Abstract
Doxorubicin-loaded PLGA nanoparticles conjugated with a new galactose-based ligand for the specific recognition by human hepatoma cellular carcinoma cells (Hep G2) were successfully produced. The new targeting compound was selected using molecular docking combined with quantum chemical calculations for modelling and comparing molecular interactions among the H1 subunit of the asialoglycoprotein receptor containing the carbohydrate recognition domain and the ligand. The ligand, bis(1-O-ethyl-β-D-galactopyranosyl)amine, was synthetized, characterized, and subsequently linked to PLGA. Unloaded (PLGA-di-GAL NP) and doxorubicin-loaded (DOX-PLGA-di-GAL NP) nanoparticles were prepared using an emulsion method and characterized. The produced DOX-PLGA-di-GAL NP are spherical in shape with a size of 258 ± 47 nm, a zeta potential of −62.3 mV, and a drug encapsulation efficiency of 83%. The in vitro drug release results obtained show a three-phase release profile. In vitro cell studies confirmed the interaction between Hep G2 cells and PLGA-di-GAL NP. Cell cytotoxicity tests showed that unloaded NP are nontoxic and that DOX-PLGA-di-GAL NP caused a decrease of around 80% in cellular viability. The strategy used in this work to design new targeting compounds represents a promising tool to develop effective hepatocyte targeting drug delivery systems and can be applied to other tissues/organs.
Highlights
Delivering drugs is a major challenge in clinical development since drugs are frequently limited by dose-limiting toxicity and to a low specificity to the desirable organ or tissue
In order to determine the effect of having a polymer chain attached to the ligand on asialoglycoprotein receptor (ASGP-R) recognition, since the target compound, PLGA-di-GAL has a long polymer chain, and as it is impossible to apply the full length of the chain in the docking study, the presence of a monomer, a dimer, a trimer and a tetramer as well as the ligands alone (1a, 2a, and 3a) were analyzed
The new targeting compound, containing two galactose units, was selected using molecular docking combined with quantum chemical calculations for modelling and comparing molecular interactions among the carbohydrate recognition domain of the
Summary
Delivering drugs is a major challenge in clinical development since drugs are frequently limited by dose-limiting toxicity and to a low specificity to the desirable organ or tissue. Can be used as drug carriers since they can circulate in the blood or cross cell membranes and be internalized. Designing NP containing moieties capable to be recognized by proteins that are expressed in target cells is a viable synthesis strategy to obtain specificity and efficiency. Apart from improving the drug therapeutic index, drug targeting by nanoparticles can offer all the advantages of drug carrier systems: the incorporation of several drugs for combination therapy or different therapeutic modalities, Polymers 2020, 12, 94; doi:10.3390/polym12010094 www.mdpi.com/journal/polymers. Polymers 2020, 12, 94 a controlled release of drug, the ability to carry hydrophobic drugs, and a protection against drug degradation, while causing lower systemic toxicity since drugs are biologically unavailable during transit in systemic circulation [1,2,3,4]. Liver diseases are difficult to treat as efficient drugs are not currently available [5]. For instance, is the fifth most common cancer in the Unites
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