Bone-Targeted Nanoplatform Combining Zoledronate and Photothermal Therapy To Treat Breast Cancer Bone Metastasis.

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.

A Distinct Endocytic Mechanism of Functionalized-Silica Nanoparticles in Breast Cancer Stem Cells.

Nanoparticles provide new fields for life medical science application, including targeted-drug delivery and cancer treatment. To maximize the delivery efficiency of nanoparticle, one must understand the uptake mechanism of nanoparticle in cells, which may determine their ultimate fate and localization in cells. Recently, the proposed-cancer stem cell (CSC) theory has been attracted great attention and regarded as new targets for the new nanodrug developmet and cancer therapies. The interaction between nanoparticles and cancer cells has been extensively studied, but the uptake mechanism of nanoparticles in CSCs has received little attention. Here, we use the pharmacological inhibitors of major endocytic pathways to study the silica nanoparticle (SiNP) uptake mechanisms in the human breast adenocarcinoma cell line (MCF-7) and MCF-7-derived breast cancer stem cells (BCSCs). The results demonstrate that the uptake of SiNPs, particularly amino-functionalized SiNPs, in MCF-7 cells is strongly affected by the actin depolymerization, whereas BCSCs more strongly inhibit the amino-functionalized SiNP uptake after the scavenger receptor disruption. These findings indicate a distinct endocytic mechanism of functionalized SiNPs in BCSCs, which is significant for designing ideal nanosized drug delivery systems and improving the selectivity for CSC-targeted therapy.

A simple and powerful co-delivery system based on pH-responsive metal-organic frameworks for enhanced cancer immunotherapy.

Tumor-associated antigens (TAAs)-loaded nanoparticles are able to be actively internalized by antigen-presenting cells (APCs) and have shown promising potential in cancer immunotherapy. However, current TAAs delivery strategy exhibits limitations of complicated synthesis process, low loading efficiency and inefficient CD8+ cytotoxic T lymphocyte activation leading to unsatisfactory therapeutic effect. Thus, the construction of novel TAAs-delivery systems for enhanced cancer therapy is highly desirable. In this work, we fabricated a very simple yet powerful antigens-delivery system for cancer immunotherapy based-on pH-responsive metal-organic frameworks (MOFs) with size about 30 nm. TAAs can be loaded into MOFs in the one-pot synthesis process and released with the degradation of MOFs in the acidic environment of endo/lysosome as the result of relatively labile metal-ligand bonds. The endosomolytic nanoparticles would facilitate protein antigens escape from endo/lysosome and optimal for enhancing antigen cross-presentation. Furthermore, the introduction of immunostimulatory unmethylated cytosine-phosphate-guanine oligonucleotide (CpG) through Watson-Crick base pairing would further enhance CD8+ cytotoxic T lymphocyte responses. We demonstrated that the method to co-delivery antigens and immunostimulatory molecules was very simple, convenient and effective and showed no obvious toxicity both in vitro and in vivo. This method gave a high antigens-loading capacity and the maximal antigen encapsulating efficiency was about 55% (w/w). Additionally, the pH-responsive co-delivery system exerted enhanced antitumor outcome (about 100% survival) in B16-OVA melanoma cancers in vivo. Furthermore, we confirmed that this high rating of therapeutic effect was attributed to the recruitment of tumor-killing immunocyte. This work demonstrates the ability of pH-responsive, endosomolytic MOFs to induce strong cellular immune responses for cancer therapy by co-delivery of CpG ODN and antigens.

Europium-Doped Gd2O3 Nanotubes Increase Bone Mineral Density in Vivo and Promote Mineralization in Vitro.

Europium-doped Gd2O3 nanotubes (Gd2O3:Eu3+ NTs) have been extensively applied in the field of bioscience for their photostability and magnetic properties. Nevertheless, the distribution and interaction between Gd2O3:Eu3+ NTs and metabolism of bone are not yet sufficiently understood. In this study, a systematic study of the toxicity and distribution of Gd2O3:Eu3+ NTs in mice after oral administration was carried out. The results showed that a small number of the Gd2O3:Eu3+ NTs could pass through biological barriers into the lung, liver, and spleen, but a high concentration was observed in bone. Furthermore, the effects of Gd2O3:Eu3+ NTs on bone metabolism were systematically studied in vitro and in vivo when accumulating in bone. After being administered to mice, the Gd2O3:Eu3+ NTs extremely enhanced the bone mineral density and bone biomechanics. In vitro the Gd2O3:Eu3+ NTs increased the alkaline phosphatase (ALP) activity and mineralization and promoted the expression of osteogenesis genes in preosteoblasts MC3T3-E1 through activation of the BMP signaling pathway. This study will be significant for appropriate application of Gd2O3:Eu3+ NTs in the biomedical field and expounding the molecular mechanism of bone metabolism.

Up-Conversion Y2O3:Yb(3+),Er(3+) Hollow Spherical Drug Carrier with Improved Degradability for Cancer Treatment.

The rare earth hollow spheres with up-conversion luminescence properties have shown potential applications in drug delivery and bioimaging fields. However, there have been few reports for the degradation properties of rare earth oxide drug carriers. Herein, uniform and well-dispersed Y2O3:Yb(3+),Er(3+) hollow spheres (YOHSs) have been fabricated by a general Pechini sol-gel process with melamine formaldehyde colloidal spheres as template. The novel YOHSs with up-conversion luminescence has good drug loading amount and drug-release efficiency; moreover, it exhibits pH-responsive release patterns. In particular, the YOHSs sample exhibits low cytotoxicity and excellent degradable properties in acid buffer. After the sample was loaded with anticancer drug doxorubicin (DOX), the antitumor result in vitro indicates that YOHS-DOX might be effective in cancer treatment. The animal imaging test also reveals that the YOHSs drug carrier can be used as an outstanding luminescent probe for bioimaging in vivo application prospects. The results suggest that the degradable drug carrier with up-conversion luminescence may enhance the delivery efficiency of drugs and improve the cancer therapy in clinical applications.

Bone-Targeted Mesoporous Silica Nanocarrier Anchored by Zoledronate for Cancer Bone Metastasis.

Once bone metastasis occurs, the chances of survival and quality of life for cancer patients decrease significantly. With the development of nanomedicine, nanocarriers loading bisphosphonates have been built to prevent cancer metastasis based on their enhanced permeability and retention (EPR) effects; however, as a passive mechanism, the EPR effects cannot apply to the metastatic sites because of their lack of leaky vasculature. In this study, we fabricated 40 nm-sized mesoporous silica nanoparticles (MSNs) anchored by zoledronic acid (ZOL) for targeting bone sites and delivered the antitumor drug doxorubicin (DOX) in a spatiotemporally controlled manner. The DOX loading and release behaviors, bone-targeting ability, cellular uptake and its mechanisms, subcellular localization, cytotoxicity, and the antimigration effect of this drug delivery system (DDS) were investigated. The results indicated that MSNs-ZOL had better bone-targeting ability compared with that of the nontargeted MSNs. The maximum loading capacity of DOX into MSNs and MSNs-ZOL was about 1671 and 1547 mg/g, with a loading efficiency of 83.56 and 77.34%, respectively. DOX@MSNs-ZOL had obvious pH-sensitive DOX release behavior. DOX@MSNs-ZOL entered into cells through an ATP-dependent pathway and then localized in the lysosome to achieve effective intracellular DOX release. The antitumor results indicated that DOX@MSNs-ZOL exhibited the best cytotoxicity against A549 cells and significantly decreased cell migration in vitro. This DDS is promising for the treatment of cancer bone metastasis in the future.