications, which correlated well with drug permeability via the Caco-2 cell monolayer. All derivatives were effectively converted to their corresponding PARP inhibitors in the cecal contents. Compared with observations in the oral administration of PARP inhibitors, AQSA-Glu and ABSA resulted in the accumulation of much greater amounts of each PARP inhibitor in the cecum. ABSA accumulated mesalazine (5-ASA) in the cecum to a similar extent as sulfasalazine (SSZ), a colon-targeted 5-ASA prodrug. In the DNBS-induced rat colitis model, AQSA-Glu enhanced the anticolitic potency of 5-AIQ. Furthermore, ABSA was more effective against rat colitis than SSZ or AQSA-Glu, and the anticolitic effects of AQSA-Glu were augmented by combined treatment with a colon-targeted 5-ASA prodrug. In addition, the colon-targeted delivery of PARP inhibitors substantially reduced their systemic absorption. Colon-targeted PARP inhibitors may improve the therapeutic and toxicological properties of inhibitors and synergize the anticolitic effects of 5-ASA.
除了肿瘤学应用外，聚（ADP - 核糖）聚合酶（PARP）抑制剂还具有作为抗炎剂的潜力。已评估将PARP抑制剂进行结肠靶向递送作为一种药物策略，以提高其对肠道炎症的安全性和治疗效果。通过与水杨酸（SA）进行偶氮偶联设计并合成了结肠靶向的PARP抑制剂5 - 氨基异喹啉（5 - AIQ）和3 - 氨基苯甲酰胺（3 - AB），得到与SA偶氮连接的5 - AIQ（AQSA）和与SA偶氮连接的3 - AB（ABSA）。AQSA与酸性氨基酸的进一步缀合产生了谷氨酸缀合的AQSA（AQSA - Glu）和天冬氨酸缀合的AQSA，这进一步增加了AQSA的亲水性。化学修饰降低了PARP抑制剂的分配系数，这与通过Caco - 2细胞单层的药物渗透性密切相关。所有衍生物在盲肠内容物中均有效地转化为其相应的PARP抑制剂。与口服PARP抑制剂的观察结果相比，AQSA - Glu和ABSA导致盲肠中每种PARP抑制剂的积累量大大增加。ABSA在盲肠中积累美沙拉嗪（5 - ASA）的程度与结肠靶向的5 - ASA前药柳氮磺吡啶（SSZ）相似。在二硝基苯磺酸（DNBS）诱导的大鼠结肠炎模型中，AQSA - Glu增强了5 - AIQ的抗结肠炎效力。此外，ABSA对大鼠结肠炎的疗效比SSZ或AQSA - Glu更有效，并且通过与结肠靶向的5 - ASA前药联合治疗增强了AQSA - Glu的抗结肠炎作用。此外，PARP抑制剂的结肠靶向递送大大降低了它们的全身吸收。结肠靶向的PARP抑制剂可能改善抑制剂的治疗和毒理学特性，并协同5 - ASA的抗结肠炎作用。
