Tumor acidity and CD44 dual targeting hyaluronic acid-coated gold nanorods for combined chemo- and photothermal cancer therapy
Introduction
Cancer is a leading cause of human death all over the world. During the last decade, a lot of efforts have been made to develop new formulations for efficient treatment of cancer. Among these formulations, nanomedicines have shown unique advantages such as prolonged blood circulation, improved biodistribution, and reduced adverse effect (Dai, Xu, Sun, & Chen, 2017; Kemp, Shim, Heo, & Kwon, 2016; Kim, Shin, Kwon, & Hyeon, 2018; Liu et al., 2018; Shi, Kantoff, Wooster, & Farokhzad, 2017). It has been confirmed that nanomedicines can passively accumulate at tumor sites during blood circulation due to the enhanced permeability and retention (EPR) effect (Fang, Nakamura, & Maeda, 2011; Maeda, Nakamura, & Fang, 2013). However, targeting groups-modified and tumor microenvironment-responsive nanomedicines have also been explored for enhanced tumor accumulation and active tumor targeting (Cheng et al., 2015, 2017).
The extracellular environment of solid tumors is generally more acidic (pH 6.0–7.0) than normal tissues (pH 7.4). It is probably due to faster production of lactic acid at tumor sites (Danhier, Feron, & Preat, 2010). In addition, endosomal/lysosomal pH of tumor cells can be even lower (pH 4.5–5.5). These pH gradients inspire design and fabrication of intelligent drug delivery systems with sharp pH sensitivity for tumor targeting or triggered release. For example, Ji and coworkers have reported tumor extracellular pH-targeting gold nanoparticles coated with a zwitterionic monolayer (Liu et al., 2013). These pH-sensitive gold nanoparticles are stable at pH 7.4 but can rapidly aggregate at pH 6.5 that subsequently leads to improved uptake by tumor cells. It has been confirmed that these pH-sensitive gold nanoparticles show much higher accumulation and retention at tumor sites than non-pH-sensitive nanoparticles. In addition to pH-induced aggregation, nanoparticles that can aggregate in response to other tumor microenvironment signals (such as glutathione) have also been reported for enhanced tumor targeting (Gao et al., 2017).
Hyaluronic acid (HA), a naturally occurring high molecular weight linear polysaccharide, plays a critical role in active theranostic systems (Huang & Huang, 2018). Besides biocompatibility and biodegradability, HA has high selective binding to CD44, a cell surface glycoprotein that is over-expressed in various tumor cells (Seok et al., 2018; Zhao et al., 2015; Zhong et al., 2016). The HA-CD44 interaction mediates and promotes a wide range of biological processes, including macrophage aggregation, cell migration, tumor growth, etc. HA-CD44 binding also elevates HA level in tumor tissues (Noh et al., 2015). Owing to their excellent physiological properties as well as high chemical modification possibility, HA and its derivatives have been widely applied in cancer theranostics as a powerful tumor-recognition moiety (Ding, Jiang, Zhang, Klok, & Zhong, 2018; Lee et al., 2016).
In addition to chemotherapy, many new technologies such as photothermal therapy (PTT), photodynamic therapy (PDT), immunotherapy, and so on have been developed for more efficient and safer treatment of cancers (Cheng et al., 2018; Lan et al., 2018; Ribas & Wolchok, 2018). Gold nanorods (AuNRs) have been widely employed as effective nanoparticle-mediated hyperthermia agents because of their unique advantages (Dong et al., 2018; Parchur et al., 2018). AuNRs possess two surface plasmon resonance (SPR) modes, including a transversal band and a longitudinal band for short and long axis polarizations, respectively. This band can be tuned within a broad wavelength range (600–950 nm) with an aspect-ratio-dependent feature. By controlling the aspect ratio, the absorption peak of AuNRs can be adjusted to the tissue window where near-infrared (NIR) light can be applied with minimal tissue absorption, non-invasive and deep penetration. By combining different treatment methods, cancer therapeutic efficiencies can be maximized owing to a synergistic effect (Wang et al., 2018; Zhu, Liu, Zhang, Hu, & Liu, 2018).
In this study, we aim at improving tumor therapeutic efficiency as well as reducing the side effects of AuNRs by surface coating of pH-responsive groups-conjugated low molecular weight hyaluronic acid (LMWHA). The coating of LMWHA has advantages in four aspects. First, lipoic acid (LA)-conjugated LMWHA can cover and replace toxic surface ligands of AuNRs, thus increase the biocompatibility of AuNRs. Second, the anionic nature of LMWHA allows loading of cationic doxorubicin (DOX), a chemical drug, which enables combined chemo- and photothermal cancer therapy. Third, the surface LMWHA can enhance selectively uptake of the LMWHA-coated nanocomposites by CD44-expressing cancer cells, which might improve tumor inhibition ability. Fourth, conjugation of pH-sensitive groups to LMWHA can induce aggregation of the nanocomposites under slightly acidic tumor microenvironment, which also helps to improve tumor therapeutic efficiency. Scheme 1 illustrates the concept of the nanosystem proposed in this work.
Improving tumor therapeutic efficiency and reducing side effects of therapeutic agents are major challenges in cancer nanomedicine these years, and development of new strategies as well as new platforms is highly required. In this work, for the first time, we modified LMWHA using pH-responsive groups for dual targeting of nanoparticles through both ligand-mediated cell uptake and acid-induced aggregation. In addition to targeting, loading of DOX could provide these LMWHA-coated AuNRs synergistic cancer cell-killing (in vitro) and tumor growth inhibiting (in vivo) ability. Taken together, our nanosystem might have potential for highly efficient and combined cancer therapy.
Section snippets
Materials
Hexadecyltrimethylammonium bromide (CTAB), gold (III) chloride trihydrate (HAuCl4·3H2O), silver nitrate (AgNO3), L-ascorbic acid, sodium borohydride (NaBH4), 4-(dimethylamino) pyridine (DMAP), 3-mercaptopropionic acid (MPA), 1,1′-carbonyldiimidazole (CDI), sulfadiazine (SD), sulfamethazine (SM), acryloyl chloride (AC), hyaluronic acid sodium salt (HA, MW 150–300 kDa), hyaluronidase, LA, anhydrous formamide (FA), and anhydrous N,N-dimethylacetamide (DMAc) were purchased from Sigma-Aldrich (St.
Synthesis and characterizations of SM/LA-LMWHA and SD/LA-LMWHA polymers
The synthesis procedure of SD/LA-LMWHA is illustrated in Scheme 2. Since it is difficult to dissolve commercially available high molecular weight HA in organic solvents such as FA, the HA has to be degraded from high molecular weight into low molecular weight. To obtain LMWHA with suitable molecular weight for coating AuNRs, commercially available HA with high molecular weight was degraded in the presence of an enzyme, hyaluronidase. The molecular weight of the degraded product (LMWHA) was
Conclusions
For pH-induced aggregation, pH-sensitive group (SM or SD) was conjugated to hydroxyl groups of LMWHA. Due to different pKa values of SM and SD, pH-sensitivity of conjugated LMWHA could be altered. After coating SM/LA-LMWHA onto AuNRs@CTAB, the obtained AuNRs@SM/LA-LMWHA had opposite surface charges but similar UV–vis absorbance peaks compared to AuNRs@CTAB. At pH 7.4, AuNRs@SM/LA-LMWHA had a size of around 50 nm. However, their size gradually increased with decreasing pH, exhibiting pH-induced
Acknowledgment
This research was supported by the Basic Science Research Program through a National Research Foundation of Korea grant funded by the Korean Government (MEST) (NRF-2017R1A5A1070259) and the National Research Foundation of Korea (NRF) funded by The Ministry of Science, ICT & Future Planning (NRF-2017R1D1A1B03033988).
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These authors contributed equally to this work.