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A novel pH-sensitive targeting polysaccharide-gold nanorod conjugate for T combined photothermal-chemotherapy of breast cancer
Guanghui Houa, Junmin Qiana, , Weijun Xua, Tiantian Suna, Yaping Wanga, Jinlei Wanga, Lijie Jia, Aili Suob,
a State Key Laboratory for Mechanical Behavior of Materials, Xi’an Jiaotong University, Xi’an, 710049, China
b Department of Oncology, The First Aﬃliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China
Combined photothermal-chemotherapy Breast cancer
Chemo-photothermal combination therapy is a promising strategy for cancer treatment. In this study, to achieve the combined photothermal-chemotherapy of breast cancer, a pH-sensitive oxidized hyaluronic acid-decorated dihydroxyphenyl/hydrazide bifunctionalized hydroxyethyl chitosan (DHHC)-gold nanorod (GNR) conjugate was developed. DHHC was synthesized by successive dihydroxyphenylation and hydrazidation of hydroxyethyl chitosan through carbodiimide reaction and click chemistry, respectively. The conjugate was obtained by che-mically bonding DHHC onto GNR via Au-catechol bonds. Doxorubicin (DOX) was loaded onto the conjugate via an acid-labile hydrazone linkage with a drug loading content of 5.1%. DOX-loaded conjugate displayed good stability in neutral aqueous solutions and exhibited pH-responsive drug release and surface charge reversal behaviors. In vitro biological studies indicated that the conjugate could be eﬀectively internalized by breast cancer MCF-7 cells and synergistic therapeutic eﬀects were demonstrated, suggesting its great potential in combined photothermal-chemotherapy of breast cancer.
The eﬀective treatment of malignant tumors is still a huge challenge due to the uncontrolled malignant hyperplasia and rapid cancer me-tastasis. Recent studies suggest that the combination of chemotherapy and photothermal therapy can achieve better therapeutic eﬃcacy than single-modality therapy because of its additive or synergistic eﬀect (Chen, Liang, Wang, & Liu, 2015; Li et al., 2015; Wang, Chen et al., 2014). Gold nanorod (GNR), one of the most eﬀective photothermal agents, has attracted extensive attention in cancer treatment due to its adjustable longitudinal surface plasmon resonance (LSPR) and high light-to-heat conversion eﬃciency (Luo et al., 2016, Li et al., 2013). The LSPR peak of GNR can be easily adjusted to the NIR region by changing its aspect ratio to convert NIR light energy into heat energy. Further-more, rod-shaped nanoparticles possess a prolonged circulation time in blood (Barua et al., 2013; Wang, Xu et al., 2014; Xu et al., 2017). Thus, GNR-based chemo-photothermal combination therapy is a desirable strategy to treat cancer. Unfortunately, the low specific surface area of GNR limits the loading amount of anti-cancer drug (Cheng et al., 2013; Lu et al., 2014). Furthermore, GNR synthesized by seed-growth method is capped by deleterious but necessary surfactant
cetyltrimethylammonium bromide (CTAB) and shows poor stability under physiological conditions. (Niidome et al., 2006). This short-coming severely restricts its biomedical applications. To address the above-mentioned problem, various materials have been employed to decorate GNR, such as polyethylene glycol (PEG) (Li et al., 2013; Tao et al., 2014), polyethyleneimine (Wang et al., 2015), poly(sodium-p-styrenesulfonate) (And & Hafner, 2005; Liu, Zhao, Wang, & Chang, 2015) and mesoporous silica (Liu et al., 2013; Zhang, Qian, Wang, Wang, & He, 2013). These modified GNRs can support drugs and achieve combined photothermal chemotherapy. However, there still exist some shortcomings. For example, although hydrophilic PEG or negatively-charged polymer shells can ensure the stability of GNR under physiological conditions and avoid unwanted serum protein ad-sorption and clearance by reticulo-endothelial system (Blanco, Shen, & Ferrari, 2015), they inhibit the cellular internalization of nanoparticles due to either the shielding eﬀect of PEG or the electrostatic repulsion between anionic polymer and negatively-charged plasma membranes (Guan et al., 2017). In contrast, positively-charged polymers can non-specifically interact with most serum proteins and cells, resulting in low drug accumulation in tumors and obvious toxic side eﬀects towards normal tissues (Han et al., 2015). Additionally, chemotherapeutic drugs