Poly(γ-benzyl-L-glutamate)-PEG-alendronate multivalent nanoparticles for bone targeting

Abstract

Hydroxyapatite (HAP), a highly specific component of bone tissue, is the main target in order to impart osteotropicity. Bone targeted nanoparticles can increase the strength of the interaction with HAP through multivalency and thus constitute a valuable strategy in the therapeutics of skeletal diseases. PBLG10k-b-PEG6k-alendronate nanoparticles (~ 75 nm) were prepared by a simple nanoprecipitation method. The calcium affinity (KCa(+2)=1.8 × 10(4)M(-1)) of these nanoparticles was evaluated using isothermal titration calorimetry. The multivalent interaction with HAP surfaces (KHAP) was studied by fluorescence and was estimated to be 1.1 × 10(10)M(-1), which is more than 4000 times stronger than the reported monovalent interaction between alendronate and HAP surfaces. Molecular modeling suggests that the number of binding sites available at the HAP surface is in large excess than what is required for the whole surface coverage by alendronate decorated nanoparticles. The lower calcium affinity of these nanoparticles than for HAP allows calcium bound nanoparticles to interact with HAP, which yields a deeper understanding of bone targeted carriers and could potentially improve their bone targeting properties.

Keywords: (1)H NMR; ATR; Adsorption; BLG-NCA; Bone targeting; CDCl(3); CF3COOK; COOH; DCC; DCTB; DEE; DMF; DMSO; DPn; EtOH; FITC; HAP; ITC; Isothermal titration calorimetry; MALDI-TOF; MeO-PEG5k-NH2; MeOH; N,N′-dicyclohexylcarbodiimide; N-carboxylic anhydride; N-hydroxysuccinimide; NCA; NHS; NMR; Nanoparticles; PBLG; PBS; PEG; TEA; TEM; TFA; THF; UV; attenuated total reflection; benzyl; bnz; carboxylic acid; degree of polymerization; deuterated chloroform; diethyl ether; dimethyl sulfoxide; dimethylformamide; ethanol; fluorescein isothiocyanate; hydroxyapatite; isothermal titration calorimetry; matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; methanol; nuclear magnetic resonance; phosphate buffer saline; poly(γ-benzyl-l-glutamate); polyethylene glycol; potassium trifluoroacetate; proton nuclear magnetic resonance; tetrahydrofuran; trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene]malonitrile; transmission electron microscopy; triethylamine; trifluoroacetic acid; ultraviolet; α-methoxy-ω-amino poly(ethylene glycol)5000, NHSPEG6k-NHS, α,ω-Bis-N-hydroxysuccinimide-poly(ethylene glycol)6000; γ-benzyl-l-glutamate-N-carboxylic anhydride.