Polydopamine-Based Composite Nanoparticles with Redox-Labile Polymer Shells for Controlled Drug Release and Enhanced Chemo-Photothermal Therapy

Tian and Lei Nanoscale Research Letters (2019) 14:186 https://doi.org/10.1186/s11671-019-3027-6 NANO EXPRESS Open Access Polydopamine-Based Composite Nanoparticles with Redox-Labile Polymer Shells for Controlled Drug Release and Enhanced Chemo-Photothermal Therapy Yefei Tian1,2* and Miao Lei1 Abstract Photothermal therapy (PTT) that utilizes phSUPPotothermal conversion agents (PTC) to ablate tumor under NIR light irradiation has attracted increasing attention due to its excellent therapeutic efficacy and improved target selectivity. Herein, a novel core-shell nanoparticle based on disulfide-crosslinked poly(methacrylic acid) (PMAA) layer coated polydopamine (PDA) particle has been successfully synthesized by precipitation polymerization. For these PDA@PMAA composite nanoparticles, PDA core exhibits high photothermal efficacy, meanwhile, the redox-labile PMAA shell serves as carriers to encapsulate anticancer drugs and selectively release them. Due to the characteristic of the disulfide bond, PMAA shell occurs at selective degradation as well as controlled drug release upon entering cancer cells. Moreover, the DOX-loaded PDA@PMAA nanoparticles demonstrated a synergistic effect, which shows a significantly improved inhibition effect against cancer cells by the combination of photothermal therapy and traditional chemotherapy with low drug dosage and short laser irradiation in an in vitro study. Keywords: Disulfide bond, Redox-responsive, Controlled drug release, Chemo-photothermal therapy Introduction Photothermal therapy (PTT), a non-invasive local cancer treatment, has been drawing great attention in cancer therapy for its high selectivity and minimal adverse effects [1]. In the PTT, the administered near-infrared (NIR) laser exposure, is absorbed by the photothermal conversion (PTC) agents and converted into local hyperthermia leading to tumor ablation [2–4]. A variety of nanomaterials have been revealed the PTC effect, such as gold nanostructures [5–7], carbon-based nanomaterials [8–12], Fe3O4 nanoclusters [13–15], CuS nanocrystals [16], and natural melanin [17], all of which exhibit strong optical absorbance in the NIR tissue optical window. Among these PTC agents, polydopamine (PDA), a mimic of the adhesive proteins found in mussels shows strong NIR absorption, high-PTC efficiency (40%), excellent biocompatibility, and biodegradability, * Correspondence: 1 School of Materials Science and Engineering, Chang’an University, Xi’an 710064, Shaanxi, People’s Republic of China 2 Engineering Research Central of Pavement Materials, Ministry of Education of PR China, Chang’an University, Xi’an 710064, People’s Republic of China which have been widely explored in the application of PTT [18, 19]. However, single use of PTT shows limited clinical efficacy due to insufficient heat delivery in target region without damaging surrounding normal tissues [20]. To address this problem, chemo-photothermal therapy with the combination of hyperthermia and chemotherapeutic agents has been exploited by many researchers for its synergistic effect resulted from the promoted drug delivery into tumors and increased drug toxicity by hyperthermia [21, 22]. To achieve optimized treatment effect, the current work is devoted to developing a novel therapeutic nanoparticle with high-performance photothermal conversion, excellent drug-loaded ability, and controlled drug release behavior. A “smart” polymer layer was introduced in our system, which crosslinked by a cleavable linker, to enable degradability and controlled drug release of carriers in a triggered fashion. Disulfide bond, which can be cleavage by free thiols, is a promising candidate as cleavable linker due to its sensitive response to redox state, high stability in blood circulation, and good biocompatibility [23]. Drug carriers incorporating disulfide bonds can undergo selective degradation upon © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Tian and Lei Nanoscale Research Letters (2019) 14:186 entering tumor cells, in which the reducing glutathione (GSH) concentration (ca. 2–10 mM) is much higher than that in the extracellular fluids [24–26]. Herein, a new type of composite nanoparticles composed of PDA spheres as the core and disulfide-bond crosslinked poly(methacrylic acid) (PMAA) as the shell was prepared, denoted as PDA@PMAA, which maintains the PTC efficacy of PDA core and the redox-labile property of polymer shell. The structure, properties, and drug release behaviors of PDA@PMAA composite nanoparticles were studied, and chemophotothermal therapeutic effect was further demonstrated via MTT assay. Methods/Experimental Materials Dopamine hydrochloride (DA-HCl) and methacryloyl chloride and glutathione (GSH) were obtained from Aladdin Reagent Corporation, Shanghai, P.R. China. Methacrylic acid (MAA) and N,N’-bis(acryloyl)cystamine (BAC) was purchased from Sigma-Aldrich. 2,2-azobisisobutyronitrile (AIBN) was obtained from Sinopharm Chemical Reagent Company and recrystallized from ethanol. Ammonia aqueous solution (NH3•H2O, 30%), acetonitrile, and anhydrous ethanol were purchased from Shanghai Lingfeng Chemical Reagent Company. Doxorubicin (DOX) in the form of the hydrochloride salt was obtained from Beijing Huafeng United Technology Company. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and other biological reagents were purchased from Invitrogen Corp. Calcein-AM was purchased from Bojin Biotech, Inc. (Xi’an). All chemical reagents were of analytical grade or better and used without further purification except as mentioned above. Characterization Transmission electron microscopy (TEM) images were observed on a Tecnai G2 20 TWIN transmission electron microscope (FEI, USA). The hydrodynamic diameters and zeta potentials of particles were conducted by a dynamic light scattering (DLS) particle size analyzer (Malvern Nano-ZS90) at a scattering angle of 90°. UVvis spectra were performed by a Perkin-Elmer Lambda 750 spectrophotometer at room temperature. Fouriertransform infrared (FT-IR) spectra were recorded using KBr-pressed plates on a Nicolet 6700 FTIR spectroscopy. The NIR-heating effects of PDA and PDA@PMAA nanoparticles were characterized using an 808-nm continuous-wave NIR laser (Changchun New Industries Optoelectronics Technology, Changchun, China; spot size: 6 mm × 7 mm) with laser irradiation at a power density of 5 W cm−2 for 300 s. Pre- and postillumination temperatures were measured by a thermocouple with an accuracy of 0.1 °C. The cellular images Page 2 of 10 were acquired with a confocal laser scanning microsc (...truncated)