Reduction-Sensitive Dextran–Paclitaxel Polymer–Drug Conjugate: Synthesis, Self-Assembly into Nanoparticles, and In Vitro Anticancer Efficacy

Abstract

Delivery systems that can encapsulate a precise amount of drug and offer a spatiotemporally controlled drug release are being actively sought for safe yet effective cancer therapy. Compared to polymer nanoparticle (NP)-based delivery systems that rely on physical drug encapsulation, NPs derived from stimuli-sensitive covalent polymer−drug conjugates (PDCs) have emerged as promising alternatives offering precise control over drug dosage and spatiotemporal drug release. Herein, we report a reduction-sensitive PDC "Dex-SS-PTXL" synthesized by conjugating dextran and paclitaxel (PTXL) through a disulfide bondbearing linker. The synthesized Dex-SS-PTXL PDC with a precise degree of substitution in terms of the percentage of repeat units of dextran covalently conjugated to PTXL (27 ± 0.6%) and the amount of drug carried by the PDC (39 ± 1.4 wt %) was found to self-assemble into spherical NPs with an average size of 110 ± 34 nm and a ζ-potential of −14.09 ± 8 mV. The reduction-sensitive Dex-SS-PTXL NPs were found to release PTXL exclusively in response to the reducing agent concentration reflective of the intracellular reducing environment of the tumor cells. Challenging BT-549 and MCF-7 cells with Dex-SS-PTXL NPs revealed significant cytotoxicity, while the IC 50 values and the mode of action (mitotic arrest) of Dex-SS-PTXL NPs were found to be comparable to those of free PTXL, highlighting the active nature of the intracellularly released drug. The developed PDC with its unique ability to self-assemble into NPs and stimuli-responsive drug release can enhance the success of the NP-based drug delivery systems during clinical translation.

Recent Progress of Paclitaxel Delivery Systems: Covalent and Noncovalent Approaches

“…[ 194 ] h) Multiple PTX attached to dextran and form micelles. [ 196 ] i) PTX attached to peptides comprised of cell‐penetration segment (SynB3) and MMP‐2‐sensitive peptide (PVGLIG) which form micelles. [ 202 ] j) PTX attached to triblock peptide consisting tumor targeting section (TTP, LHRH), MMP‐2 sensitive section (PLGLAG), and cell penetrating section (CPP, T2).…”

“…Using different types of polysaccharides, Kanwal et al linked PTX and dextran with disulfide bond and prepared ≈110 nm micelle spherical particles (Figure 7h). [196] NMR characterized the exact loading amount of PTX to be 27 ± 0.6% PTX per 100 repeated units of dextran and in vitro cumulative release gave a distinctive reduction-triggered cleavage of PTX upon 10 × 10 −3 m DTT. Apart from increased cell viability, they also conducted cell cycle and western blot analyses to confirm identical modes of PTX cytotoxicity via mitotic arrest (G2/M).…”

“…Dextran [ 196] (S)-11-(ethoxycarbonyl)-5,13,16,19tetraoxo-3-oxa-6,12,15,18tetraazatetracos-23-ynoic acid…”

“…NAC enhanced adhesion of micelles on mucus layer [194]. h) Multiple PTX attached to dextran and form micelles [196]. i) PTX attached to peptides comprised of cell-penetration segment (SynB3) and MMP-2-sensitive peptide (PVGLIG) which form micelles [202].…”

Polysaccharide-Drug Conjugates: A Tool for Enhanced Cancer Therapy

“…So, conjugation of TXL with dextran and folic acid may improve the anti-cancer efficacy of Taxol [ 123 ]. A Dex–SS–PTX conjugate showed significant cytotoxicity in BT-549 and MCF-7 cells [ 124 ].…”