Triggered-release polymeric conjugate micelles for on-demand intracellular drug delivery

Abstract

Nanoscale drug delivery platforms have been developed over the past four decades that have shown promising clinical results in several types of cancer and inflammatory disorders. These nanocarriers carrying therapeutic payloads are maximizing the therapeutic outcomes while minimizing adverse effects. Yet one of the major challenges facing drug developers is the dilemma of premature versus on-demand drug release, which influences the therapeutic regiment, efficacy and potential toxicity. Herein, we report on redox-sensitive polymer-drug conjugate micelles for on-demand intracellular delivery of a model active agent, curcumin. Biodegradable methoxy poly(ethylene glycol)-poly(lactic acid) copolymer (mPEG-PLA) was conjugated with curcumin via a disulfide bond or ester bond (control), respectively. The self-assembled redox-sensitive micelles exhibited a hydrodynamic size of 115.6 ± 5.9 (nm) with a zeta potential of -10.6 ± 0.7 (mV). The critical micelle concentration was determined at 6.7 ± 0.4 (μg mL(-1)). Under sink conditions with a mimicked redox environment (10 mM dithiothreitol), the extent of curcumin release at 48 h from disulfide bond-linked micelles was nearly three times higher compared to the control micelles. Such rapid release led to a lower half maximal inhibitory concentration (IC50) in HeLa cells at 18.5 ± 1.4 (μg mL(-1)), whereas the IC50 of control micelles was 41.0 ± 2.4 (μg mL(-1)). The cellular uptake study also revealed higher fluorescence intensity for redox-sensitive micelles. In conclusion, the redox-sensitive polymeric conjugate micelles could enhance curcumin delivery while avoiding premature release, and achieving on-demand release under the high glutathione concentration in the cell cytoplasm. This strategy opens new avenues for on-demand drug release of nanoscale intracellular delivery platforms that ultimately might be translated into pre-clinical and future clinical practice.

Nitric oxide-releasing graft polymer micelles with distinct pendant amphiphiles

“…When necessary, PHEMA can be replaced with biodegradable polymers e.g. 17 The main driving force of micelle self-assembly is the decreased system free energy as a consequence of the removal of hydrophobic segments from the aqueous medium to form micelle core and the exposure of hydrophilic segment into water. 22 The proton NMR peak area integration gave a molecular weight (M n ) of 3,612 Da for mPEG-PLA, and 1,630 Da for TPGS, individually.…”

“…12 In addition, the poor NO payloads, too rapid NO liberation and the lack of targeting has impeded the clinical translation of many small molecular NO donors, which necessitates the exploitation of macromolecular scaffold system. 16,17 Although NO-releasing micellar nanocarriers have been shown able to mimic endogenous NO production, the meticulous control of NO spatiotemporal delivery is still challenging. 14 Among these, self-assembled micelles made of amphiphilic building blocks (e.g.…”

Controlling and Monitoring Intracellular Delivery of Anticancer Polymer Nanomedicines

“…The redox sensitive micelles could enhance curcumin delivery while avoiding premature release as compared to control micelles containing an ester linker. [89] Poly(ethylene glycol) methyl ether methacrylate-b-poly(2-hydroxyethyl methacrylate), in which the poly(2-hydroxyethyl methacrylate) segment was modified with 3-(pyridin-2-yldisulfanyl)propanoic acid (PDP) (PEGMEA-b-PDPHEMA), allowed the linkage of paclitaxel via esterification reaction and subsequent selfassembly of the amphiphilic copolymer into micelles. [90] While the disulfide bond has been mostly used, another interesting motif that can be used to prepare redox responsive poly mer nanomedicines is the α,β-unsaturated carbonyl group.…”

Multifunctional dextran micelles as drug delivery carriers and magnetic resonance imaging probes

“…Aqueous micelle self-assembled from amphiphilic polymer, especially natural polymer, has shown various advantages, including reduced drug cytotoxicity as drug carriers, long blood circulation time, convenience for further surface functions, good biocompatibility, and low critical micelle concentration (CMC) [33][34][35][36][37]. In addition to their applications as drug delivery system, polymeric micelles can be used to load hydrophobic magnetic nanoparticles inside their hydrophobic core, forming a closed-packing structure.…”