Yao Qingqing, Gao Jie, Liu Linsheng, Shi Jinfang, Zafar Hajra, Khan Muhammad Ijaz, Zhu Jianguo, Raza Faisal, Zhu Ying
Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Colloids Surf B Biointerfaces. 2025 Oct;254:114793. doi: 10.1016/j.colsurfb.2025.114793. Epub 2025 May 15.
Although hydrophobic anti-tumor drugs such as paclitaxel (PTX) have been used to treat various cancers, their clinical application is limited due to their poor water solubility, low bioavailability and adverse drug reactions. Peptide hydrogels are being increasingly used for antitumor drug delivery due to their diverse synthesis and function and excellent biocompatibility. From the perspective of economic and clinical benefits, it is essential to design peptide hydrogels for anti-tumor drug delivery that can achieve tumor microenvironment responsiveness with short sequences. We designed a short peptide, KK (KIKIPPIKIK), consisting of 10 amino acids with a corner structure. The angular structure of KK is conducive to forming a network structure under neutral conditions for PTX inclusion. The drug-loaded short peptide hydrogel delivered PTX to the tumor site by injection and continuously released the drug under slight acidic stimulation of the tumor. The short peptide was synthesized by solid-phase peptide synthesis and verified by in vitro release experiments as a carrier for the delivery of hydrophobic antitumor drugs. Electron transmission microscopy was used to observe the microstructure differences of the short peptides under neutral and acidic conditions. Circular dichroism revealed the difference of secondary structure of the peptide under neutral and acidic conditions. The injectability of the short peptide hydrogel was verified by rheological experiments. The cytotoxicity in vitro and anti-tumor effect in vivo showed that the drug-loaded short peptide hydrogel could improve the anti-tumor effect. The biological safety of the short peptide hydrogel was confirmed by cell biocompatibility in vitro and in vivo. In summary, the pH-sensitive peptide can form a stable drug-loaded hydrogel in vitro, enabling sustained release of PTX upon injection into tumor tissue, thereby achieving long-term therapeutic efficacy with reduced toxic side effects. Moreover, it is noteworthy that the functional properties of this peptide can be achieved with just 10 amino acids, resulting in decreased synthetic costs and difficulties while maximizing clinical benefits.
尽管诸如紫杉醇（PTX）等疏水性抗肿瘤药物已被用于治疗各种癌症，但其临床应用因水溶性差、生物利用度低和药物不良反应而受到限制。由于其多样的合成方式、功能以及优异的生物相容性，肽水凝胶正越来越多地用于抗肿瘤药物递送。从经济和临床效益的角度来看，设计能够以短序列实现肿瘤微环境响应性的用于抗肿瘤药物递送的肽水凝胶至关重要。我们设计了一种由10个氨基酸组成的具有转角结构的短肽KK（KIKIPPIKIK）。KK的转角结构有利于在中性条件下形成用于包载PTX的网络结构。载药短肽水凝胶通过注射将PTX递送至肿瘤部位，并在肿瘤的轻微酸性刺激下持续释放药物。该短肽通过固相肽合成法合成，并经体外释放实验验证为疏水性抗肿瘤药物递送的载体。利用电子透射显微镜观察短肽在中性和酸性条件下的微观结构差异。圆二色性揭示了该肽在中性和酸性条件下二级结构的差异。通过流变学实验验证了短肽水凝胶的可注射性。体外细胞毒性和体内抗肿瘤作用表明，载药短肽水凝胶可提高抗肿瘤效果。短肽水凝胶的生物安全性通过体外和体内细胞相容性得到证实。综上所述，这种pH敏感肽在体外可形成稳定的载药水凝胶，注射到肿瘤组织后能够实现PTX的持续释放，从而在降低毒副作用的同时实现长期治疗效果。此外，值得注意的是，仅用10个氨基酸就能实现该肽的功能特性，在将临床效益最大化的同时降低了合成成本和难度。
