Poly(glyoxylates): a new class of depolymerizable materials with amplified response to stimuli and applications in drug delivery

摘要

Introduction: In recent years, there has been significant interest in stimuli-responsive materials. While successful in the lab, a challenge in their application is that numerous stimuli-mediated events are required to impart changes in properties. Self-immolative polymers (SIPs) were developed to address this limitation. Upon cleavage of a single stimulus-responsive end-cap, an SIP undergoes complete end-to-end depolymerization. Several SIP backbones including polycarbamates, and poly(o-phthalaldehyde)s have been developed. However, their application has been hindered by: 1) expensive, multistep monomer syntheses; 2) depolymerization to toxic species such as quinone methides or o-phthalaldehyde. Described here is poly(ethyl glyoxylate) (PEtG) as a linear SIP and its application in stimuli-responsive micelles for drug delivery. PEtG can be synthesized from the commercially available monomer ethyl glyoxylate (EtG). Depolymerization produces glyoxylic acid hydrate, a metabolic intermediate in the glyoxylic acid cycle which has been shown to be non-toxic (Fig. 1b). Methods: EtG was distilled twice over P_2O_5, dissolved in CH_2Cl_2, and then polymerized for 1 h at -20 °C in the presence of NEt_3 (Fig. 2) To end-cap the polymer, 1 was added. The solution was allowed to reach ambient temperature over 24 h then heated at 40 °C for 16 h. The polymer 2 was precipitated in methanol. A similar strategy could be used to also prepare PEtG with end-caps responsive to stimuli such as H_2O_2 or thiols by varying the structure of end-cap 1. Block copolymer 3 was formed by coupling with an azide-terminated poly(ethylene oxide) (PEO, 2 kg/mol) in N,N-dimethylformamide (DMF) in the presence of CuSO4 and sodium ascorbate. Self-assembly was performed by the addition of a dimethylsulfoxide (DMSO) solution of block copolymer into water followed by the removal of DMSO by dialysis. Doxorubicin loading was accomplished using a dialysis procedure. Micelle degradation was triggered by irradiation with UV light (wavelength: 300-350 nm, 23 mWcm~(-2)), while controls were kept in the dark. Results and Discussion: Polymerization of EtG afforded polymer 2 with a number average molar mass (Mn) of 42 kg/mol and a dispersity (D) of 2.0 based on size exclusion chromatography (SEC) in tetrahydrofuran relative to polystyrene standards. End-cap 1 is cleavable with UV light and also has an alkyne for conjugation of another polymer. Coupling of PEO was confirmed by a combination of SEC and NMR spectroscopy. Self-assembly of the resulting amphiphilic copolymer 3 afforded micelles with diameters of ～50 nm as measured by dynamic light scattering and transmission electron microscopy (Fig. 3a). Irradiation with UV light for 10 min resulted in rapid depolymerization of the micelles as measured by NMR spectroscopy. In contrast a non-irradiated control was stable for 24 h. To demonstrate the application of these micelles for triggered anti-cancer drug delivery, they were loaded with doxorubicin (Dox). Irradiation resulted in release of 75% of Dox over 50 h, in comparison with a control that was not irradiated and released only 20% of the drug over this time (Fig. 3b). Conclusions: PEtG was synthesized and capped with a moiety imparting responsiveness to UV light and enabling conjugation of PEO to afford an amphiphilic SIP. The copolymer assembled into micelles and these micelles rapidly depolymerized in response to UV light. The anti-cancer drug Dox was loaded into the micelles and they afforded selected release of Dox upon irradiation. These results, combined with the depolymerization of PEtG to non-toxic glyoxylic acid suggest the promise of these materials for drug delivery applications. It is also possible to easily tune the responsiveness to different stimuli by changing the end-cap.