Abstract
Previously we synthesized redox sensitive polyurethane micelles, core crosslinked by diisocyanates (PU-CCL). To improve the intracellular drug release and tumor cellular toxicity of anticancer drugs loaded into polyurethane micelles, we now describe redox sensitive polyurethane micelles with tunable surface charge switchabilities, crosslinked with pH cleavable Schiff bonds, as anticancer drug carriers. Different amounts of 1,6-diaminohexane were connected onto the pendant carboxyl groups of amphiphilic multi-blocked polyurethane (PU-SS-COOH), resulting in polyurethanes with various ratios of pendant carboxyl and amine groups (denoted as PU-SS-COOH-NH2-1, PU-SS-COOH-NH2-2 and PU-SS-COOH-NH2-3). The surface charge switched as the pH was increased for PU-SS-COOH-NH2-1, PU-SS-COOH-NH2-2 and PU-SS-COOH-NH2-3. Then the PU-SS-COOH-NH2-3 micelles, dissolved in water, were crosslinked by glutaraldehyde resulting in surface charge switchable and reduction responsive polyurethane micelles with acid cleavable crosslinks (PU-ACCL). The crosslinked polyurethane micelles (PU-ACCL) demonstrated superior particle stability in phosphate buffered saline (PBS, pH = 7.4) solution without reducing agents, whereas the drug release rate was markedly accelerated by the addition of glutathione (GSH). Notably, the drug release from PU-ACCL was further accelerated in acidic fluid as the result of acid induced cleavage of the crosslinks. In vitro cytotoxicity studies demonstrated that doxorubicin (DOX)-loaded PU-ACCL micelles displayed increased cytotoxicity against tumor cells which was comparable to that obtained for DOX loaded into uncrosslinked polyurethane micelles. The reduction responsive and surface charge switchable polyurethane micelles with acid cleavable crosslinks, which have superior extracellular stability and provide rapid intracellular drug release, may hold great potential as a bio-triggered drug delivery system for cancer therapy.
Highlights
Stimuli-responsive self-assembled micelles based on amphiphilic blocked copolymers or surfactants have been developed as drug carriers in recent years, to encapsulate and protect hydrophobic drugs from premature release and immune clearance.1–6 The release of the payloads from these responsive micelles happens in a controlled manner on arrival at the target site, only when triggered by external stimuli, such as light, temperature, pH, redox potential, enzymes and ionic strength.7–12 Recently, multi-responsive assemblies have been developed to optimize the release of functional species in different environments
The Schiff's base is relatively stable in physiological conditions, while it can be considered to be completely decomposed at a pH value below 6.5.20–23 the primary amine groups are formed again in an acidic microenvironment a er the cleavage of the Schiff base bonds which may facilitate the cellular uptake of PU micelles and the endosome escape process
The results showed that empty PU-SS-COOH, PU-SS-COOH-NH2-3 and PUACCL micelles had very low cytotoxicity in two different cell lines, even at micelle concentrations of up to 1 mg mLÀ1, suggesting the nontoxic nature of the PU micelles to Human Umbilical Vein Endothelial Cells (HUVECs) and HepG2 cells (Fig. S5†)
Summary
Stimuli-responsive self-assembled micelles based on amphiphilic blocked copolymers or surfactants have been developed as drug carriers in recent years, to encapsulate and protect hydrophobic drugs from premature release and immune clearance. The release of the payloads from these responsive micelles happens in a controlled manner on arrival at the target site, only when triggered by external stimuli, such as light, temperature, pH, redox potential, enzymes and ionic strength. Recently, multi-responsive assemblies have been developed to optimize the release of functional species in different environments. Stimuli-responsive self-assembled micelles based on amphiphilic blocked copolymers or surfactants have been developed as drug carriers in recent years, to encapsulate and protect hydrophobic drugs from premature release and immune clearance.. Multi-responsive assemblies have been developed to optimize the release of functional species in different environments. Biodegradable multi-segmented polyurethanes (PUs) with stimuli responsive properties have been widely studied as drug carriers due to their good 17888 | RSC Adv., 2018, 8, 17888–17897. Paper redox and pH responsive properties and enhanced drug release efficiency (PU-ACCL). It is reasonable to expect an enhanced anticancer activity of DOX when loaded into glutaraldehyde crosslinked PU micelles (PU-ACCL). To the best of our knowledge, redox sensitive PU micelles crosslinked by pH labile Schiff base bonds have not been reported previously (Scheme 1)
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