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Bone-Targeted Nanoplatform Combining Zoledronate and Photothermal Therapy To Treat Breast Cancer Bone Metastasis Wentong Sun,‡ Kun Ge,*,‡,§ Yan Jin,‡ Yu Han,‡ Haisong Zhang,§ Guoqiang Zhou,‡ Xinjian Yang,‡ Dandan Liu,‡ Huifang Liu,‡ Xing-Jie Liang,⊥ and Jinchao Zhang*,‡ Downloaded via GUILFORD COLG on July 17, 2019 at 03:52:01 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
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Key Laboratory of Chemical Biology of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, P.R. China § Hebei Key Laboratory of Chronic Kidney Diseases and Bone Metabolism, Affiliated Hospital of Hebei University, Baoding 071000, P.R. China ⊥ Chinese Academy of Sciences (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, No. 11, First North Road, Zhongguancun, Beijing 100190, P.R. China S Supporting Information *
ABSTRACT: Bone metastasis, a clinical complication of patients with advanced breast cancer, seriously reduces the quality of life. To avoid destruction of the bone matrix, current treatments focus on inhibiting the cancer cell growth and the osteoclast activity through combination therapy. Therefore, it could be beneficial to develop a bone-targeted drug delivery system to treat bone metastasis. Here, a bone-targeted nanoplatform was developed using gold nanorods enclosed inside mesoporous silica nanoparticles (Au@MSNs) which were then conjugated with zoledronic acid (ZOL). The nanoparticles (Au@ MSNs-ZOL) not only showed bone-targeting ability in vivo but also inhibited the formation of osteoclast-like cells and promoted osteoblast differentiation in vitro. The combination of Au@MSNs-ZOL and photothermal therapy (PTT), triggered by near-infrared irradiation, inhibited tumor growth both in vitro and in vivo and relieved pain and bone resorption in vivo by inducing apoptosis in cancer cells and improving the bone microenvironment. This single nanoplatform combines ZOL and PTT to provide an exciting strategy for treating breast cancer bone metastasis. KEYWORDS: breast cancer bone metastasis, mesoporous silica nanoparticles, bone target, zoledronate, photothermal therapy
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activity of osteoclasts, but they have negligible effects on cancer cells. Therefore, it could be beneficial to develop a bone-targeted drug delivery system to simultaneously inhibit cancer cell proliferation and osteoclast activity. Some targeted agents have already been developed to enhance antiresorptive therapy, such as antibody agents and bisphosphonates.1,3 Bisphosphonates, a kind of small molecular drug, are widely used in the treatment of cancer bone metastasis and osteoporosis in postmenopausal women because of their bone-targeting ability and stability.1,3 Zoledronic acid (ZOL), a third-generation bisphosphonate, has been reported to inhibit
one metastases occur at the advanced stage of breast cancer, and about 85% of them are associated with osteolytic lesions, which decrease patients’ life expectancy to only several years.1 Patients with bone metastasis have a higher mortality rate and suffer from pain and clinical complications such as fracture, spinal cord compression, and hypercalcemia, which seriously reduce the quality of life.2 Currently, there are two primary strategies to treat bone metastasis: inhibiting cancer cell growth and inhibiting the activity of osteoclasts. Chemotherapy is the main approach to inhibiting cancer cell growth, and efficient drug delivery to the bone metastasis is essential for success.3 However, the skeleton has a poorer blood supply than other tissues, which not only reduces the efficiency of drug delivery to bone but also leads to severe side effects caused by the lack of tissue specificity.4 Bonetargeted antiresorptive drugs are important for inhibiting the © XXXX American Chemical Society
Received: January 5, 2019 Accepted: June 11, 2019
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DOI: 10.1021/acsnano.9b00097 ACS Nano XXXX, XXX, XXX−XXX
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Figure 1. Characterization of Au@MSNs and Au@MSNs-ZOL. (A) TEM images and (B) N2 adsorption−desorption isotherms and pore size distribution curves (inset) of Au@MSNs. (C) UV−vis spectrum of the Au@MSNs at 808 nm. (D) FTIR spectra of the Au@MSNs, free ZOL, and Au@MSNs-ZOL. (E) TG analysis curves of Au@MSNs and Au@MSNs-ZOL under a flow of air. (F) Temperature increase of an aqueous dispersion of Au@MSNs-ZOL (concentration at 0.2 mg/mL) following laser irradiation at different powers for 10 min. Thermographic images of water (G) and an aqueous dispersion of Au@MSNs-ZOL (H) at different time points under laser irradiation (808 nm) at 1.2 W/cm2. (I) ZOL release profiles for Au@MSNs-ZOL at pH 7.4 at 37 and 42 °C. Scale bar is 50 nm.
% in nanoparticles) had antitumor activity in vitro and in vivo.11 Therefore, based on the bone-targeting ability and antitumor acitivity of ZOL, translating high doses of ZOL to bone may provide a promising therapeutic treatment for breast cancer bone metastases. MSNs, with their large specific surface area, good biocompatibility, and easily functionalized surface, have been employed as drug-delivery systems for several years.12−15 In our previous work, we created a ZOL-conjugated MSN nanodelivery system with high ZOL loading capacity (about 166.8 mg/g).9 The overall growth inhibition rate of cancer cells was nearly 50% after treatment with MSNs-ZOL nanoparticles. To further inhibit cancer cell growth, while also decreasing the toxicity to normal cells, we decided to add a photothermal agent to our system. Photothermal therapy (PTT) is an effective method to ablate diverse cancers, even bone cancers, under a near-infrared (NIR) laser.16−18 Moreover, hyperthermia has been reported to increase the sensitivity to anticancer drugs and promote the efficiency of chemotherapy.19,20 In this work, we constructed a bone-targeted nanoplatform with gold nanorods enclosed inside
osteolysis and restore bone density in some bone erosion diseases.5−7 Due to its strong affinity for bone, ZOL mainly distributes to and accumulates in bone rather than other tissues,5,8 and it has been employed as a bone-targeting agent in combination with chemotherapeutics in vitro and in vivo. Chaudhari et al. fabricated ZOL-conjugated docetaxel-encapsulating PLGA-PEG nanoparticles, which had significantly enhanced cytotoxicity against MCF7 and BO2 cells and showed higher retention in bone and tumor in vivo.5 Our previous work showed that bone-targeted mesoporous silica nanoparticles (MSNs) conjugated with ZOL and loaded with DOX had enhanced cytotoxicity and decreased the migration of A549 cells.9 Recently Qiao et al. developed ZOL-conjugated Gddoped mesoporous silica-coated upconversion nanoparticles loaded with plumbagin and poly(acrylic acid) , which can target bone and attenuate tumorigenesis and osteoclastogenesis in breast cancer bone metastasis.10 Their work further demonstrated that ZOL localized at the sites with high osteoclast activity in priority and targeted to bone metastasis sites. Moreover, high doses of ZOL (ZOL loading capacity >10 wt B
DOI: 10.1021/acsnano.9b00097 ACS Nano XXXX, XXX, XXX−XXX
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ACS Nano
Figure 2. Biological interactions between Au@MSNs-ZOL and MDA-MB231 cells in vitro. (A) TEM images of ultrathin sections of cells after treatment with Au@MSNs-ZOL (final concentration of 40 μg/mL) for 4 h. (B−G) MDA-MB231 cells were treated with Au@MSNs, Au@ MSNs-ZOL, Au@MSNs+NIR, and Au@MSNs-ZOL+NIR for 24 h (the final concentrations of Au@MSNs and Au@MSNs-ZOL were 40 μg/ mL). Cell viability (B), the number of apoptotic cells (C), cell migration statistics at 24 h (D) and 48 h (E), cell invasion statistics at 24 h (F), and IL-8 level at 24 h (G) were measured. The figures show cell migration images (H) and invasion images (I). Scale bars in (H) and (I) are 200 μm. *p < 0.05, **p < 0.01, and ***p < 0.001 for Au@MSNs, Au@MSNs-ZOL, Au@MSNs+NIR, and Au@MSNs-ZOL+NIR vs control group; #p < 0.05, ##p < 0.01, and ###p < 0.001 for Au@MSNs-ZOL+NIR vs Au@MSNs, Au@MSNs-ZOL, and Au@MSNs+NIR.
imaging and for enhancing the anticancer effect.21−23 MSNs have good biocompatibility and a high loading capacity for small molecular drugs.12,24 ZOL, as a bone-targeting agent, can
MSNs (Au@MSNs), which were then conjugated with ZOL. The gold nanorods, which act as NIR photothermal agents and as photoacoustic (PA) imaging agents, were employed for C
DOI: 10.1021/acsnano.9b00097 ACS Nano XXXX, XXX, XXX−XXX
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ACS Nano
an aqueous dispersion of Au@MSNs-ZOL at a concentration of 0.2 mg/mL increased to 40.7, 42.3, 45.1, and 47.0 °C in 10 min at powers of 0.6, 1.2, 1.5, and 1.8 W/cm2 (Figure 1F). The photothermal conversion capacity of Au@MSNs-ZOL was examined following irradiation with a laser
