Treatment Of Bone Metastases Research Articles

Whole-cycle management norms of bone health in breast cancer

Bone health management of breast cancer runs through the whole cycle of patient treatment. During the process of adjuvant treatment for early breast cancer, clinicians should be pay attention to the prevention of bone loss caused by treatment. Adjuvant use of bone-modifying agents can help improve the prognosis of some patients, and patients with bone metastases should be given multidisciplinary comprehensive treatment and use bone-modifying agents to prevent the occurrence bone related adverse events. Therefore, no matter for the treatment of early or advanced breast cancer, it is necessary to manage bone health, formulate appropriate treatment strategies, and deal with adverse events of drugs. Good bone health management will help improve the quality of life and survival of patients. The breast cancer expert committee of the National Cancer Quality Control Center organized relevant experts to deeply explore the full cycle management of bone health in breast cancer based on Evidence-based medicine evidence. The risk classification and treatment strategy of cancer treatment-induced bone loss in early breast cancer, the applicable population and benefits of adjuvant treatment of bone modifying drugs, the diagnosis and treatment of bone metastasis in advanced breast cancer, and the treatment of adverse reactions of bone modifying drugs were elaborated in detail. We hope to guide clinicians to better deal with bone health problems in clinical practice by putting forward reasonable suggestions for patients with breast cancer.

The emerging role of osteoclasts in the treatment of bone metastases: rationale and recent clinical evidence.

The occurrence of bone metastasis is a grave medical concern that substantially impacts the quality of life in patients with cancer. The precise mechanisms underlying bone metastasis remain unclear despite extensive research efforts, and efficacious therapeutic interventions are currently lacking. The ability of osteoclasts to degrade the bone matrix makes them a crucial factor in the development of bone metastasis. Osteoclasts are implicated in several aspects of bone metastasis, encompassing the formation of premetastatic microenvironment, suppression of the immune system, and reactivation of quiescent tumor cells. Contemporary clinical interventions targeting osteoclasts have proven effective in mitigating bone-related symptoms in patients with cancer. This review comprehensively analyzes the mechanistic involvement of osteoclasts in bone metastasis, delineates potential therapeutic targets associated with osteoclasts, and explores clinical evidence regarding interventions targeting osteoclasts.

Development of a New Focal Mouse Model of Bone Metastasis in Renal Cell Carcinoma.

Developing animal models of bone metastasis in renal cell carcinoma (RCC) is challenging as immunodeficient mice are required. The aim of this study was to develop a simple immune model of RCC bone metastasis. RENCA tumor cells were injected into the right femurs of BALB/c mice. Sixty mice were grouped into each twenty-mouse group according to the tumor cell concentration, and the presence or absence and extent of bone metastasis in the total length of the femur were compared using hematoxylin and eosin staining of the excised tissues. Bone metastasis was significantly higher in the high concentration group than in the other groups (p<0.05), with 10 mice developing bone metastasis at two weeks and nine mice developing bone metastasis at three weeks. The extent of bone metastasis was significantly greater in the high concentration group than in the other groups (p<0.05). Multiple logistic regression analysis was performed to examine the factors influencing bone metastasis, and only the high concentration was a significant factor (p<0.05). We developed a normal immunity mouse model of local bone metastasis from RCC. This model could prove valuable for research into the treatment of bone metastases in RCC.

Game-changing insights on vertebral skeletal stem cells in bone metastasis and therapeutic horizons.

Greenblatt and his team have unveiled vertebral skeletal stem cells (vSSCs) as a critical player in the landscape of bone metastasis. This commentary delves into the transformative discoveries surrounding vSSCs, emphasizing their distinct role in bone metastasis compared to other stem cell lineages. We illuminate the unique properties and functions of vSSCs, which may account for the elevated susceptibility of vertebral bones to metastatic invasion. Furthermore, we explore the exciting therapeutic horizons opened by this newfound understanding. These include potential interventions targeting vSSCs, modulation of associated signaling pathways, and broader implications for the treatment and management of bone metastasis. By shedding light on these game-changing insights, we hope to pave the way for novel strategies that could revolutionize the prognosis and treatment landscape for cancer patients with metastatic bone disease.

In Vitro Assessment of 4-Acetyl-Antroquinonol B and Erinacine A in Suppressing Breast Cancer-Induced Osteoclastogenesis.

Bone metastasis in metastatic breast cancer commonly results in osteolytic lesions due to osteoclast activity, promoting bone destruction and tumor progression. The bioactive fungal isolates, 4-acetyl-antroquinonol B (4-AAQB) and erinacine A, have diverse pharmacological and biological activities. However, their effects on breast cancer bone metastasis treatment remain unclear. Our study aimed to examine the impact of 4-AAQB or erinacine A on breast cancer metastases in bone. The effects of 4-AAQB and erinacine A on breast cancer-induced osteoclastogenesis, breast cancer migration, production of prometastatic cytokine (TGF-β) and marker (MMP-9), as well as potential MAPK signaling transductions were assessed. The results revealed that 4-AAQB and erinacine A effectively suppressed breast cancer-induced osteoclastogenesis and migration, and reduced TGF-β and MMP-9 production via Erk or JNK signaling transductions, specifically in breast cancer cells or in breast cancer cells-induced osteoclasts. Based on these findings, either 4-AAQB or erinacine A showed promise in preventing breast cancer metastases in bone.

Downregulation of osteoprotegerin in colorectal cancer cells promotes liver metastasis via activating tumor-associated macrophage

Osteoprotegerin (OPG) is a secreted cytokine that functions as a decoy receptor for receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL). Anti-RANKL treatment for bone metastasis has been widely accepted for solid tumors. However, the mechanism of OPG-RANKL-RANK signaling in systemic colorectal cancer (CRC) metastasis remains unclear. In this study, we investigated the relevance and function of OPG expression in CRC liver metastasis. First, we performed in silico analysis using The Cancer Genome Atlas public database and found that lower OPG expression in CRC was associated with poor overall survival. Immunohistochemistry analyses using resected specimen from patients with CRC in our institute confirmed the result. Patient-matched primary CRC and liver metastases showed a significant downregulation of OPG expression in metastatic lesions. In CRC cell lines, OPG expression did not suppress cell proliferation and migration. However, OPG expression inhibited macrophage migration by suppressing the RANKL-RANK pathway. Moreover, in vivo mouse liver metastasis models showed that OPG expression in CRC cells suppressed liver metastases. In addition, treatment with an anti-RANKL neutralizing antibody also suppressed liver metastases. These results showed that downregulation of OPG expression in CRC cells promotes liver metastasis by activating tumor-associated macrophage, which can become a candidate for targeted therapy with anti-RANKL neutralizing antibody for CRC liver metastasis.

Zuogui pill disrupt the malignant cycle in breast cancer bone metastasis through the Piezo1-Notch-1-GPX4 pathway and active molecules fishing

Background: Breast cancer bone metastasis is closely associated with the bone microenvironment. Zuogui Pill (ZGP), a clinically approved formulation in China, effectively regulates the bone microenvironment for the prevention and treatment of osteoporosis.Purpose: Few reports have utilized the ZGP for bone metastasis models. This study investigated the intervention and bone-protective properties of ZGP against breast cancer bone metastasis, explored the potential mechanism, and screened for its active compositions by molecules fishing.Methods: To investigate the intervention efficacy of ZGP and its protein-level mechanism of action, the mouse bone metastasis model and in vitro cell co-culture model were constructed. Affinity ultrafiltration, molecular docking, cellular thermal shift assay and physical scale detection were used to investigate the affinity components of the RANKL protein in ZGP.Results: The administration of ZGP combined with zoledronic acid inhibited the development of tumors and secondary lung metastasis in mice. This translated to a prolonged survival period and enhanced quality of life. ZGP could disrupt the malignant cycle by modulating the Piezo1-Notch-1-GPX4 signaling pathway in the "bone-cancer" communication in the cell co-culture model. Furthermore, 25 chemical components of ZGP were identified, with 10 active compounds exhibiting significant affinity for the RANKL protein.Conclusion: The findings of this work highlighted ZGP's potential for intervening in the progression of breast cancer bone metastasis. Thus, this investigation served as an experimental foundation for expanding the application scope of ZGP and for advancing drug development efforts in bone metastasis treatment.

Layer by layer assembly of strontium substituted nanowire hydroxyapatite and hybrid of carbon derivatives as potential biomaterial for bone metastasis treatment

To devise a highly effective implant for addressing bone metastasis with the unique capability of self-oxygen generation, a multifunctional film was engineered using a Layer-by-Layer technique. The film, comprised of strontium-substituted hydroxyapatite nanowires (SrwHAP) and a graphitic carbon nitride/graphene oxide (g-CN/GO) hybrid, was meticulously designed. To optimize the film's interaction with mesenchymal stem cells (MSCs), the number of layers was adjusted. Subsequent surface coating involved extracellular matrix (ECM) derived from osteogenic cells. The final film, ((CN/GO). SrwHAP)2. ECM, exhibited pronounced MSC attachment and an accelerated proliferation rate. Key osteogenic markers such as alkaline phosphatase activity, mineralization, RUNX2, and osteocalcin expression remarkably increased when compared to the glass substrate. Notably, the presence of LED irradiation yielded further enhancements in proliferation and osteogenic markers, attributed to the photocatalytic properties of the (CN/GO) hybrid alongside O2 generation. Direct co-culturing of MSCs and breast cancer cells (MCF7) on its surface, coupled with LED irradiation not only bolstered the osteogenic potential of MSCs but also reduced tumor colonies over time. Impressively, ((CN/GO). SrwHAP)2. ECM also demonstrated potent antibacterial properties against Gram-positive bacteria (Staphylococcus aureus). Based on the results obtained, ((CN/GO). SrwHAP)2. ECM emerges as a promising candidate for addressing bone defects in patients afflicted by breast cancer bone metastasis.

Survival Prediction Model for Patients with Hepatocellular Carcinoma and Extrahepatic Metastasis Based on XGBoost Algorithm.

Accurate estimation of survival is of utmost importance in patients with hepatocellular carcinoma (HCC) and extrahepatic metastasis. This study aimed to develop a survival prediction model using real-world data. A total of 993 patients with treatment-naïve HCC and extrahepatic metastasis were included from 13 Korean hospitals between 2013 and 2018. Patients were randomly divided into a training set (70.0%) and a test set (30.0%). The eXtreme Gradient Boosting (XGBoost) algorithm was applied to predict survival at 3, 6, and 12 months. The mean age of the patients was 60.8 ± 12.3 years, and 85.4% were male. During the study period, 96.1% died, and median survival duration was 4.0 months. In multivariate analysis, Child-Pugh class, number and size of tumors, presence of vascular or bile duct invasion, lung or bone metastasis, serum AFP, and primary anti-HCC treatment were associated with survival. We constructed a model for survival prediction based on the relevant variables, which is available online (https://metastatic-hcc.onrender.com/form). Our model demonstrated high performance, with areas under the receiver operating characteristic curves of 0.778, 0.794, and 0.784 at 3, 6, and 12 months, respectively. Feature importance analysis indicated that the primary anti-HCC treatment had the highest importance. We developed a model to predict the survival of patients with HCC and extrahepatic metastasis, which demonstrated good discriminative ability. Our model would be helpful for personalized treatment and for improving the prognosis.

Therapeutic Effects of CT-guided Microwave Ablation Combined with Cementoplasty in the Treatment of Bone Metastasis

Background: The incidence of malignant tumors causing bone metastasis was increasing. Therefore, it was urgent to treat patients with bone metastasis. Objectives: This study aimed to evaluate the role of computed tomography (CT)-guided microwave ablation combined with cementoplasty in the treatment of patients with bone metastasis. Patients and Methods: A total of 20 patients with bone metastasis who were treated with CT-guided microwave ablation combined with cementoplasty were included in this study, according to the inclusion and exclusion criteria. The follow-up data of all patients were collected, and no patients were lost to follow-up during this period. The Quality of Life Questionnaire-Bone Metastases Module 22 (QLQ-BM22), the EuroQOL Five-Dimension Questionnaire (EQ-5D), and the Quality-Adjusted Life Year (QALY) measure were used to assess the treatment effects. Results: Based on the results, 37 operations performed on 20 patients were successful. Minor complications were observed in seven cases. There were significant differences in the QLQ-BM22 scores when comparing the pre-treatment and post-treatment results (P &lt; 0.05). Moreover, the pre-treatment and post-treatment QALY scores exhibited significant differences (P &lt; 0.05). However, there was no significant difference between the pre-treatment and post-treatment EQ-5D scores (P &gt; 0.05). Conclusion: The combination of CT-guided microwave ablation with cementoplasty was proven to be an effective approach in extending the survival time and enhancing the quality of life in patients with bone metastasis.

Reoperation after surgery for bone metastasis of renal cell carcinoma.

The prognosis of metastatic renal cell carcinoma (RCC) has markedly improved with the advent of molecular targeted therapies and immune checkpoint inhibitors. However, the therapeutic response in patients with bone metastasis remains low; therefore, surgery still plays a significant role in treatment of bone metastasis. It is important to maintain quality of life for patients with bone metastasis from RCC and avoid reoperation after surgery for bone metastasis. Therefore, we investigated the risk factors for reoperation after surgery in patients with bone metastasis from RCC. We retrospectively studied 103 bones of 97 patients who underwent surgery for bone metastasis of RCC from 2001 to 2023 at our institutions. Reoperation was performed in 10 (9.7%) of 103 bones. There was no correlation between reoperation-free survival and any of the following variables: preoperative and postoperative radiotherapy, site of bone metastasis, indication for surgery (solitary bone metastasis or impending or pathologic fractures), surgical method (intramedullary nailing fixation, curettage, or en bloc resection), preoperative embolization, or survival. The risk of reoperation for bone metastasis of RCC does not appear to be based on the surgical method.

Mechanism of synergistic inhibitory effect of benzyl isothiocyanate and zoledronic acid combination on breast cancer induction of osteoclast differentiation.

Bone is the most favored site for metastasis for each major subtype of breast cancer. Therapeutic modalities for alleviation of clinical symptoms associated with bone metastasis include surgical resection, radiation, and bone-targeted therapies, including bisphosphonates (e.g., zoledronic acid; ZA) and a humanized antibody against receptor activator of nuclear factor-κB ligand (denosumab). However, the bone-targeted therapies are expensive, and have poor pharmacokinetic attributes and/or serious adverse effects. Therefore, novel strategies are needed for treatment of bone metastasis or to increase effectiveness of existing bone-targeted therapies. We have shown previously that benzyl isothiocyanate (BITC) is a novel inhibitor of osteoclast differentiation in vitro and bone metastasis in vivo. The present study shows that BITC + ZA combination synergistically inhibits osteoclast differentiation induced by addition of conditioned media from breast cancer cells. These effects were associated with a significant increase in levels of several antiosteoclastogenic cytokines, including interferons, interleukin (IL)-3, IL-4, and IL-27. Kyoto Encyclopedia of Genes and Genomes pathway analysis of RNA-seq data from BITC and/or ZA-treated cells revealed downregulation of genes of many pathways (e.g., actin cytoskeleton, Hippo signaling, etc.) by treatment with BITC + ZA combination, but not by BITC alone or ZA alone. Confocal microscopy confirmed severe disruption of actin cytoskeleton upon treatment of MCF-7 and MDA-MB-231 cells with the BITC + ZA combination. This combination also decreased the nuclear level of yes-associated protein, a core component of Hippo signaling. In conclusion, the present study offers a novel combination for prevention or treatment of bone metastasis of breast cancer.

Immunotherapeutic treatment of lung cancer and bone metastasis with a mPLA/mRNA tumor vaccine.

Malignant expansion and rapid metastasis are the main limiting factors to successful treatment of lung cancer. Messenger RNA (mRNA) tumor vaccines are a promising immunotherapeutic treatment for lung cancer as well as other metastatic cancers. Herein, we developed a mPLA/mRNA tumor vaccine (mLPR) to escort mRNA into the cytoplasm and improve immune response with the help of TLR4 agonist mPLA. After nasal administration, the mLPR vaccine stimulated the maturation of dendritic cells, reprogramed M2 macrophages into M1 macrophages, as well cross-activated innate and adaptive immune responses. The mLPR vaccine inhibited the development of lung cancer and reduced bone metastasis by means of immune cell activation, IFN-γ/IL-12 cytokine secretion, and natural killer cell-mediated antibody dependent cellular cytotoxicity. The mPLA/mRNA tumor vaccine will provide ideas and application prospects for the use of mRNA tumor vaccine in the treatment of lung cancer. STATEMENT OF SIGNIFICANCE: Lung cancer and bone metastasis seriously affect patient survival, and traditional treatment methods are inefficient and have many side effects. We have constructed an mRNA vaccine that simultaneously activates the innate immune and adaptive responses of the body, in order to achieve better immunotherapeutic effects. To sum up, we confirmed through vaccine design and in vitro and in vivo immunological studies that the mLPR vaccine stimulated the maturation of dendritic cells, reprogrammed M2 macrophages into M1 macrophages, as well cross activated in vivo and adaptive immune responses.

Electrochemotherapy in the Treatment of Bone Metastases: A Systematic Review.

Cancers are one of the most frequent causes of death and disability in humans. Skeletal involvement has a major impact on the quality of life and prognosis of cancer patients. Electrochemotherapy is a palliative and minimally invasive oncologic treatment that was first used to treat subcutaneous nodules for malignant tumors. The aim of our review is to evaluate the results of electrochemotherapy in the treatment of bone metastases. A systematic review of the literature indexed in the PubMed MEDLINE and Cochrane Library databases using the search key words "electrochemotherapy" AND ("metastasis" OR "metastases") was performed. The Preferred Reporting Items for Systematic Reviews and MetaAnalyses was followed. Inclusion criteria were proven involvement of the appendicular skeleton in metastatic carcinoma or melanoma, through at least one percutaneous electrochemotherapy session on the metastatic bone lesion. The exclusion criterion was no skeletal metastatic involvement. Eight articles were finally included. We reached a population of 246 patients. The mean age and follow up were 60.1 years old and 11.4 months, respectively. The most represented primary tumor was breast cancer (18.9%). A total of 250 bone lesions were treated with electrochemotherapy. According to RECIST criteria, in our population we observed 55.5% stable diseases. The mean pre-electrochemotherapy VAS value was 6.9, which lowered to 2.7 after treatment. Adverse events occurred in 3.4% of patients. Electrochemotherapy as a minimally invasive and tissue-sparing treatment should be considered for patients with no other alternative to obtain tumor control and improvement in quality of life.

Designing a Marketing Strategy for Samarium 153 ethylenediaminetetramethylene phosphonic acid (Sm 153-EDTMP) for Palliative Treatment of Cancer that Spreads to The Bones

This research is proposed to identify marketing strategic of Samarium ethylenediaminetetramethylene phosphonic acid (Sm 153-EDTMP) that is used for palliative treatment of bone metastasis towards utilization policy by the Nuclear Medicine Doctors. The data is obtained from the questionnaire that were spread out to Nuclear Medicine Doctors in a number of Hospital in Indonesia as respondents. The respondents were 35 of Nuclear Medicine Doctors. This number represents 80 % of Nuclear Medicine Doctors population in Indonesia. The research methodology is accomplished by descriptive explorative analysis. The results are: (1) dose, side effect of Sm 153-EDTMP that is more tolerating than morphine, (2) according to the local product promotion, Sm 153-EDTMP is able to be delivered more effectively to the user through detailing, symposium, internet (3) the price of the local product of Sm 153-EDTMP that is way more cheaper than morphine. By paying attention to marketing strategies through product advantages, promotional forms and prices SM 153-EDTMP shows that these products can be used by Nuclear Medicine specialists (SpKN) as a palliative treatment for cancer that spreads to the bones.

Post biphosphonate mandible osteonecrosis: A case study and literature review.

Bisphosphonates have proven effective in reducing pain and skeletal events in bone metastases treatment. However, there is a long-term complication called osteonecrosis of the jaw, which has been reported for more than a decade. Despite various professional recommendations, there is no international consensus on the best therapeutic strategy. Prevention is crucial, and a multidisciplinary approach must be tailored to each stage of the condition. We present a case of osteonecrosis of the jaw in a patient with metastatic breast cancer who was receiving 4 mg injectable zoledronic acid. The patient stopped treatment with zoledronic acid and received systemic treatment (analgesics, antibiotics), with the resolution of symptoms. ONJ is a serious condition associated with taking BP that can impact oral health and quality of life. Our study highlights the effectiveness of systematic treatment in managing ONJ with BP-related alterations. Preventative measures, such as regular dental consultations, play a vital role in reducing the risk of ONJ. Multidisciplinary management is essential to addressing the different stages of the condition.

Activatable Semiconducting Polymer Nanoinducers Amplify Oxidative Damage via Sono-Ferroptosis for Synergistic Therapy of Bone Metastasis.

Bone metastases are secondary malignant tumors that commonly occur after the spread of advanced cancer cells. We herein report the activatable semiconducting polymer nanoinducers (ASPNFP) that can amplify oxidative damage via sono-ferroptosis for bone metastasis treatment. ASPNFP are constructed by encapsulating plasma amine oxidase-based semiconducting polymer nanoparticles (SPNP) and Fe3O4 nanoparticles into singlet oxygen (1O2)-responsive nanocarriers. ASPNFP generate 1O2 under ultrasound (US) irradiation via a sonodynamic effect to destroy the stability of 1O2-responsive nanocarriers, allowing US-triggered releases of SPNP and Fe3O4 nanoparticles. SPNP decompose polyamines in tumor cells to produce acrolein and hydrogen peroxide (H2O2), in which H2O2 promotes Fenton reaction mediated by Fe3O4 nanoparticles for inducing enhanced ferroptosis and generation of hydroxyl radicals (•OH). The generated acrolein, 1O2, and •OH can simultaneously amplify the oxidative damage. ASPNFP thus mediate an amplified sono-ferroptosis effect to inhibit the growth of bone metastasis and restrict tumor metastasis.

The Bone Microenvironment Soil in Prostate Cancer Metastasis: An miRNA Approach.

Bone metastatic prostate cancer (PCa) is associated with a high risk of mortality. Changes in the expression pattern of miRNAs seem to be related to early aspects of prostate cancer, as well as its establishment and proliferation, including the necessary steps for metastasis. Here we compiled, for the first time, the important roles of miRNAs in the development, diagnosis, and treatment of bone metastasis, focusing on recent in vivo and in vitro studies. PCa exosomes are proven to promote metastasis-related events, such as osteoblast and osteoclast differentiation and proliferation. Aberrant miRNA expression in PCa may induce abnormal bone remodeling and support tumor development. Furthermore, miRNAs are capable of binding to multiple mRNA targets, a dynamic property that can be harnessed for the development of treatment tools, such as antagomiRs and miRNA mimics, which have emerged as promising candidates in PCa treatment. Finally, miRNAs may serve as noninvasive biomarkers, as they can be detected in tissue and bodily fluids, are highly stable, and show differential expression between nonmetastatic PCa and bone metastatic samples. Taken together, the findings underscore the importance of miRNA expression profiles and miRNA-based tools as rational technologies to increase the quality of life and longevity of patients.

Calcium phosphate hybrid micelles inhibit orthotopic bone metastasis from triple negative breast cancer by simultaneously killing cancer cells and reprogramming the microenvironment of bone resorption and immunosuppression.

Triple negative breast cancer (TNBC) is prone to develop drug resistance and metastasis. Bone is the most common distant metastasis site of breast cancer cell. Patients with bone metastasis from TNBC suffer from unbearable pain due to the growth of bone metastasis and bone destruction. Simultaneously blocking the growth of bone metastasis and reprogramming the microenvironment of bone resorption and immunosuppression is a promising strategy to treat bone metastasis from TNBC. Herein, we prepared a pH and redox responsive drug delivery system, named DZ@CPH, by encapsulating docetaxel (DTX) with hyaluronic acid-polylactic acid micelle then reinforcing with calcium phosphate and zoledronate for targeting to bone metastasis from TNBC. DZ@CPH reduced the activation of osteoclast and inhibited bone resorption by decreasing the expression of nuclear factor κB receptor ligand and increasing the expression of osteoprotegerin in drug-resistant bone metastasis tissue. At the same time, DZ@CPH inhibited the invasion of bone metastatic TNBC cells by regulating the apoptosis-related and invasion-related protein expression. It also increased the sensitivity of orthotopic drug-resistant bone metastasis to DTX by inhibiting the expression of P-glycoprotein, Bcl-2 and transforming growth factor-β in tissue of drug-resistant bone metastasis. Moreover, the ratio between M1 type macrophage to M2 type macrophage in bone metastasis tissue was increased by DZ@CPH. In a word, DZ@CPH blocked the growth of bone metastasis from drug-resistant TNBC through inducing the apoptosis of drug-resistant TNBC cells and reprogramming the microenvironment of bone resorption and immunosuppression. DZ@CPH has a great potential in clinical application for the treatment of bone metastasis from drug-resistant TNBC. STATEMENT OF SIGNIFICANCE: Triple negative breast cancer (TNBC) is prone to develop bone metastasis. Now bone metastasis is still an intractable disease. In this study, docetaxel and zoledronate co-loaded calcium phosphate hybrid micelles (DZ@CPH) were prepared. DZ@CPH reduced the activation of osteoclasts and inhibited bone resorption. At the same time, DZ@CPH inhibited the invasion of bone metastatic TNBC cells by regulating the expression of apoptosis and invasion related protein in bone metastasis tissue. Moreover, the ratio between M1 type macrophages to M2 type macrophages in bone metastases tissue was increased by DZ@CPH. In a word, DZ@CPH blocked vicious cycle between the growth of bone metastasis and bone resorption, which greatly improved the therapeutic effect on bone metastasis from drug-resistant TNBC.

Hierarchically Released Liquid Metal Nanoparticles for Mild Photothermal Therapy/Chemotherapy of Breast Cancer Bone Metastases via Remodeling Tumor Stromal Microenvironment.

Currently, the treatment strategy for bone metastasis is mainly to inhibit the growth of tumor cells and the activity of osteoclasts, while ignoring the influence of the tumor stromal microenvironment (TSM) on the progression of bone metastasis. Herein, a dual-target liquid metal (LM)-based drug delivery system (DDS) with favorable photothermal performance is designed to spatially program the delivery of multiple therapeutic agents to enhance the treatment of bone metastasis through TSM remodeling. Briefly, mesoporous silicon-coated LM is integrated into zeolitic imidazolate framework-8 (ZIF-8) with both bone-seeking and tumor-targeting capacities. Curcumin (Cur), a tumor microenvironment modulator, is encapsulated into ZIF-8, and doxorubicin (DOX) is enclosed inside mesoporous silicon. Specific accumulation of the LM-based DDS in bone metastases first relieves the tumor stroma by releasing Cur in response to the acidic tumor microenvironment and then releases DOX deep into the tumor under near-infrared light irradiation. The combined strategy of the LM-based DDS and mild photothermal therapy has been shown to effectively restrain cross-talk between osteoclasts and tumor cells by inhibiting the secretion of transforming growth factor-β, degrading extracellular matrix components, and increasing infiltration of CD4+ and CD8+ T cells, which provides a promising strategy for the treatment of bone metastases.