The impact of the HPMA polymer structure on the targeting performance of the conjugated hydrophobic ligand

Abstract

Thanks to the enhanced cancer cell affinity, modification of polymeric drug carriers with an active targeting ligand has been one of the most effective strategies to achieve better therapeutic efficacy. However, hydrophobic ligands (e.g. folate), when conjugated to hydrophilic carriers, encounter the problem of reduced targeting effectiveness due to the fact that the ligand may be buried inside the carrier. In the present study, we studied the impact of the hydrophilic polymer structure on the targeting efficiency of the conjugated folate (FA). After modification with folate, the linear N-(2-hydroxypropyl)-methacrylamide (HPMA) polymer (P-FA, 27.3 kDa) exhibited a neutral surface charge (1.5 mV), while the graft HPMA polymer (GP-FA, 117.4 kDa) possessed a mild negative charge (−7.2 mV), which suggests different exposure levels of negatively charged folate on the surface of P-FA and GP-FA. Notably, on folate receptor positive MCF-7 cells, P-FA exhibited comparable cell uptake with the unmodified linear polymer, whereas GP-FA resulted in 2-fold higher cell internalization over the untargeted graft polymer. Meanwhile, the involvement of folate receptor mediated endocytosis and augmented folate binding affinity of GP-FA were observed in comparison with P-FA. Moreover, GP-FA exhibited significantly enhanced tumor accumulation relative to GP, while marginally improved tumor accumulation was observed for P-FA compared with P. In summary, the structure of the hydrophilic polymer plays a vital role in the targeting efficiency of the conjugated hydrophobic ligand.