Facile Preparation of Reduction-Responsive Micelles Based on Biodegradable Amphiphilic Polyurethane with Disulfide Bonds in the Backbone

Abstract

In this paper, we synthesized a biodegradable amphiphilic polymer of polyurethane-polyethylene glycol with disulfide bonds in the main chain (PEG-PU(SS)-PEG). DLS and SEM showed that the polymer could self-assemble into micelles in aqueous solution and could be used to load the hydrophobic anticancer drug DOX. Intriguingly, drug release in vitro indicated that DOX-loaded PEG-PU(SS)-PEG micelles had good stability under the extracellular physiological environment, but the disulfide bonds broke rapidly and DOX was released quickly under the intracellular reducing conditions. CCK-8 assays showed that DOX-loaded PEG-PU(SS)-PEG micelles had a high in vitro antitumor activity in C6 cells, whereas blank PEG-PU(SS)-PEG micelles were nontoxic to C6 cells. It was also found that there was strong and persistent accumulation of DOX-loaded PEG-PU(SS)-PEG as compared with PEG-PU-PEG both by the cell internalization tests and the flow cytometry measurements. Hence, PEG-PU(SS)-PEG micelles will have a potential use for clinical treatment of cancer in the future.

Polymer-Based Systems for Controlled Release and Targeting of Drugs

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The current need to find new advanced approaches to carry biologically active substances (conventional organic drugs, peptides, proteins (such as antibodies), and nucleic acid-based drugs (NABDs such as siRNA and miRNA)) in the body fluids, to realize targeted therapies and even personalized ones, goes hand in hand with research on the performance of new materials to better realize appropriate drug vectors [1].Polymeric materials can be designed and manufactured to obtain delivery systems with the appropriate characteristics in terms of drug release and performance [2]. For use in human applications, the polymer must primarily be biocompatible and non-toxic, and then functionalizable to give the appropriate structural and functional characteristics, such as to make it easily workable, processed, and engineered to obtain the desired system, and to be applied in drug delivery and targeting and/or in diagnosis of diseases.The further possibility of decorating the surface of these polymeric systems (due to the characteristics of the material that constitutes the matrix) with ligands capable of interacting specifically with membrane receptors on cells represents a unique advantage for obtaining targeted drug release to a specific organ, tissue, or cell type [3][4][5][6][7].In this issue, some current examples of design and production of polymeric materials, as well as of searching strategies to modify existing ones, for the making of innovative systems for drug delivery and/or regenerative medicine are collected.In particular, polymeric systems from nanoscale (micelles [8,9], nanoparticles [10,11]) to microscale structures (microparticles [12,13]), and to macrodevices (hydrogels [14] and films [15]) were produced. All the described systems were designed for the controlled and targeted release of conventional or biological drugs, such as paclitaxel [10], or siRNA [11] in the treatment of diseases such as cancer [8] and buccal and skin infections [15,16] by the systemic or local administration route [17].

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“…For use in human applications, the polymer must primarily be biocompatible and non-toxic, and then functionalizable to give the appropriate structural and functional characteristics, such as to make it easily workable, processed, and engineered to obtain the desired system, and to be applied in drug delivery and targeting and/or in diagnosis of diseases.The further possibility of decorating the surface of these polymeric systems (due to the characteristics of the material that constitutes the matrix) with ligands capable of interacting specifically with membrane receptors on cells represents a unique advantage for obtaining targeted drug release to a specific organ, tissue, or cell type [3][4][5][6][7].In this issue, some current examples of design and production of polymeric materials, as well as of searching strategies to modify existing ones, for the making of innovative systems for drug delivery and/or regenerative medicine are collected.In particular, polymeric systems from nanoscale (micelles [8,9], nanoparticles [10,11]) to microscale structures (microparticles [12,13]), and to macrodevices (hydrogels [14] and films [15]) were produced. All the described systems were designed for the controlled and targeted release of conventional or biological drugs, such as paclitaxel [10], or siRNA [11] in the treatment of diseases such as cancer [8] and buccal and skin infections [15,16] by the systemic or local administration route [17]. The starting polymeric materials were chosen from hydrophilic polysaccharides [11,16] to hydrophobic polyesters [9,14], obtaining blended materials or copolymers, which were used to obtain drug delivery systems by using techniques such as microfluidics or hot punching [12,13].Polymeric porous microparticles are currently emerging due to their potential for various applications, such as floating drug delivery systems and inhaled formulations.…”

“…In particular, polymeric systems from nanoscale (micelles [8,9], nanoparticles [10,11]) to microscale structures (microparticles [12,13]), and to macrodevices (hydrogels [14] and films [15]) were produced. All the described systems were designed for the controlled and targeted release of conventional or biological drugs, such as paclitaxel [10], or siRNA [11] in the treatment of diseases such as cancer [8] and buccal and skin infections [15,16] by the systemic or local administration route [17].…”

“…In particular, polymeric systems from nanoscale (micelles [8,9], nanoparticles [10,11]) to microscale structures (microparticles [12,13]), and to macrodevices (hydrogels [14] and films [15]) were produced. All the described systems were designed for the controlled and targeted release of conventional or biological drugs, such as paclitaxel [10], or siRNA [11] in the treatment of diseases such as cancer [8] and buccal and skin infections [15,16] by the systemic or local administration route [17]. The starting polymeric materials were chosen from hydrophilic polysaccharides [11,16] to hydrophobic polyesters [9,14], obtaining blended materials or copolymers, which were used to obtain drug delivery systems by using techniques such as microfluidics or hot punching [12,13].…”

“…Zhang and coworkers described the realization of nanoparticles starting from a temperature-responsive PEGylated polyaspartamide derivative, which were used to carry paclitaxel, showing suitable characteristics that make it a promising drug delivery system [10]. In another paper, biodegradable polymeric micelles based on a polyurethane-polyethylene glycol copolymer with disulfide bonds in the main chain (PEG-PU(SS)-PEG) were produced [8]. These systems were able to enable quick release of entrapped doxorubicin under intracellular reducing conditions.…”