Preparation of Copolymer Paclitaxel Covalently Linked via a Disulfide Bond and Its Application on Controlled Drug Delivery

Abstract

A novel controlled drug delivery system based on copolymer covalently linked paclitaxel via a disulfide bond was constructed. Copolymer with poly(ethylene glycol) (PEG) side chains and carboxyl groups on the backbone was prepared by radical copolymerization of tert-butyl acrylate and poly(ethylene glycol) methyl ether acrylate, followed by selectively hydrolyzing tert-butyl groups to carboxyl groups. Utilizing the carboxyl group as an active reaction site, paclitaxel, a well-known chemotherapeutic drug, could be covalently linked to the backbone of a copolymer via a disulfide bond, and the loading content of paclitaxel could reach up to 32 wt %. In aqueous solution, this drug-loaded copolymer could self-assemble into a spherical micelle, with the hydrophobic drug as the core and hydrophilic PEG as the shell. The mean diameter of the micelles evaluated by transmission electron microscopy (TEM) and dynamic light scattering (DLS) was approximately 60 nm. The in vitro cytotoxicity experiments showed that the copolymer was biocompatible and suitable to use as a drug carrier. After covalently loading the drug, the copolymer showed apparent cytotoxicity to OS-RC-2 cells (kidney tumor cells) and low cytotoxicity to macrophage cells (human normal cells), indicating that the disulfide bond was stable in human normal cells, but would be broken in tumor cells. This selective bond scission behavior is potentially favorable for reducing the toxic and side effects of chemotherapeutic drugs.

Disulfide bond based polymeric drug carriers for cancer chemotherapy and relevant redox environments in mammals

“…ADR‐HSA NPs showed significantly enhanced antitumor effects compared with PBS and ADR/HSA NPs. Chen et al . synthesized a copolymer with PEG side chains and carboxyl groups on the backbone.…”

“…ADR-HSA NPs showed significantly enhanced antitumor effects compared with PBS and ADR/HSA NPs. Chen et al 135 synthesized a copolymer with PEG side chains and carboxyl groups on the backbone. PTX was covalently linked to the copolymer backbone via a disulfide bond, which utilized the We have developed DDS based on methoxy PEG-poly( -benzyl L-glutamate)-disulfide-docetaxel (mPEG-PBLG-SS-DTX) to improve the cancer therapy effect.…”

Facile Fabrication of Tumor Redox‐Sensitive Nanoassemblies of Small‐Molecule Oleate Prodrug as Potent Chemotherapeutic Nanomedicine

“…The high drug loading efficiency and rapid release of free PTX from the hydrophobic conjugate within the tumor cells would significantly improve the therapeutic efficacy. Although disulfide bond has been widely used as redox‐sensitive linkage for designing anticancer conjugates, including PTX conjugates, to our knowledge, this is the first attempt to develop prodrug‐nanoplatform based on disulfide bond‐bridged hydrophobic conjugates of PTX and fatty acids for systemic delivery of PTX. In such a uniquely engineered prodrug‐nanosystem, prodrug strategy and nanotechnology are integrated into one system to facilitate the chemotherapy efficiency of PTX.…”

Polymer–paclitaxel conjugates based on disulfide linkers for controlled drug release

“…As a special class of functional polymeric materials, PDCs have labile linkages between drug molecules and polymers, and therefore can allow drug molecules to be released through the cleavage of linkages under a specific stimulus like pH, reducing agents and light. [11][12][13][14][15] As compared with polymeric micelle CDDSs loading drug via physical entrapment, PDCs typically have well-controlled drug loadings and continuous release without burst release effect. [16][17][18][19] Noting that some anticancer drugs like paclitaxel (PTX) are highly hydrophobic, PDCs micelles can be easily constructed by using water-soluble polymer to covalently load hydrophobic drug molecules.…”