Sythesis of Glycopeptide Nanoparticles and Investigation of Their Efficacy in Cancer Therapy

Platinum drugs are highly efficient in the treatment of cancer despite of their adverse side effects. To reduce side-effects, development of nanocarriers with precise biological functions is a critical requirement. Platinum... [ view full abstract ]

Platinum drugs are highly efficient in the treatment of cancer despite of their adverse side effects. To reduce side-effects, development of nanocarriers with precise biological functions is a critical requirement. Platinum drugs are most commonly delivered by conjugating the drug directly to the drug carrier, less via physical encapsulation. The therapeutic potency of platinum-based anticancer drugs can be substantially improved through the use of polymeric nanocarrier systems to target cancer cells efficiently.

In this work, we synthesised a series of glycopeptide triblock copolymers with three different sugars able to self-assemble into nanoparticles when conjugated with cis-platin (cis-Pt). The monomer trimethylsilyl-protected propargyl methacrylate (TMSpMA) was polymerized in the presence of a furan protected maleimide functionalized reversible addition-fragmentation chain transfer (RAFT) agent. P(TMSpMA) Macro-RAFT agent was then chain extented with the monomer of 1,1-Di-tert-butyl 3-(2-(Methacryloyloxy)ethyl)-butane-1,1,3-tricarboxylate (MAETC). On the other hand, poly(β-benzyl L-glutamate) (PBLG) was prepared through the ring-opening polymerization of BLG-NCA and PBLG was coupled with P(TMSpMA-b-MAETC) via click reaction to give corresponding triblok glycopeptide polymer. After deprotection of trimethylsilyl units, a range of glucosylated triblock copolymer were synthesized by reacting a mixture of 2-azideoethyl β-D-glucopyranoside (GlcEtN₃), 2-azideoethyl β-D-mannopyranoside (ManEtN₃) and 2-azidoethyl β-L-fucopyranoside (FucEtN₃) with P(PMA-b-MAETC-b-PLBG) using copper-catalyzed azide−alkyne cycloaddition (CuAAC). The resulting polymer was used as a macromolecular ligand for the conjugation with platinum drug. Thermogravimetric analysis revealed full conjugation. The resulting drug loaded nanoparticles had hydrodynamic diameters of around 100 nm.

They were all readily taken up intracellularly by the breast cancer cell lines MCF-7 and MDA-MB-231, prostat cancer cell line PC3 and the renal cancer cell line 769-P. All cell lines expressed a high preference for the fucosylated nanoparticles. The nanocarriers were themselves nontoxic, but exhibited high cytotoxicity and increased efficacy when conjugated with the cis-Pt drug. This finding suggests that these glycopeptide based nanoparticles can be used for targeted drug delivery toward cancer cells.