Recent advances in the targeted fluorescent probes for the detection of metastatic bone cancer

Tumors of the breast, prostate, and lung are most likely to metastasize to the bone and typically indicates a poor cure and survival rate in cancer patients. Detection of metastatic bone cancer in early stage would save many lives and greatly improve patients' quality of life. Clinically, bone scintigraphy is often utilized to visualize bone metastases due to its relatively low cost and high sensitivity. Recently, a growth number of analytical researches aimed at developing targeted fluorescent probes to noninvasively image bone metastases with improved spatial resolution and specificity has been reported. In this review, we will summarize and discuss the recent published fluorescent probes on the accurate detection of metastatic bone cancer. First, the design principles of various targeted probes for imaging bone metastases will be presented, highlighting the signal moieties, targeting ligands, and physicochemical properties of the bone-specific probes. Next, the up-to-date bone-targeting fluorescent probes will be summarized and overviewed. Finally, future perspectives and challenges confronting the researchers in this field will be discussed.We believe this review will encourage novel ideas to develop smart targeted molecular probes for bone metastasis imaging,image-guided surgery, and therapeutic imaging materials.     

Recent Advances in Nanomedicine for the Diagnosis and Treatment of Prostate Cancer Bone Metastasis

Patients with advanced prostate cancer can develop painful and debilitating bone metastases. Currently available interventions for prostate cancer bone metastases, including chemotherapy, bisphosphonates, and radiopharmaceuticals, are only palliative. They can relieve pain, reduce complications (e.g., bone fractures), and improve quality of life, but they do not significantly improve survival times. Therefore, additional strategies to enhance the diagnosis and treatment of prostate cancer bone metastases are needed. Nanotechnology is a versatile platform that has been used to increase the specificity and therapeutic efficacy of various treatments for prostate cancer bone metastases. In this review, we summarize preclinical research that utilizes nanotechnology to develop novel diagnostic imaging tools, translational models, and therapies to combat prostate cancer bone metastases.     

Dual-Targeting Biomimetic Semiconducting Polymer Nanocomposites for Amplified Theranostics of Bone Metastasis

Bone metastasis is a type of metastatic tumors that involves the spreads of malignant tumor cells into skeleton, and its diagnosis and treatment remain a big challenge due to the unique tumor microenvironment. We herein develop osteoclast and tumor cell dual-targeting biomimetic semiconducting polymer nanocomposites (SPFeN_OC) for amplified theranostics of bone metastasis. SPFeN_OC contain semiconducting polymer and iron oxide (Fe₃O₄) nanoparticles inside core and surface camouflaged hybrid membrane of cancer cells and osteoclasts. The hybrid membrane camouflage enables their targeting to both metastatic tumor cells and osteoclasts in bone metastasis through homologous targeting mechanism, thus achieving an enhanced nanoparticle accumulation in tumors. The semiconducting polymer mediates near-infrared (NIR) fluorescence imaging and sonodynamic therapy (SDT), and Fe₃O₄ nanoparticles are used for magnetic resonance (MR) imaging and chemodynamic therapy (CDT). Because both cancer cells and osteoclasts are killed synchronously via the combinational action of SDT and CDT, the vicious cycle in bone metastasis is broken to realize high antitumor efficacy. Therefore, 4T1 breast cancer-based bone metastasis can be effectively detected and cured by using SPFeN_OC as dual-targeting theranostic nanoagents. This study provides an unusual biomimetic nanoplatform that simultaneously targets osteoclasts and cancer cells for amplified theranostics of bone metastasis.     

Perturbations of pathway co-expression network identify a core network in metastatic breast cancer

Metastases are the main cause of death in advanced breast cancer (BC) patients. Although chemotherapy and hormone therapy are current treatment strategies, drug resistance is frequent and still not completely understood.In this study, a bioinformatics analysis was performed on BC patients to explore the molecular mechanisms associated with BC metastasis. Microarray gene expression profiles of metastatic and non metastatic BC patients were downloaded from Gene Expression Omnibus (GEO) dataset. Raw data were normalized and merged using the Combat tool. Pathways enriched with differently expressed genes were identified and a pathway co-expression network was generated using Pearson’s correlation. We identified from this network, which includes 17 pathways and 128 interactions, the pathways that most influence the network efficiency. Moreover, protein interaction network was investigated to identify hub genes of the pathway network. The prognostic role of the network was evaluated with a survival analysis using an independent dataset.In conclusion, the pathway co-expression network could contribute to understanding the mechanism and development of BC metastases.     

Prospective study to assess the clinical efficacy of bone scintigraphy--ROC analysis

The value of preoperative bone scans in patients with primaly breast and prostate cancer was evaluated prospectively. The methodology and some clinical results were described previously. The clinical efficacy of the bone scan was assessed by using ROC analysis and we obtained the following results. 1) Preoperative bone scan of carcinomas of the breast is effective for patients with clinical stage IIIA, IIIB and IV. It is not so effective for patients with clinical stage I and II, but there is no denying the importance of it, because it provides a base-line scan for comparison to subsequent scans obtained in the postoperative period. 2) Preoperative bone scan of prostate carcinomas is effective, especially for clavicle, the ribs and the cervical spine, when compared with bone X-ray. 3) Bone scan is effective means for patients who were diagnosed uncertainly to have bone metastasis.     

Prospective study to assess the clinical efficacy of bone scintigraphy--some analyses of clinical data

The value of preoperative bone scans in patients with primary breast and prostate cancer was evaluated prospectively. Of 414 patients with breast cancer, clinical stage I is 14, II is 219, IIIA is 59, IIIB is 39 and IV is 14. Of 88 patients with prostate cancer, clinical stage I is 14, II is 15, III is 18 and IV is 41. 11 percent of patients with breast cancer and 54 percent of patients with prostate cancer had bone metastases. Clavicle, ribs, thoracic spine, lumbar spine and pelvis metastasized most frequently. The incidences of bone metastases were 18.4% with Scirrhous carcinoma, 15.4% with Medullary tubular carcinoma and 3.8% with Papillotubular carcinoma. The methodology and results of ROC analysis were described in our other papers. Some results of data analysis were described in this paper.     

Towards the stable chelation of radium for biomedical applications with an 18-membered macrocyclic ligand

Targeted alpha therapy is an emerging strategy for the treatment of disseminated cancer. [²²³Ra]RaCl₂ is the only clinically approved alpha particle-emitting drug, and it is used to treat castrate-resistant prostate cancer bone metastases, to which [²²³Ra]Ra²⁺ localizes. To specifically direct [²²³Ra]Ra²⁺ to non-osseous disease sites, chelation and conjugation to a cancer-targeting moiety is necessary. Although previous efforts to stably chelate [²²³Ra]Ra²⁺ for this purpose have had limited success, here we report a biologically stable radiocomplex with the 18-membered macrocyclic chelator macropa. Quantitative labeling of macropa with [²²³Ra]Ra²⁺ was accomplished within 5 min at room temperature with a radiolabeling efficiency of >95%, representing a significant advancement over conventional chelators such as DOTA and EDTA, which were unable to completely complex [²²³Ra]Ra²⁺ under these conditions. [²²³Ra][Ra(macropa)] was highly stable in human serum and exhibited dramatically reduced bone and spleen uptake in mice in comparison to bone-targeted [²²³Ra]RaCl₂, signifying that [²²³Ra][Ra(macropa)] remains intact in vivo. Upon conjugation of macropa to a single amino acid β-alanine as well as to the prostate-specific membrane antigen-targeting peptide DUPA, both constructs retained high affinity for ²²³Ra, complexing >95% of Ra²⁺ in solution. Furthermore, [²²³Ra][Ra(macropa-β-alanine)] was rapidly cleared from mice and showed low ²²³Ra bone absorption, indicating that this conjugate is stable under biological conditions. Unexpectedly, this stability was lost upon conjugation of macropa to DUPA, which suggests a role of targeting vectors in complex stability in vivo for this system. Nonetheless, our successful demonstration of efficient radiolabeling of the β-alanine conjugate with ²²³Ra and its subsequent stability in vivo establishes for the first time the possibility of delivering [²²³Ra]Ra²⁺ to metastases outside of the bone using functionalized chelators, marking a significant expansion of the therapeutic utility of this radiometal in the clinic.

The therapeutic alpha-emitter ²²³Ra can be stably complexed in vivo, creating opportunities for the development of targeted radiopharmaceutical agents with this radionuclide.     

Mitotic protein kinase-driven crosstalk of machineries for mitosis and metastasis

Accumulating evidence indicates that mitotic protein kinases are involved in metastatic migration as well as tumorigenesis. Protein kinases and cytoskeletal proteins play a role in the efficient release of metastatic cells from a tumor mass in the tumor microenvironment, in addition to playing roles in mitosis. Mitotic protein kinases, including Polo-like kinase 1 (PLK1) and Aurora kinases, have been shown to be involved in metastasis in addition to cell proliferation and tumorigenesis, depending on the phosphorylation status and cellular context. Although the genetic programs underlying mitosis and metastasis are different, the same protein kinases and cytoskeletal proteins can participate in both mitosis and cell migration/invasion, resulting in migratory tumors. Cytoskeletal remodeling supports several cellular events, including cell division, movement, and migration. Thus, understanding the contributions of cytoskeletal proteins to the processes of cell division and metastatic motility is crucial for developing efficient therapeutic tools to treat cancer metastases. Here, we identify mitotic kinases that function in cancer metastasis as well as tumorigenesis. Several mitotic kinases, namely, PLK1, Aurora kinases, Rho-associated protein kinase 1, and integrin-linked kinase, are considered in this review, as an understanding of the shared machineries between mitosis and metastasis could be helpful for developing new strategies to treat cancer.Subject terms: Oncogenes, Mitosis, Metastasis     

Effect of Diets,Familial History,and Alternative Therapies on Genomic Instability of Breast Cancer Patients

This study evaluates a correlation between family history, micronutrients intake, and alternative therapies with genetic instability, before and during breast cancer treatment. For this study, a total of 150 women were selected. Among those, 50 women were breast cancer patients on chemotherapy, while 50 breast cancer patients were on radiotherapy, and 50 were healthy females. All the participants signed the informed consent form and answered the public health questionnaire. Samples of buccal epithelial and peripheral blood cells were collected and analyzed through micronucleus and comet assays. The cells were evaluated for apoptosis and DNA damage. Results showed the association of patients’ family history with an increase in toxicogenetic damage before and during cancer therapy. On the other hand, patients with late-onset cancer also presented genetic instability before and during therapy, along with those who did not take sufficient vegetables and alternative therapies. A positive correlation was observed between the genetic instability and alternative therapies, while inverse correlation was recorded with the vegetable consumption. Results clearly explain that the nutritional aspects and alternative therapies influence the genetic instability before and during cancer therapies especially in radiotherapy treated patients. Our data could be used for the monitoring therapies and management of breast cancer patients.

     

3D Culture Models of Malignant Mesothelioma Reveal a Powerful Interplay Between Photodynamic Therapy and Kinase Suppression Offering Hope to Reduce Tumor Recurrence

In this issue, Cramer et al. introduce 3D culture models of metastatic mesothelioma to investigate basic cancer biology and new combination therapies for combating this complex and lethal disease. The results suggest that erlotinib‐enhanced photodynamic therapy could further improve the efficacy of intraoperative light‐activation to mop up residual tumor deposits in the clinic following surgical removal of macroscopic mesothelioma metastases.     

Signaling Pathways and Natural Compounds in Triple-Negative Breast Cancer Cell Line

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, having a poor prognosis and rapid metastases. TNBC is characterized by the absence of estrogen, progesterone, and human epidermal growth receptor-2 (HER2) expressions and has a five-year survival rate. Compared to other breast cancer subtypes, TNBC patients only respond to conventional chemotherapies, and even then, with limited success. Shortages of chemotherapeutic medication can lead to resistance, pressured index therapy, non-selectivity, and severe adverse effects. Finding targeted treatments for TNBC is difficult owing to the various features of cancer. Hence, identifying the most effective molecular targets in TNBC pathogenesis is essential for predicting response to targeted therapies and preventing TNBC cell metastases. Nowadays, natural compounds have gained attention as TNBC treatments, and have offered new strategies for solving drug resistance. Here, we report a systematic review using the database from Pubmed, Science Direct, MDPI, BioScince, Springer, and Nature for articles screening from 2003 to 2022. This review analyzes relevant signaling pathways and the prospect of utilizing natural compounds as a therapeutic agent to improve TNBC treatments in the future.     

Recent Advances in Nanotechnology for the Treatment of Melanoma

Melanoma is one of the most aggressive forms of skin cancer, with few possibilities for therapeutic approaches, due to its multi-drug resistance and, consequently, low survival rate for patients. Conventional therapies for treatment melanoma include radiotherapy, chemotherapy, targeted therapy, and immunotherapy, which have various side effects. For this reason, in recent years, pharmaceutical and biomedical research has focused on new sito-specific alternative therapeutic strategies. In this regard, nanotechnology offers numerous benefits which could improve the life expectancy of melanoma patients with very low adverse effects. This review aims to examine the latest advances in nanotechnology as an innovative strategy for treating melanoma. In particular, the use of different types of nanoparticles, such as vesicles, polymers, metal-based, carbon nanotubes, dendrimers, solid lipid, microneedles, and their combination with immunotherapies and vaccines will be discussed.     

Chemo–immunotherapy for chemo-resistance and metastasis of triple-negative breast cancer by combination of iron-oxide nanoparticles and dual-targeting doxorubicin liposomes

Triple-negative breast cancer (TNBC) lacks specific regimens for targeted therapy. Repeat chemotherapy promotes the evolution of TNBC into highly chemo-resistant tumors that metastasize to multiple organs simultaneously. Herein, polyacrylic acid-coated ultrasmall superparamagnetic iron-oxide nanoparticles (PAA@IONs) and dual-targeting doxorubicin liposomes achieved chemo–immunotherapy through intermittent administration. They inhibited tumor-drug resistance and multiorgan-specific metastasis significantly by targeting tumors and the microenvironment. We deciphered an immunosuppressive pre-metastatic niche and discovered that PAA@IONs could target tumors, tumor-draining lymph nodes (TDLNs), the liver, bone, and lungs. They promoted the polarization of macrophages into M1 macrophages in these organs and tissues. This action remodeled the immunosuppressive microenvironment and induced a sustained immune response, thereby reducing organ-specific metastasis. Overcoming the disadvantages of doxorubicin-induced cardiotoxicity as well as low tumor specificity, dual peptide-modified liposomes could target CD206 and CD13 simultaneously, and reverse chemo-resistance. These properties resulted in a significant decrease in the numbers of myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) in the liver, lungs, and bone, thereby reducing protein expression of Ki-67 in TDLNs, and dramatically increasing the number of cluster of differentiation (CD)8⁺ T cells and CD8⁺ T cell/T-regulatory-cell ratio in tumors and TDLNs (P < 0.0001). Compared with the control (P < 0.05 and P < 0.01, respectively) or free drug (P < 0.0001 and P < 0.01, respectively), multi-organ metastases were suppressed significantly, tumor-growth rate reduced, and survival prolonged. Our drug-delivery system overcame TNBC chemo-resistance and inhibited multiorgan-specific metastases. It circumvents the lack of effective therapeutic targets, the problem of patient selection due to a low mutation rate, and can simultaneously offer the possibility of avoiding surgery and considerable postoperative complications.     

Current Photoactive Molecules for Targeted Therapy of Triple-Negative Breast Cancer

Cancer is the second leading cause of death worldwide; therefore, there is an urgent need to find safe and effective therapies. Triple-negative breast cancer (TNBC) is diagnosed in ca. 15–20% of BC and is extremely aggressive resulting in reduced survival rate, which is mainly due to the low therapeutic efficacy of available treatments. Photodynamic therapy (PDT) is an interesting therapeutic approach in the treatment of cancer; the photosensitizers with good absorption in the therapeutic window, combined with their specific targeting of cancer cells, have received particular interest. This review aims to revisit the latest developments on chlorin-based photoactive molecules for targeted therapy in TNBC. Photodynamic therapy, alone or combined with other therapies (such as chemotherapy or photothermal therapy), has potential to be a safe and a promising approach against TNBC.     

Resveratrol in management of bone and spinal cancers

Bone cancer is a malignant primary tumour of the bone with different typing, such as, osteosarcoma, chondrosarcoma, Ewing’s sarcoma and fibrosarcoma. Despite the clinical efficacy of conventional therapies of bone cancer, most patients eventually relapse and the disease remains incurable. Therefore, new therapeutic strategies are needed to improve patient outcome. In this review article, we have discussed the role of resveratrol in preventing bone and spinal cancers and therapeutics. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a natural polyphenol, which has been widely reported as an anticancer molecule. Resveratrol exhibits multiple tumour-suppressing activities in bone cancer by affecting a series of critical events. It has the protective effects against oxidative injury, possesses antiproliferative activity and induces apoptosis in cancer cells. Resveratrol might be a good option for the treatment of different types of bone and spinal cancers.     

An Insight into the Anti-Angiogenic and Anti-Metastatic Effects of Oridonin: Current Knowledge and Future Potential

Cancer is one of the leading causes of death worldwide, with a mortality rate of more than 9 million deaths reported in 2018. Conventional anti-cancer therapy can greatly improve survival however treatment resistance is still a major problem especially in metastatic disease. Targeted anti-cancer therapy is increasingly used with conventional therapy to improve patients’ outcomes in advanced and metastatic tumors. However, due to the complexity of cancer biology and metastasis, it is urgent to develop new agents and evaluate the anti-cancer efficacy of available treatments. Many phytochemicals from medicinal plants have been reported to possess anti-cancer properties. One such compound is known as oridonin, a bioactive component of Rabdosia rubescens. Several studies have demonstrated that oridonin inhibits angiogenesis in various types of cancer, including breast, pancreatic, lung, colon and skin cancer. Oridonin’s anti-cancer effects are mediated through the modulation of several signaling pathways which include upregulation of oncogenes and pro-angiogenic growth factors. Furthermore, oridonin also inhibits cell migration, invasion and metastasis via suppressing epithelial-to-mesenchymal transition and blocking downstream signaling targets in the cancer metastasis process. This review summarizes the recent applications of oridonin as an anti-angiogenic and anti-metastatic drug both in vitro and in vivo, and its potential mechanisms of action.     

Combined OX40 Agonist and PD-1 Inhibitor Immunotherapy Improves the Efficacy of Vascular Targeted Photodynamic Therapy in a Urothelial Tumor Model

Purpose: Vascular targeted photodynamic therapy (VTP) is a nonsurgical tumor ablation approach used to treat early-stage prostate cancer and may also be effective for upper tract urothelial cancer (UTUC) based on preclinical data. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model. Experimental design: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses. Results: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and prolonged survival to a greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells. Conclusions: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.     

Prospective study to assess the clinical efficacy of bone scintigraphy--comparative study of the efficacy in breast carcinoma and prostate carcinoma

Prospective study of bone scintigraphy was performed on 414 patients with breast carcinoma and 88 patients with prostate carcinoma. In 468 of them, confirmative diagnoses of bone, whether metastasis was existent or not, were made after the observations over a year. Finally, the incidences of bone metastasis were 11 percent for breast carcinoma and 54 percent for prostate carcinoma respectively. The efficacy of preoperative bone scintigraphy in breast carcinoma was comparable to that in prostate carcinoma with regard to improvement of predictive probability of bone metastasis: raising up the probability in the positive cases and bringing down in the negative cases.     

Sodium bicarbonate,an inorganic salt and a potential active agent for cancer therapy

Cancer is a serious threat to humans due to its high mortality. The efforts to fully understand cancer and to fight against it have never been stopped. The traditional therapies, such as surgery, radiotherapy and chemotherapy, are useful but cannot meet the increasing demands of patients. As such, novel approaches against cancer are urgently required. It has been found that the acidic tumor microenvironment plays important roles in promoting the cancer progression. In recent years, sodium bicarbonate (NaHCO₃), a simple inorganic salt, has been found to be able to reverse the pH of tumor microenvironment and inhibit the invasion, metastasis, immune evasion, drug resistance and hypoxia of tumor cells. Thus, NaHCO₃-based therapy is a potential approach for the treatment of cancer, and the related studies have been increasingly reported. Herein, we aim to provide a comprehensive understanding of the acidic tumor microenvironment and summarize the applications and mechanisms of NaHCO₃ in cancer therapy. The combination of NaHCO₃ with chemotherapy, immunotherapy or nanoparticles systems is discussed. In addition, the concerns of NaHCO₃ in clinical use and the potential ways to use NaHCO₃ for cancer therapy are also discussed.     

Ruthenium complexes can target determinants of tumour malignancy

Metastases are more decisive for tumour prognosis than primary lesions, because of their multiple locations, low accessibility to surgery and/or radiotherapy, and generally poor responsiveness to chemotherapy. The metastasis should therefore be the primary target for drug therapy. Among ruthenium complexes, NAMI-A is a leading compound that shows selective effects for solid tumour metastases related to a mechanism of action involving the inhibition of the processes of tumour invasiveness. NAMI-A opens an avenue to new perspectives in cancer chemotherapy. This includes novel compounds directed at targets selectively expressed by tumour metastases, thus reducing the typical side effects of the current metal-based drugs that are active via their unselective DNA interaction.