Abstract
In the present study, a novel pH-responsive amphiphilic copolymer, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] conjugated poly(β-amino esters) (DSPE-b-PEG-b-PAE-b-PEG-b-DSPE), was designed and successfully synthesized via Michael-type step polymerization. The chemical structure of the pentablock copolymer was confirmed with proton nuclear magnetic resonance (1H-NMR) and Fourier transform infrared (FT-IR) spectroscopy. The copolymer was able to self-assemble into core/shell polymeric micelles in aqueous solution at low concentrations, and its critical micelle concentration (CMC) value was 4.5 mg l−1 determined by fluorescence spectrophotometry. The pKb value of the copolymer was about 6.5, confirmed by acid–base titration, indicating the pH-sensitivity of the polymeric micelle. The hydrodynamic diameter, distribution and zeta potential of the polymeric micelles at different pH conditions were monitored by dynamic light scattering (DLS). Doxorubicin (DOX) was encapsulated into the core of the micelles with a high drug loading content (15.9%) and entrapment efficacy (60.4%). In vitro experiments demonstrated that the release behaviour of DOX from the DOX-loaded polymeric micelles (DOX-PMs) was pH-triggered. When the pH decreased from 7.4 to 5.0, the drug release rate was markedly accelerated. MTT assay showed that the copolymer had negligible cytotoxicity whereas the DOX-PMs displayed high toxicity for tumour cells such as B16F10, HepG2 and HeLa cell lines. The results demonstrated that these pH-sensitive polymeric micelles could be used as potential anti-cancer drug carriers for cancer chemotherapy with controlled release.
Highlights
To date, various therapeutic strategies for cancer have been emerging and have attracted more and more attention, but chemotherapy is still the most efficient method in clinical practice [1,2,3]
To obtain the amphiphilic pentablock copolymer which could self-assemble into polymeric micelles and respond to the acidity of targeted sites, we first synthesized pH-sensitive poly(β-amino esters) (PAE) with diacrylate esters on the two terminals using Michael-type step polymerization
The pH-responsive amphiphilic copolymer DSPE-b-PEG-b-poly(β-amino ester) (PAE)-b-PEG-b-DSPE was successfully synthesized via Michael-type polymerization, and its self-assembled polymeric micelles were prepared and used as carriers for the hydrophobic anti-cancer drug DOX
Summary
Various therapeutic strategies for cancer have been emerging and have attracted more and more attention, but chemotherapy is still the most efficient method in clinical practice [1,2,3]. When the pH is lower than the pKb, the PAE is able to be protonated sequentially and becomes soluble because of the ionization of the amine residues This physico-chemical property of PAE provides a significant potential in pH-triggered controlled drug release. We designed and synthesized a novel amphiphilic pH-sensitive copolymer containing PEGylated lipid and PAE block, and prepared the polymeric micelles which were used as carriers for anti-cancer drug delivery and controlled release. The tertiary amine groups of the PAE segment could be ionized, leading to swelling of the polymeric micelles and resulting in accelerated drug release rate from the DOX-PMs. The copolymers should display very little or no cytotoxicity, whereas the DOX-PMs should show high cytotoxic effect against tumour cells. The physico-chemical properties of the copolymer and polymeric micelles, including CMC value, particle size and zeta potential, pH-sensitivity, etc. should be well evaluated by various experimental techniques
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