Complexation of oncolytic peptide with carboxylatoquaterphen[3]arene for ameliorating its antitumor efficacy†

Hepatocellular carcinoma is the most common primary liver cancer with high mortality and poor prognosis. Oncolytic therapy using peptide agents is a promising approach for the above-mentioned malignant tumor; however, their typically low stability often leads to insufficient bioavailability. Herein, we proposed a supramolecular strategy to improve the metabolic stability of the LTX-315 oncolytic peptide via direct complexation with a macrocyclic host. A negatively charged carboxylatoquaterphen[3]arene (CQP3) bearing 12 benzenes on its skeleton was designed and synthesized. CQP3 exhibited strong binding affinity toward LTX-315 with a high association constant of (1.51 ± 0.10) × 10⁶ M⁻¹ and excellent recognition selectivity under a complicated physiological environment. This complexation was attractive as traditional macrocycles could only recognize specific amino acid residues of peptide guests owing to their strict cavity limitation. A series of in vitro and in vivo safety tests preliminarily proved that CQP3 possessed good biocompatibility. Complexation with CQP3 enhanced the metabolic stability of LTX-315 and its cytotoxicity at the cellular level after incubation with plasma. In vivo antitumor efficacy studies further demonstrated that LTX-315 co-administrated with equimolar CQP3 was capable of improving the curative outcomes in hepatocellular carcinoma-bearing nude mice.