Hyaluronic acid-grafted polyamidoamine dendrimers enable long circulation and active tumor targeting simultaneously

• HA was successfully conjugated with PAMAM dendrimers, and TPT was loaded.
• The modification of HA significantly reduced the cytotoxicity of PAMAM.
• The fine in vitro and in vivo targeting efficiency of HA-PAMAM/TPT was confirmed.
• HA-PAMAM/TPT showed prolonged circulation in normal rats, similar to pegylation.
• HA-PAMAM/TPT demonstrated higher antitumor activity in S-180 sarcoma mice.

Herein, we developed dualfunctional hyaluronic acid (HA)-grafted polyamidoamine (PAMAM) dendrimers for simultaneous systemic long circulation and active tumor targeting and delivery of topotecan hydrochloride (TPT). The possibility of these modified dendrimers as nanocarriers for promoting tissue distribution and antitumor efficiency, as well as a drug release profile, cytotoxicity and cellular uptake, was investigated. The fine targeting efficiency of HA-PAMAM/TPT was confirmed by the CD44 receptor-mediated high cellular uptake efficiency and low cytotoxicity in HCT-116 cells, and the in vivo higher tumor distribution percentage than in other tissues in mice bearing an S-180 tumor. Pharmacokinetic studies showed that the t1/2 and MRT of TPT were significantly extended after intravenous administration of HA-PAMAM/TPT in normal rats. Moreover, TPT-loaded nanovehicles demonstrated higher antitumor activity compared with free drug and PAMAM/TPT. Overall, HA-PAMAM may be an alternative vector for the effective targeted delivery of and tumor therapy with antitumor drugs.