Effect of growing glycosylation extents on the self-assembly and active targeting in vitro of branched poly(ethylene oxide)-poly(propylene oxide) block copolymers

In this work, we investigated for the first time the effect of the gradual increase of the glycosylation extent on self-assembly of a highly hydrophilic four-arm poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) block copolymer, Tetronic^® 1107. After the initial characterization that confirmed the chemical modification, the effect of the glycosylation extent on the critical micellar concentration (CMC) was characterized by dynamic light scattering. Conjugation of a D-gluconic acid (the oxidized form of D-glucose) in each terminal block resulted in a dramatic decrease of the CMC by 8- to 11-fold. In contrast, further glycosylation with lactobionic acid (an oxidized form of lactose) and gluconic acid + lactobionic acid had a detrimental effect due to the increase of the amphiphile hydrophilicity. Then, glycosylated PMs successfully encapsulated the tyrosine kinase inhibitor imatinib, increasing its aqueous solubility by up to 100 times. Glycosylated polymeric micelles showed very good cell compatibility in the Rh30 cell line. These cells are a model of rhabdomyosarcoma, a tumor that overexpresses glucose transporter-1 that is targeted by the sugar residues. Finally, we compared the cytotoxicity of free and nanoencpasulated imatinib to inhibit the proliferation a in which tyrosine kinase signaling promotes growth and glucose transporter-1 (GLUT-1; for which glucose is the main substrate) is overexpressed. Nano-encapsulation reduced the inhibitory concentration 50 (IC₅₀) from 27.80 ± 3.70 μM for the free drug to 0.33 ± 0.01 μM for the PMs modified with gluconic acid, representing an 84-fold increase in the anti-cancer efficacy in vitro. Overall results highlight the potential of tuned glycosylation to increased the micellization trend of these amphiphiles and, at the same time, increase accumulation in cells that overexpress sugar receptors.