Short peptide hydrogel with angular structure for hydrophobic antitumor drug delivery and controlled release

Abstract

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 (KIKI^DPPIKIK), 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.