α-Amylase- and Redox-Responsive Nanoparticles for Tumor-Targeted Drug Delivery

Abstract

Paclitaxel (PTX) is an effective antineoplastic agent and shows potent antitumor activity against a wide spectrum of cancers. Yet, the wide clinical use of PTX is limited by its poor aqueous solubility and the side effects associated with its current therapeutic formulation. To tackle these obstacles, we report, for the first time, α-amylase- and redox-responsive nanoparticles based on hydroxyethyl starch (HES) for the tumor-targeted delivery of PTX. PTX is conjugated onto HES by a redox-sensitive disulfide bond to form HES-SS-PTX, which was confirmed by results from NMR, high-performance liquid chromatography-mass spectrometry, and Fourier transform infrared spectrometry. The HES-SS-PTX conjugates assemble into stable and monodispersed nanoparticles (NPs), as characterized with Dynamic light scattering, transmission electron microscopy, and atomic force microscopy. In blood, α-amylase will degrade the HES shell and thus decrease the size of the HES-SS-PTX NPs, facilitating NP extravasation and penetration into the tumor. A pharmacokinetic study demonstrated that the HES-SS-PTX NPs have a longer half-life than that of the commercial PTX formulation (Taxol). As a consequence, HES-SS-PTX NPs accumulate more in the tumor compared with the extent of Taxol, as shown in an in vivo imaging study. Under reductive conditions, the HES-SS-PTX NPs could disassemble quickly as evidenced by their triggered collapse, burst drug release, and enhanced cytotoxicity against 4T1 tumor cells in the presence of a reducing agent. Collectively, the HES-SS-PTX NPs show improved in vivo antitumor efficacy (63.6 vs 52.4%) and reduced toxicity in 4T1 tumor-bearing mice compared with those of Taxol. These results highlight the advantages of HES-based α-amylase- and redox-responsive NPs, showing their great clinical translation potential for cancer chemotherapy.

Triggered Drug Release From Liposomes: Exploiting the Outer and Inner Tumor Environment

“…Different nanocarriers have been designed upon this concept such as micelles (115), nanoparticles based on hydroxyethyl starch (116), gold-nanoparticle (117) and liposomes (118)(119)(120). Most of the materials used to obtain these nanosystems contain characteristic disulfide (S-S) bonds.…”

Colloidal hydroxyethyl starch for tumor-targeted platinum delivery

“…42 A good manufacturing practice, high water solubility, tailorability, biocompatibility, biodegradability, and well-dened and proven in vivo safety features not only facilitate HES to be widely applied in clinics as PVE, 36,[43][44][45] cryoprotectant, [46][47][48][49] organ preservation solutions, 50 granulocytes separation solutions, [51][52][53] and cell culture medium, 54 but also to be a promising drug carrier with promising clinical translation potential. [55][56][57] To this end, various drug delivery systems have been recently developed based on HES, including HES and small drug conjugates; [27][28][29][30]32,34,58 HES and protein conjugates; 56,59 HES-derived nanocolloidosomes; 60 and HES-based nanoparticles, [61][62][63][64][65][66][67] capsules, [68][69][70][71] and hydrogels. [72][73][74][75] Although HES has been applied in clinics for over 50 years, its fundamental conformation, structure, and morphology are largely unknown.…”

Stimuli‐Responsive Prodrug Chemistries for Drug Delivery

“…Li et al . demonstrated enhanced delivery of PTX to tumor cells using enzyme and redox dual‐responsive carriers, by conjugating PTX to hydroxyethyl starch (HES) using a disulfide linker (HES‐SS‐PTX).…”