Tumor-targeting delivery of hyaluronic acid–platinum(iv) nanoconjugate to reduce toxicity and improve survival

Abstract

Cisplatin, although promising in clinical use, is seriously limited by systemic side effects. Consequently, a stimuli-sensitive Pt(IV) pro-drug was synthesized and tethered to ethylenediamine modified hyaluronic acid to form a tumor-targeting HA-EDA–Pt(IV) nanoconjugate with reduced adverse reactions and enhanced efficacy. The nanoconjugate with adjustable Pt(IV) segments possessed satisfactory size and potential, exhibited spherical shapes and demonstrated sustained release of platinum species. Cell experiments confirmed that nanoscale conjugates selectively recognized the HA receptor, effectively penetrated the cell membrane and were finally reduced to active forms with persistent antitumor activity. Toxicological evaluation suggested that the nanomedicine significantly alleviated toxic side effects. Alterations of the pharmacokinetic profiles and parameters implied in vivo behavioral discrepancy after conjugation. Polymer–drug conjugates improved the life quality of mice bearing melanoma, prolonged survival, minimized organ toxicity and body weight loss. The favorable tumor-targeting effect was also verified by tissue distribution and in vivo imaging analysis. This HA-EDA–Pt(IV) nanoconjugate is expected to overcome the bottleneck of present platinum drugs and holds great potential in clinical application for cancer therapy.