Bioreducible Micelles Research Articles

Optimization of bioreducible micelles self‐assembled from amphiphilic hyperbranched block copolymers for drug delivery

ABSTRACTDendritic polymers‐based unimolecular micelles with enhanced stability are attractive carriers. However, the preparation of dendrimers or dendrons with higher generation remains substantially synthetic challenge due to the increased steric hindrance, multistep and tedious preparation, and low yields. The adoption of Boltorn H40, a commercially available dendritic polymer of Boltorn family containing multiple hydroxyl groups with various functionalities as a dendrimer‐based starting core template for the generation of hyperbranched polymers, offers a straightforward solution to address this problem. To develop universal strategies toward H40‐based amphiphilic block copolymers, the “grafting from” and “grafting to” approaches were both applied in this study. The reduction‐insensitive block copolymers, H40‐b‐poly(ɛ‐caprolactone)‐b‐poly(oligo(ethylene glycol) monomethyl ether methacrylate) (H40‐b‐PCL‐b‐POEGMA), were synthesized by “grafting from” including sequential ring‐opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The core structure and the polymer composition of the nonreducible amphiphilic hyperbranched block copolymers were optimized toward better properties and performance for drug delivery applications, and H40‐PCL15‐b‐POEGMA23 was screened as the best polymer construct relative to H20‐PCL15‐b‐POEGMA23 and H40‐PCL15‐b‐POEGMA32 in terms of micelle stability and drug loading capacity. Therefore, the reducible H40‐b‐PCL‐SS‐POEGMA with an identical core and polymer composition to that of H40‐PCL15‐b‐POEGMA23 was further prepared by “grafting to” using click coupling between H40‐PCL‐azide and P(OEGMA)‐alkyne. The delivery efficacy evaluated by an in vitro cytotoxicity study revealed that the resulting DOX‐loaded reducible micelles of H40‐PCL15‐SS‐POEGMA23 produced greater cytotoxicity in cancer cells than in normal cells and macrophages, therefore, are promising carriers for anticancer drug delivery. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1383–1394

Acid-Labile Degradation of Injectable Fiber Fragments to Release Bioreducible Micelles for Targeted Cancer Therapy.

Cancer chemotherapy is confronted with difficulties enhancing the tumor accumulation, improving the bioavailability, and relieving the adverse effect of chemotherapeutic agents. To address the challenges, this study proposes a feasible strategy to realize a sustained release of drug-loaded micelles from fiber fragments after intratumoral injection. Camptothecin (CPT) is grafted on hyaluronic acid (HA) via 3,3'-dithiodipropionic acid to obtain reduction-sensitive promicelle polymers (PMCPT), which are conjugated with poly(d,l-lactide) via 2-propionic-3-methylmaleic anhydride (CDM) to obtain acid-labile copolymers for the preparation of injectable fiber fragments. Fiber fragments show remarkable acid-sensitive degradation, and the released PMCPT are spontaneously self-assembled into micelles, followed by subsequent HA-mediated internalization into tumor cells and reduction-sensitive release of drugs in the cytosol. Compared to fresh micelles prepared by ultrasonication, the micelles released via the degradation of fiber fragments display similar behaviors, such as the size and morphology, glutathione-sensitive drug release, cellular uptake efficiency, and cytotoxicity. Taking advantage of the aggregation-induced emission (AIE) effect of tetraphenylethene (TPE), the micelle release, cellular uptake, and tumor accumulation have been elucidated from the self-assembly induced fluorescence light-up in vitro and after intratumoral injection. Compared to the intratumoral injection of free micelles, sustained micelle release from fiber fragments resulted in significantly higher antitumor efficacy with respect to the inhibition of tumor growths, prolonging of animal survivals, and induction of cell apoptosis in tumor tissues. Thus, the micelle-releasing fiber fragments integrated with double targeting capabilities and double stimuli responsiveness have demonstrated a superior capacity to sustainably deliver chemotherapeutic agents directly within tumor cells.

Bioreducible Micelles Self-Assembled from Poly(ethylene glycol)-Cholesteryl Conjugate As a Drug Delivery Platform

The ability of polymeric micelles to self-assemble into nanosized particles has created interest in their application as potential anticancer drug delivery systems. A poly(ethylene glycol)-cholesteryl conjugate (Chol-ss-PEG-ss-Chol) connected by cleavable disulfide linkages was synthesized and used as a nanocarrier for in vitro release of doxorubicin (DOX). Owing to its amphiphilic structure, Chol-ss-PEG-ss-Chol was able to self-assemble into micelles with an average diameter 18.6 nm in aqueous solution. The micelles formed large aggregates due to the shedding of the PEG shell through cleavage of disulfide bonds in a reductive environment. The in vitro release studies revealed that Chol-ss-PEG-ss-Chol micelles released 80% and approximately 9% of the encapsulated DOX within 6 h under reductive and non-reductive conditions, respectively. The glutathione (GSH)-mediated intracellular drug delivery was investigated in a KB cell line. The cytotoxicity of DOX-loaded micelles indicated a higher cellular anti-proliferative effect against GSH-pretreated than untreated KB cells. Furthermore, confocal laser scanning microscopy (CLSM) measurement demonstrated that Chol-ss-PEG-ss-Chol micelles exhibited faster drug release in GSH-pretreated KB cells than untreated KB cells. These results suggest the potential usefulness of disulfide-based polymeric micelles as controlled drug delivery carriers.

Bioreducible Micelles with Endosomal Buffering and Multidrug Resistance-Reversing Function Enhance Anti-Tumor Efficacy of Doxorubicin.

The clinical success of anthracyclines-containing chemotherapy for breast cancer is mainly restricted by cardiac damage and the development of multidrug resistance (MDR). For efficient reversal of drug resistance, doxorubicin (DOX) loaded multifunctional bioreducible micelles were constructed from a new amphiphilic copolymer consisting of polyethylene glycol and poly[bis(2-hydroxylethyl)-disulfide-diacrylate-β-histamine and characterized. The introduction of imidazole group endowed the micelles with endosomal buffering capacity and improved the endosomal escape. The reduction-responsiveness of the micelles promoted DOX release. The activity of P-glycoprotein, one of the most well-described drug-efflux pumps, and glutathione S-transferase, an important detoxification enzyme, were also inhibited by the micelles. The accumulation of DOX in tumor after intravenous administration of the drug-loading micelles was increased in drug resistant tumor-bearing mice. These results indicated that the micelle was a promising drug delivery system for MDR cancer therapy.

Biocompatible and bioreducible micelles fabricated from novel α-amino acid-based poly(disulfide urethane)s: design, synthesis and triggered doxorubicin release

Novel α-amino acid-based poly(disulfide urethane)s have been developed for the construction of smart triblock copolymer micelles that show good biocompatibility, fast reductive degradation, and triggered intracellular drug release behavior.

Bioreducible Micelles Self-Assembled from Amphiphilic Hyperbranched Multiarm Copolymer for Glutathione-Mediated Intracellular Drug Delivery

A new type of biodegradable micelles for glutathione-mediated intracellular drug delivery was developed on the basis of an amphiphilic hyperbranched multiarm copolymer (H40-star-PLA-SS-PEP) with disulfide linkages between the hydrophobic polyester core and hydrophilic polyphosphate arms. The resulting copolymers were characterized by nuclear magnetic resonance (NMR), Fourier transformed infrared (FTIR), gel permeation chromatography (GPC), and differential scanning calorimeter (DSC) techniques. Benefiting from amphiphilic structure, H40-star-PLA-SS-PEP was able to self-assemble into micelles in aqueous solution with an average diameter of 70 nm. Moreover, the hydrophilic polyphosphate shell of these micelles could be detached under reduction-stimulus by in vitro evaluation, which resulted in a rapid drug release due to the destruction of micelle structure. The glutathione-mediated intracellular drug delivery was investigated against a Hela human cervical carcinoma cell line. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements demonstrated that H40-star-PLA-SS-PEP micelles exhibited a faster drug release in glutathione monoester (GSH-OEt) pretreated Hela cells than that in the nonpretreated cells. Cytotoxicity assay of the doxorubicin-loaded (DOX-loaded) micelles indicated the higher cellular proliferation inhibition against 10 mM of GSH-OEt pretreated Hela cells than that of the nonpretreated ones. As expected, the DOX-loaded micelles showed lower inhibition against 0.1 mM of buthionine sulfoximine (BSO) pretreated Hela cells. These reduction-responsive and biodegradable micelles show a potential to improve the antitumor efficacy of hydrophobic chemotherapeutic drugs.

Bioreducible micelles and hydrogels with tunable properties from multi-armed biodegradable copolymers

Multi-armed biodegradable block copolymers with a bioreducible core mPCL-b-PEO were for the first time synthesized by thiol-yne click chemistry. They self-assembled into bioreducible micelles and hydrogels in aqueous solution, which demonstrated tunable size, mechanical and drug-release properties.