Abstract
Polymeric micelles (PMs) have been used to improve the poor aqueous solubility, slow absorption and non-selective biodistribution of chemotherapeutic agents (CAs), albeit, they suffer from disassembly and premature release of payloads in the bloodstream. To alleviate the thermodynamic instability of PMs, different core crosslinking approaches were employed. Herein, we synthesized the poly(ethylene oxide)-b-poly((2-aminoethyl)diselanyl)ethyl l-aspartamide)-b-polycaprolactone (mPEG-P(LA-DSeDEA)-PCL) copolymer which self-assembled into monodispersed nanoscale, 156.57 ± 4.42 nm, core crosslinked micelles (CCMs) through visible light-induced diselenide metathesis reaction between the pendant selenocystamine moieties. The CCMs demonstrated desirable doxorubicin (DOX)-loading content (7.31%) and encapsulation efficiency (42.73%). Both blank and DOX-loaded CCMs (DOX@CCMs) established appreciable colloidal stability in the presence of bovine serum albumin (BSA). The DOX@CCMs showed redox-responsive drug releasing behavior when treated with 5 and 10 mM reduced glutathione (GSH) and 0.1% H2O2. Unlike the DOX-loaded non-crosslinked micelles (DOX@NCMs) which exhibited initial burst release, DOX@CCMs demonstrated a sustained release profile in vitro where 71.7% of the encapsulated DOX was released within 72 h. In addition, the in vitro fluorescent microscope images and flow cytometry analysis confirmed the efficient cellular internalization of DOX@CCMs. The in vitro cytotoxicity test on HaCaT, MDCK, and HeLa cell lines reiterated the cytocompatibility (≥82% cell viability) of the mPEG-P(LA-DSeDEA)-PCL copolymer and DOX@CCMs selectively inhibit the viabilities of 48.85% of HeLa cells as compared to 15.75% of HaCaT and 7.85% of MDCK cells at a maximum dose of 10 µg/mL. Overall, all these appealing attributes make CCMs desirable as nanocarriers for the delivery and controlled release of DOX in tumor cells.
Highlights
The recent advancements in synthetic chemistry and nanotechnology fostered the development of different nanocarriers for the delivery and controlled release of chemotherapeutic agents (CAs) in tumor cells [1,2,3,4,5,6]
To circumvent the in vivo instability of Polymeric micelles (PMs), covalent crosslinking of the micellar shell or core were often employed [10]. As the former suffered from aggregation, reduced stealthiness and weakened EPR effect [18,19,20,21], core crosslinking has attracted considerable attention in the fabrication of stable PMs intended for anticancer drug delivery applications (DDAs) [22,23,24]
The synthesis of mPEG-P(LA-DSeDEA)-PCL with pendant Sec moiety was conducted by sequential ROP reaction of mPEG–OH with Benzyl-l-Aspartate N-Carboxy Anhydride (BLA-NCA) and ε-caprolactone followed by hydrolysis of the benzyl ester group and subsequent coupling with selenocystamine dihydrochloride (DSeDEA) through EDC/NHS click chemistry (Scheme 1)
Summary
The recent advancements in synthetic chemistry and nanotechnology fostered the development of different nanocarriers for the delivery and controlled release of chemotherapeutic agents (CAs) in tumor cells [1,2,3,4,5,6]. To achieve the on-demand release of CAs in the region of interest, stimuli-responsive core crosslinking agents with dynamic covalent bonds (DCBs) are in high demand [10,12,15,25] In this regard, S–S and Se–Se bonds containing PMs [23,26,27] have shown preferential sensitivity towards tumor tissue redox signals (2–10 mM reduced glutathione (GSH) and 1 mM H2O2) over extracellular cancer environments (2–10 μM reduced GSH and 20 nM H2O2) [17,28,29]. The amphiphilic copolymer self-assembled into stable CCMs owing to visible light-induced diselenide metathesis reactions between the Sec moieties [23,25,34] In this copolymer architecture, the biocompatible and FDA approved hydrophilic mPEG segment would form the shell of the micelles and help to avoid the non-specific interactions between serum proteins, cellular structures, and the micelles surface. Reagents were used as received without further purification
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
