Disulfide-Linked Amphiphilic Polymer-Docetaxel Conjugates Assembled Redox-Sensitive Micelles for Efficient Antitumor Drug Delivery

Abstract

Here, we prepared novel redox-sensitive drug delivery system based on copolymer-drug conjugates methoxy poly(ethylene glycol)-poly(γ-benzyl l-glutamate)-disulfide-docetaxel (mPEG-PBLG-SS-DTX) to realize the desirable cancer therapy. First, copolymers of methoxy poly(ethylene glycol)-poly(γ-benzyl l-glutamate) (mPEG-PBLGs) with different molecular weight (mPEG2000-PBLG1750 and mPEG5000-PBLG1750) were synthesized via the ring open polymerization (ROP) of 5-benzyl-l-glutamate-N-carboxyanhydride (γ-Bzl-l-Glu-NCA) initiated by monoamino-terminated mPEG (mPEG-NH2). Then, the docetaxel (DTX) was conjugated to the block polymers through a linkage containing disulfide bond to obtain mPEG-PBLG-SS-DTXs, including mPEG2000-PBLG1750-SS-DTX and mPEG5000-PBLG1750-SS-DTX. The obtained copolymer-drug conjugates mPEG2000-PBLG1750-SS-DTX and mPEG5000-PBLG1750-SS-DTX could self-assemble into nanosized micelles in aqueous environment via dialysis method with a low critical micelle concentration (CMC, 3.98 and 6.94 μg/mL, respectively). The size of the micelles was approximately 101.3 and 148.9 nm, respectively, with a narrow size distribution. They released approximately 40% DTX in a sustained way in the presence of 50 mM DTT after 120 h in comparison with only approximately 10% DTX released from micelles in the absence of DTT. The high cytotoxicity was identified for mPEG-PBLG-SS-DTXs micelles against MCF-7/ADR and A549 cells, and the IC50 of mPEG-PBLG-SS-DTXs micelles against MCF-7/ADR for 24 h was roughly a 15th of the value of free DTX. Moreover, the mPEG-PBLG-SS-DTXs micelles could be efficiently uptaken by MCF-7/ADR and A549 cells. Thus, the present constructed mPEG-PBLG-SS-DTXs micelles were very promising for effective cancer therapy.

Multifunctional Mixed Micelles for Efficient Docetaxol Delivery for Cancer Therapy

“…Furthermore, the micelle concentration of the kick point was defined as the CMC. As evident from the data shown in Figure , the CMC of the mixed micelles was 5.08 μg mL −1 , which was analogous to that of the PEG–PBLG‐SS‐DTX micelles . The relatively low CMC might guarantee stability of the mixed micelles after intravenous administration and dilution in the circulation.…”

“…In this study, we constructed a multifunctional drug delivery system combining redox sensitivity and tumor‐targeting capacity based on our synthesized redox‐sensitive polymer–drug conjugate methoxy poly(ethylene glycol)–poly(γ‐benzyl l ‐glutamate)‐disulfide‐docetaxel (PEG 2000 –PBLG 1750 ‐SS‐DTX) and active‐targeting polymer PEG–FA. As revealed in Scheme , the redox‐sensitive PEG–PBLG‐SS‐DTX copolymer and tumor‐targeted PEG–FA self‐assembled into multi‐functional mixed micelles in an aqueous environment, which tended to accumulate in tumor tissues due to the EPR effect after intravenous injection.…”

Block copolymer prodrugs: Synthesis, self‐assembly, and applications for cancer therapy

“…Other anticancer drugs, such as cisplatin, PTX (Zhang, Zhang, et al, ) and tioguanine (van der Vlies, Hasegawa, & Hubbell, ) have also been utilized to conjugate to the polymers for preparation of BCPs via disulfide bonds, all of which could self‐assemble into micellar nanoparticles for in vivo delivery. Disulfide bonds provided the possibility for controlled release inside targeting tumor cells.…”

Micelles Formed by Polypeptide Containing Polymers Synthesized Via N-Carboxy Anhydrides and Their Application for Cancer Treatment

“…In 2016, Zhang et al [37] reported the synthesis of a novel redox-sensitive drug delivery system based on poly(ethylene glycol)-b-poly(γ-benzyl L-glutamate)-SS-docetaxel (mPEG-b-PBLG-SS-DTX) conjugates. Copolymers of methoxy poly(ethylene glycol)-b-poly(γ-benzyl L-glutamate) (mPEG-PBLGs) with different molecular weights were synthesized via the ROP of BLG-NCA initiated by mPEG-NH 2 .…”