Polymersome Formation by Amphiphilic Polyglycerol-b-polydisulfide-b-polyglycerol and Glutathione-Triggered Intracellular Drug Delivery

Abstract

This article reports the synthesis, spontaneous selfassembly, highly efficient drug encapsulation, and glutathione (GSH)triggered intracellular sustained drug delivery of an ABA-type amphiphilic triblock copolymer, namely, polyglycerol-b-poly-(disulfide)-b-polyglycerol (PG-b-PDS-b-PG). The bioreducible PDS block with reactive pyridyldisulfide groups present at the chain terminals was attached to thiol-terminated heterotelechelic PG by a thiol− disulfide exchange reaction producing the amphiphilic PG-b-PDS-b-PG. It formed a stable polymersome in aqueous medium with a critical aggregation concentration of 0.02 mg/mL and average hydrodynamic diameter (D h ) of 230 nm and showed highly efficient and stable encapsulation of doxorubicin (Dox) with a remarkably high drug loading efficiency (DLE) and drug loading content (DLC) of 54% and 16%, respectively. Fluorescence spectroscopy studies revealed GSH-triggered drug release and strong dependence of the release kinetics on the GSH concentration due to degradation of the amphiphilic block copolymer and disassembly of the polymersome. MTT assay indicated excellent biocompatibility of the block copolymer as >90% cells (HeLa or MDA-MB-231) were found to be alive after 96 h of incubation with a polymer concentration of up to 1.0 mg/mL, which was further validated by the hemolysis assay. Cytotoxicity assay of the Dox-loaded polymersome exhibited time and dose-dependent sustained killing of HeLa as well as MDA-MB-231 cells wherein after 48 h of incubation >50% cell killing was noticed with a Dox concentration of ∼4.0 and ∼8.7 μg/mL, respectively, while the free Dox showed faster cell killing. Flow cytometry and live cell fluorescence microscopy studies revealed time-dependent cellular uptake of the drug-loaded polymersome followed by diffusion of the drug to the nucleus. Cells with artificially enhanced GSH were killed at a much faster rate indicating that intracellular GSH-triggered disassembly is the key drug release mechanism.

Angiopep-2-Modified Carboxymethyl Chitosan-Based pH/Reduction Dual-Stimuli-Responsive Nanogels for Enhanced Targeting Glioblastoma

“…The drug-loading content (DLC) and the drug-loading efficiency (DLE) of CMCSN were measured by the UV spectrum and calculated by the following equations: DLC (%) = (weight of DOX in CMCSN)/(weight of CMCSN) × 100% and DLE (%) = (weight of DOX in CMCSN)/(weight of DOX) × 100%. 22 2.3. Characterization of DOX-ANG-CMCSN.…”

Acetal‐Based Functional Epoxide Monomers: Polymerizations and Applications

“…While epichlorohydrin is widely employed owing to its flexible transformation, glycidol is particularly used for the synthesis of functional epoxide monomers bearing acetal groups by reacting with vinyl ether (Figure 2b). In the case of EEGE (one of the most widely used glycidyl ether monomers bearing an acetal group as a latent hydroxyl group), [ 34–36 ] the vinyl ether group reacts with glycidol under moderate acidic conditions to produce the acetal linkage in a single step with high yield. [ 19 ] As various vinyl ethers can be incorporated into glycidol, our group has successfully prepared a series of acetal functionalized epoxide monomers using diverse vinyl ether groups such as cyclic and acyclic vinyl ethers.…”

Dually Responsive Poly(N-vinylcaprolactam)-b-poly(dimethylsiloxane)-b-poly(N-vinylcaprolactam) Polymersomes for Controlled Delivery

“…To improve the efficacy of anticancer drugs, polymer-drug delivery carriers, including polymer conjugates, nanoparticles, and micelles, have been used to shield the therapeutics and prevent their premature release in healthy tissues [ 2 , 3 , 4 , 5 , 6 , 7 ]. Among those, polymer vesicles assembled from block copolymers, i.e., polymersomes, have been recognized as effective nanocarriers because of their cell-mimetic membranes, improved colloidal and mechanical stability, and increased efficiency in drug entrapment, unlike liposomes [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ].…”

“…Borchert et al reported a quick dissolution of poly(2-vinylpyridine)- b -poly(ethylene glycol) (PEG) polymersomes at the pH drop from 7.4 to 5.5, triggering a fast release of 4-methoxy coumarin fluorescent dye [ 28 ]. Although the close-to-physiological pK a of the membrane copolymer was exploited for the disassembly of a non-degradable membrane, [ 10 ] degradable polymersomes that produce nontoxic byproducts of low molecular weight (<20 kDa) would be more desirable for systemic delivery.…”