Synthesis and evaluation of novel amphiphilic macromolecules as drug carriers and therapeutics.

摘要

Novel amphiphilic star-like macromolecules (ASM) and amphiphilic scorpion-like macromolecules (AScM) with double-chained and single-chained tails were synthesized and characterized. All macromolecules are composed of mucic acid-based hydrophobic "heads" and poly(ethylene glycol)-based hydrophilic "tails". Two different ASMs (M12P5 and M12P2x2) and two different AScMs (NC12P5 and NC12P2x2) were investigated to explore how branched PEG chains influence particle size, water-solubility, drug loading capacity, drug release rate and micelle stability. A hydrophobic, anti-inflammatory drug (indomethacin) was used to evaluate the encapsulation ability and release rate from the macromolecules. The double-chained macromolecules reduced the micellar sizes (10 nm for AScM, 22 nm for ASM) compared to single-chained macromolecules (18 nm for AScM, 48 nm for ASM). Through oil/water emulsion methods, drug-loading efficiency of ASM reached nearly 50%, higher than the self-assembled micelle AScMs, which display a drug-loading efficiency 30%. Indomethacin-loaded ASM released 52% of free drug within 50 hours, compared with 78% for AScM. Dynamic light scattering experiments showed that ASM minimized protein interactions. Double-chained macromolecules perform as well or better than single-chained ones as drug delivery systems.;Several AScMs, which bear carboxylate groups on hydrophilic and hydrophobic domains, were also prepared. These macromolecules formed extremely stable micelles in aqueous solution with an average size of 20-35 nm and critical micelle concentration (CMC) as low as 10-7 M. Zeta potential values and micellar sizes in neutral buffer solutions correlated well with the carboxylate location and numbers. All macromolecules are capable of inhibiting unregulated uptake of highly-oxidized low density lipoproteins (LDL) by macrophages. This inhibition is caused by the interaction of scavenger receptors with negatively charged macromolecules, and closely responds to the number and location of negative charges. The AScM with one carboxylate at the hydrophobic domain and one carboxylate at hydrophilic domain exhibited the best LDL inhibition. To further enhance the treatment, a ligand GW 3965 was loaded into the AScM micelle.