Stimuli-Responsive Micelles with Detachable Poly(2-ethyl-2-oxazoline) Shell Based on Amphiphilic Polyurethane for Improved Intracellular Delivery of Doxorubicin

Abstract

Polyurethanes (PUs) have various biomedical applications including controlled drug delivery. However, the incompletely release of drug at tumor sites limits the efficiency of these drug loaded polyurethane micelles. Here we report a novel polymer poly(2-ethyl-2-oxazoline)-SS-polyurethane-SS-poly(2-ethyl-2-oxazoline) triblock polyurethane (PEtOz-PU(PTMCSS)-PEtOz). The hydrophilic pH-responsive poly(2-ethyl-2-oxazoline) was used as an end-block to introduce pH responsiveness, and the hydrophobic PU middle-block was easily synthesized by the reaction of poly (trimethylene carbonate) diol containing disulfide bonds (PTMC-SS-PTMC diol) and bis (2-isocyanatoethyl) disulfide (CDI). PEtOz-PU(PTMCSS)-PEtOz could self-assemble to form micelles (176 nm). The drug release profile of PEtOz-PU(PTMCSS)-PEtOz micelles loaded with Doxorubicin (DOX) was studied in the presence of acetate buffer (10 mM, pH 5.0) and 10 mM dithiothreitol (DTT). The results showed that under this environment, DOX-loaded polyurethane micelles could release DOX faster and more thoroughly, about 97% of the DOX was released from the DOX-loaded PEtOz-PU(PTMCSS)-PEtOz micelle. In addition, fluorescent microscopy and cell viability assays validated that the DOX-loaded polyurethane micelle strongly inhibits the growth of C6 cells, suggesting their potential as a new nanomedicine against cancer.

Biomedical Polyurethanes for Anti-Cancer Drug Delivery Systems: A Brief, Comprehensive Review

“…One of the more interesting examples of such a system is the pH and redox dual-stimuli-responsive PU micelles prepared from PTMC–SS–PTMC, CDI, and PEOtz–OH ( Figure 7 ). In vitro drug release profiles and cell experiments confirmed that the obtained PU micelles caused controlled DOX release to C6 cells [ 41 ]. Another example of a dual system is dendritic PUs synthesized from dipentaerythritol, HDI, mPEG-2000, and glycerol.…”

“…Biodegradable PU used in PU-DDSs production can be obtained via polyaddition [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ] or the polycondensation process [ 69 ]. IPDI, HDI, LDI, CDI, HMDI, and BDI were used as IC components in biodegradable PUs synthesis.…”

“…Dual-controlled anti-cancer DDSs were also obtained [ 41 ]. One of the more interesting examples of such a system is the pH and redox dual-stimuli-responsive PU micelles prepared from PTMC–SS–PTMC, CDI, and PEOtz–OH ( Figure 7 ).…”

Polymeric capsules and micelles as promising carriers of anticancer drugs

“…35 Poly(2-ethyl-2-oxazoline) (PEtOz) is considered as an alternative to PEG because of biocompatibility, biodegradability and ability to prolong the circulation time of nanocarriers. 36 Both PEG and PEtOz can constitute hydrophilic segments of copolymers forming polymeric micelles.…”

“…52,130 Hence, the fabrication of pH responsive capsules is a very common practice -for example regarding doxorubicin-loaded polyelectrolyte microcapsules built of sodium poly(styrene sulfonate) and poly(allylamine hydrochloride), 131 micelles made of mPEG-b-PCL, 52 PEG-PBLA, 20,130 and PEtOz-bpolyurethane-SS-b-PEtOz. 36,132 In the abovementioned cases, the release of cytostatic drug was intensified as the pH decreased, because a slightly acidic conditions contributed to the rapid disassembling of polymer micelles.…”