Role of generation on folic acid-modified poly(amidoamine) dendrimers for targeted delivery of baicalin to cancer cells

•Four generations of PAMAM-FA were synthesized to deliver BAI.•The role of generation on the physiochemical properties and biological effects of PAMAM-FA/BAI complexes was investigated.•PAMAM-FA demonstrated the potential for targeted delivery of BAI into cancer cells to improve its anti-tumor efficacy.•Cellular uptake efficiency and the cytotoxicity of PAMAM-FA/BAI were significantly related to the generation of PAMAM.

Baicalin (BAI) has been reported to exert antitumor effects. However, BAI has limited water solubility, non-specific tumor targeting, and low bioavailability, which severely limited its clinical application. The aim of this study was to develop folic acid (FA) covalently conjugated-polyamidoamine (PAMAM) dendrimers (PAMAM-FA) as carrier systems for improvement of water solubility and tumor-specificity of BAI, and study the role of generation on the physiochemical properties and biological effects of PAMAM-FA/BAI complexes. In this work, four generations of PAMAM-FA were synthesized to entrap BAI. The average sizes of G3-FA/BAI, G4-FA/BAI, G5-FA/BAI, and G6-FA/BAI complexes were 174.4 nm, 184.5 nm, 258.8 nm, and 247.5 nm, respectively, and the zeta potentials of four PAMAM-FA/BAI complexes were − 2.9 mV, − 6.6 mV, − 9.3 mV, − 9.0 mV, respectively. The entrapment efficiencies of four PAMAM-FA/BAI complexes were 91.1%, 53.5%, 80.3%, and 91.9%, respectively, and the drug loading of PAMAM-FA/BAI complexes were about 22%. The formed PAMAM-FA/BAI complexes allowed sustained release of BAI in acidic PBS (pH 5.4). In cellular uptake assay, PAMAM-FA/BAI complexes demonstrated increased drug uptake level in folate receptor (FR)-positive Hela cancer cells than FR-negative A549 cells, and the cellular uptake efficiency of PAMAM-FA is closely related with the generation of PAMAM. The MTT assay results showed that PAMAM-FA/BAI complexes demonstrated enhanced toxicity against Hela cells than non-FA-modified PAMAM/BAI complexes, and the G6-FA/BAI demonstrated the best inhibition efficiency. The cell cycle and cell apoptosis analysis further demonstrated the tumor-specific therapeutic efficacy of PAMAM-FA/BAI. These results suggested that the PAMAM-FA have the potential for targeted delivery of BAI into cancer cells to enhance its anti-tumor efficacy.

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