Losartan Alleviates the Side Effects and Maintains the Anticancer Activity of Axitinib.

Axitinib is one of the most potent inhibitors of the vascular endothelial growth factor (VEGF) receptor and shows strong antitumor activity toward various malignant tumors. However, its severe side effects affect the quality of life and prognosis of patients. Losartan, which functions as a typical angiotensin receptor blocker, controls the average arterial pressure of patients with essential hypertension and protects against hypertension-related secondary diseases, including proteinuria and cardiovascular injury. To explore the effects of losartan on side effects caused by axitinib and its antitumor activity, several animal experiments were conducted. This study first analyzed and explored the effect of losartan on the amelioration of side effects in Wistar rats caused by axitinib. The results showed that the systolic blood pressure of Wistar rats was significantly increased by about 30 mmHg in 7 days of axitinib treatment, while the combination of losartan significantly reduced the blood pressure rise caused by axitinib. The Miles experimental model and mouse xenograft tumor model were further used to evaluate the effect of losartan on the antitumor effect of axitinib. The result clearly demonstrated that losartan has no significant influence on axitinib-related low vascular permeability and antitumor activity. In summary, our results showed that the combination of axitinib and losartan significantly reduced the side effects and maintained the antitumor effects of axitinib. This study provides information for overcoming VEGF receptor inhibitor-related side effects.

Tumor vasculature-targeting PEGylated peptide-drug conjugate prodrug nanoparticles improve chemotherapy and prevent tumor metastasis.

Metastasis is the main cause of death in cancer patients; therefore, new strategies or technologies that can inhibit the growth of primary tumors and their metastatic spread are extremely valuable. In this study, we selected an E-selectin-binding peptide as a targeting ligand and an inhibitor of metastasis, and conjugated this peptide with SN38 and PEG to produce an amphiphilic PEGylated peptide-drug conjugate (PDC). Novel self-assembled nanoparticles were then formed by the amphiphilic conjugate. The particles were actively targeted to the tumor vasculature by the peptide and passively to the tumor site by the enhanced permeability and retention (EPR) effect. As a nano-prodrug, this multifunctional conjugate (PEG-Pep-SN38) could reduce tumor growth, with an effect similar to that of irinotecan. Moreover, it could prolong the survival of mice bearing primary HCT116 tumors, which was not observed for its parent drug, SN38, nor the clinical prodrug of SN38 (irinotecan). Furthermore, this PDC prodrug prevented B16-F10 colonization in the lungs of mice. This study describes a new tumor vasculature-targeting PDC nano-prodrug with convenient preparation and high potential for cancer therapy, with the potential to be applied to other chemotherapeutic drugs.