Sandwich Structure-like Meshes Fabricated via Electrospinning for Controllable Release of Zoledronic Acid

Novel sandwich structure-like nanofiber multilayered meshes were fabricated via electrospinning. The purpose of the present work was to control zoledronic acid release via the novel structure of sandwich structure-like meshes. The in vitro release experiments reveal that the drug release speed and initial burst release were controllable by adjusting the thicknesses of electrospun barrier mesh and drug-loaded mesh. Compared with those of other drug delivery systems, the main advantages of the sandwich structure-like fiber meshes are facile preparation conditions and the generality for hydrophobic and hydrophilic pharmaceuticals.

The curative effect of zoledronic acid and pamidronic acid on treating ostealgia in malignant tumor with bone metastases and its side effects on serum calcium and phosphorus

Objective： Bisphosphonates were widely used with the rate of malignant tumor with bone metastases increasing rapidly. The aim of this study was to evaluate zoledronic acid and pamidronic acid on treating ostealgia of malignant tumor with bone metastases and serum calcium, phosphorus and alkaline phosphorus movement. Methods： One Hundred cancer patients with bone metastases were diagnosed according to pathological and imaging methods. After zoledronic acid or pamidronic acid intravenous infusion one and two months, ostealgia degree, serum calcium, serum phosphorus and alkaline phosphorus were observed before bisphosphonates treatment, one and two months after treatment, respectively. Results： Ostealgia degree did not change significantly after diphosphonates treatment from one to two months （P 〉 0.05）. The linear correlation between serum calcium and serum phosphorus on bone metastases cancer patients before therapy was dismissed after bisphosphonates treatment one month and did not recover in two months. The incidence of hypo-calcium after diphosphonate treatment one month （54%） and two months （56%） were significantly increased than that before treatment （36%） （X2 = 6.55, P = 0.011; X2 = 8.05, P = 0.005）. Serum calcium and serum phosphorus were both decreased after treatment one month （t = 4.39, P = 0.000; t = 2.50, P = 0.014） and two months （t = 4.32, P = 0.000; t = 2.49, P = 0.010）. There had no difference between zoledronic acid and pamidronic acid on treating of ostealgia and serum calcium and phosphorus changing. Conclusion： Zoledronic acid and pamidronic acid can relief ostealgia of cancer patients with bone metastases and induce hypo-calcium, break the linear relationship between calcium and phosphorus. There have no difference between zoledronic acid and pamidronic acid on treating ostealgia and inducing hypo-calcium and hypo-phosphorus.

Zoledronic acid combined with androgendeprivation therapy may prolong time to castration-resistant prostate cancer in hormone-naı¨ve metastatic prostate cancer patients e A propensity scoring approach

Objective:To clarify the oncological benefit of zoledronic acid for hormone-naive metastatic prostate cancer,patient outcome of androgen deprivation therapy with zoledronic acid(ADT+Z)and androgen deprivation therapy alone(ADT)was compared.Methods:Fifty-two patients with pathologically confirmed metastatic prostate cancer were prospectively enrolled and treated with combined androgen blockade(goserelin and bicalutamide)with zoledronic acid(4 mg every 4 weeks for 24 months).A propensity score-match with logistic regression analysis was applied to select 50 pair-matched cohorts(both from ADT+Z and from historical control cohorts who had undergone ADT alone),and patient outcomes were compared.Results:Patients with ADT+Z had significantly longer time to progression(TTP)than those with ADT(median TTP;24.2 vs.14.0 months,p=0.0092),while no significant difference of overall survival between two groups(p=0.1502).Multivariate analysis for biochemical recurrence revealed treatment with ADT was the sole independent prognostic factor(HR:1.724,95%CI:1.06-2.86,p=0.0297).Conclusion:Combination of zoledronic acid with ADT may prolong time to castration resistant prostate cancer.

The Clinical Effect of Zoledronic Acid Combined with Teriparatide in Perverting Recurrent Fracture of Osteoporotic Vertebral Compressive Fractures in the Elderly after Percutaneous Kyphoplasty

Background: Zoledronic acid and teriparatide have been proved to be effective in improving bone metabolism and preventing fractures, but there is no clear clinical report on the efficacy of their combined application. Purpose: To discuss the clinical effect of zoledronic acid combined with teriparatide in perverting recurrent fracture of osteoporotic vertebral compressive fractures (OVCF) in the elderly after percutaneous kyphoplasty (PKP). Method: A randomized clinical trial was conducted at the First Affiliated Hospital of Hebei North University in China from September 2018 and September 2019. A total of 60 patients with OVCF were enrolled in the study (zoledronic acid: 20 cases;teriparatide: 20 cases;zoledronic acid + teriparatide: 20 cases). Observe and compare the changes of bone mineral density (BMD), pro-collagen type I N-terminal propeptide (PINP) and cross-linked C-terminal telopeptide of type I collagen (β-CTX) before surgery, 6 months and 1 year after surgery. At the same time, secondary fracture events and adverse reaction events were recorded during the follow-up period. Results: After normalized treatment, the bone metabolism indexes of PINP and β-CTX were improved and BMD was increased in three groups. Adverse Reactions: There was no statistical significance in the incidence of fever, gastrointestinal reactions and myalgia among the three groups (P > 0.05). The incidence of recurrent fractures in group A was higher than that in group C (P < 0.05), but there was no significant difference between group B and group C (P > 0.05). Conclusion: Zoledronic acid combined with teriparatide is superior to Zoledronic acid in preventing the risk of recurrent fracture after PKP for old patients with OVCF, but it has no significant advantage over teriparatide.

Efficacy and safety of radiotherapy combined with zoledronic acid in the treatment of lung cancer with bone metastasis: a meta-analysis

Objective: To evaluate the efficacy and safety of radiotherapy combined with zoledronic acid fOr the treatment of bone metastases. Methods: Use Pubmed, Cochrane Library, Embase, CBM, CNKI, Wanfang, Weipu tools to search-related databases at home and abroad. From 2013.1 to March 2019, radiotherapy combined with zoledronic acid and radiotherapy alone for bone metastasis of lung cancer were collected. Experimental studies;quality evaluation and data extraction for each of the included studies, and Cochrane risk bias assessment tools for quality evaluation of the literature. Data processing was performed using RevMan 5.3 and Stata 15.0 software, including risk ratio (OR), 95% CI, I2, and P values. Line sensitivity test, publication bias evaluation is using Egger's, Bgge's method quantitative calculation using Revman 5.3 and Stata 15.0 software for statistical analysis. Results: The total of 8 articles was included, and the number of cases was 703. The results of the meta-analysis showed that the radiotherapy, combined with the zoledronic acid group was effective in the treatment of lung cancer with bone metastasis. The meta-analysis was Z = 6.31 (P < 0.00001), OR (95% CI = 3.57, (2.41, 5.30)), the difference was statistically significant. The combined effect of bone metastases was better than that of the single-stage group. The meta-analysis results were Z = 3.18 (P = 0.001) and OR (95% CI = 3.21, (1.57, 6.59)), indicating the therapeutic effect of the two groups in the treatment of bone metastases. The difference is statistically significant. Adverse reactions include: (1) bone marrow suppression, blood toxicity;(2) fever and rash;(3) nausea, vomiting, and fatigue;(4) liver damage and loss of appetite, meta-analysis results are: bone marrow suppression, blood toxicity: Z =0.73 ( P = 0.47), OR (95% CI = 0.58 (0.13, 2.54));fever, rash: Z = 0.36 (P = 0.36), OR (95% CI = 1.3 (0.31, 5.38));nausea, vomiting, Weakness: Z = 0.29 (P = 0.77), OR (95% CI = 0.85 (0.27, 2.62));liver function damage and loss of appetite: Z = 0.00 (P = 1.00), OR (95% CI = 1.00 (0.17, 6.00)). The P values of the four meta-analyses were all greater than 0.05, and the difference was not statistically significant, indicating that the addition of zoledronic acid to the bone metastasis of lung cancer did not aggravate the changes of the above four adverse reactions. Conclusion: Radiotherapy combined with the zoledronic acid group is better than the single radiotherapy group in treating pain caused by bone metastasis. It can effectively treat bone metastasis and will not aggravate the occurrence of adverse reactions.

Clinical research on zoledronic acid in treatment of pain caused by bone metastasis of malignant tumors

Objective:To evaluate the efficacy and safety of zoledronic acid for the pain caused by metastatic tumor of bone.Methods:52 patients with metastatic tumor of bone were randomly divided into two groups.The zoledronic acid group received 4 mg zoledronic acid infusion for 30 minutes and the control group received 90 mg pamidronate infusion for 6 hours. Results:The effective rates in zoledronic acid group and control group were 73.08%and 69.23%respectively.No significant difference was observed between the two groups.The median pain relief onset at days 5 and 7,respectively,and no significant difference was observed.The ECOG scores on the 7th day after medication:the differences in the zoledronic acid group before and after medication and between the two groups were both significant(P<0.001 and P=0.0448).The adverse reac- tion was no significant difference between the two groups.Conclusion:Zoledronic acid is efficient and safe in the treatment of pain caused by metastatic tumor of bone and it has low adverse reaction rate and convenient shorter using time.

Comparative study of 99Tc-MDP and zoledronic acid in the treatment of osteoporosis

Objective:To compare the efficacy and mechanism of zoledronic acid and Tc-MDP in the treatment of osteoporosis.Methods:From July 2011 to November 2015,232 patients with primary osteoporosis were selected and treated in The First Affiliated Hospital of Hainan Medical College were selected and were divided into the 116 patients in the Tc-MDP group and 116 patients in the zoledronic acid group accorded to the treatment ways.The zoledronic acid group were given zoledronic acid treatment,1 time in one year.The Tc-MDP group were given Tc-MDP treatment,and the treatment were treated for 10 days for 1 course,1 course for 3 months,and a total of 3 years of treatment were observed.The prognosis and the changes of bone mineral density and hematological parameters were recorded.Results:The total effective rates of the zoledronic acid group and Tc-MDP group were 99.1%and 90.0%,respectively,and the zoledronic acid group were significantly higher than the Tc-MDP group(P<0.05).The bone mineral density of lumbar vertebrae and hip after treatment were significantly higher than that of the two groups before treatment,and the zoledronic acid group were also significantly higher than the Tc-MDP group(P<0.05).The joint tenderness scores of the two groups were significantly lower than those before treatment,and the Tc-MDP group were also significantly lower than the zoledronic acid group(P<0.05).There were no significant differences in serum calcium and blood phosphorus levels compared between the two groups(P>0.05),and the erythroeyte sedimentation rate(ESR)levels were lower than before treatment(P<0.05),The ESR levels of the Tc-MDP group were also significantly lower than that of the zoledronic acid group(P<0.05).Conclusion:The zoledronic acid and the application of Tc-MDP in the treatment of osteoporosis can increase bone density,relieve joint tenderness symptoms,reduce ESR content,and will not affect patients'blood calcium and blood phosphorus levels.However,zoledronic acid increases bone density significantly are better than the Yunke,and Yunke relieves joint pain significantly are more than zoledronic acid.

A multicenter phase II trial of domestic product of zoledronic acid in the treatment of malignant hypercalcemia

Objective:To evaluate the effect and safety of clinical use of zoledronic acid in the treatment of malignant hypercalcemia.Methods:A multi-center,open phase II clinical trial was conducted in 15 cases with malignant hypercalcemia who received zoledronic acid intravenously for 15 min.The level of blood calcium and side effects were recorded regularly within 28 days after injection.Results:One case was dropped out due to bad compliance.The complete response rate(the corrected serum calcium was reduced to normal level)was 100.00%(14/14).The medium time of complete response rate was 5.07 days.The medium maintain time was 22.30 days.Slight,or moderate fever was observed.Conclusion:Zoledronic acid can effectively reduce the malignant hypercalcemia.The use of zoledronic acid appears to be safety and convenient.

Severe and Prolonged Hypocalcaemia Post Zoledronic Acid Infusion in a Patent with Sleeve Gastrectomy

Background: Zoledronic acid is commonly used to treat hypercalcaemia and osteoporosis, as well as to prevent skeletal complications from haematological and solid organ malignancies. Case presentation: We report the case of a 38 year old lady who presented with severe hypocalcaemia following the administration of zoledronic acid. Her significant background history included vitamin D deficiency and sleeve gastrectomy three years ago. She had prolonged hypocalcaemia requiring IV calcium replacement for two months. Her prolonged hypocalcaemia was attributed to her vitamin D deficiency at the time of zoledronic acid infusion as well as her history of bariatric surgery. Conclusion: This case emphasises the importance of ensuring vitamin D levels are replete prior to zoledronic acid infusion and ensuring the calcium levels are checked frequently in patients with a history of bariatric surgery obtaining zoledronic acid.

Chemotherapy,transarterial chemoembolization,and nephrectomy combined treated one giant renal cell carcinoma(T3aN1M1)associated with Xp11.2/TFE3:A case report

BACKGROUND Renal cell carcinoma(RCC)with Xp11.2 translocation/TFE3 gene fusion is a rare and distinct subtype of RCC that is classified under tumors with translocation of the microphthalmia-associated transcriptional factor.CASE SUMMARY We report an adult case of Xp11.2 translocation advanced RCC with metastasis(T3a N1M1),after targeted treatment,alcohol ablation,and transarterial chemoembolization,who eventually underwent successful surgical excision.No recurrence or transfer was seen within one year,and the survival period was more than 3 years.A review of the relevant literature was conducted to improve our understanding of the pathogenesis,epidemiology,clinical manifestations,diagnosis,differential diagnosis,treatment,and other aspects of the disease.CONCLUSION Transarterial chemoembolization and ablation did not achieve the desired tumor reduction in this patient,but had a significant effect on reducing intraoperative bleeding and inhibiting tumor activity.

Zoledronic acid inhibits growth of hepatocellular carcinoma cells in vitro and in vivo

Background Growing preclinical evidence shows that zoledronic acid （ZOL） exhibits direct antitumor activity in various cancer cell lines. However, the cytotoxic effects of ZOL on human hepatocellular carcinoma （HCC） cells have not been established. In the present study, we investigated the effect of ZOL on HCC both in vitro and in vivo. Methods Cytotoxicity and cell cycles were assessed with Sulforhodamine B colorimetric assay and flow cytometry. Expression levels of cell cycle phase-linked proteins were examined. The effect of ZOL on HCC in vivo was explored based on H22-subcutaneous injection （s.c.） and H22-intraperitoneal injection （i.p.） mice model. Results ZOL inhibited the growth of SK-HEP-1 and H22 cells and induced S-phase arrest through downregulating cdc2 protein and upregulating cyclin A. It inhibited the growth of s.c tumors, and increased the survival of both H22-s.c. and H22-i.p. mice in vivo. Conclusion ZOL inhibits qrowth of HCC cells in vitro and in vivo.

Sequential treatment with doxorubicin and zoledronic acid has no additive effects in an aggressive model of established bone metastases

Aim: Bisphosphonates are used as an adjuvant treatment in breast cancer bone metastasis patients, often simultaneously with chemotherapeutic agents. Interestingly, their sequential combination has been reported to have synergistic anti-tumor effects on bone metastases in preclinical models. We studied the effects of doxorubicin (DOX) and zoledronic acid (ZOL) and their combination on established bone metastases in the MDA-MB-231(SA) GFP bone metastasis model. Methods: Tumor burden and osteolytic bone lesions were quantitated by fluorescence imaging and radiography, respectively. The mice were randomized in four groups receiving vehicle, DOX, ZOL or both DOX and ZOL in a sequential combination on day 14. Serum marker of osteoclast number was followed weekly, and blood ionized calcium was measured at sacrifice. Bone and tumor area, apoptosis and proliferation of tumor cells were analyzed from histological sections. Results: ZOL prevented hypercalcemia and osteolytic lesion progression, whereas DOX induced apoptosis in the MDA-MB-231(SA)GFP cells. However, neither of the treatments alone nor in sequential combination were able to reduce tumor burden in bone. Furthermore, no additive effects on tumor cell apoptosis were observed in the ;combination group. Conclusion: No additive effects in combination of DOX and ZOL were observed in this aggressive model of breast cancer bone metastasis.

Multiplexed bioluminescence imaging of cancer cell response to hypoxia and inflammation in the caudal-artery injection model of bone metastasis during zoledronic acid treatment

Aim:Therapeutic agents suppressing bone remodeling have been clinically approved to delay metastatic progression and skeletal-related events in patients with bone metastasis.However,therapeutic agents including zoledronic acid(ZA)are insufficient to regress established bone metastasis.Therefore,new treatment strategies are desired,and unraveling the status of cancer cells during bone metastatic progression will help develop therapeutic strategies.Methods:We developed a unique multiplexed reporter system for bioluminescent imaging(MRS-BLI)using three luciferase reporter genes.This system allows for the noninvasive and quantitative monitoring of tumor growth and activities of nuclear factor-kappa B(NF-κB)and hypoxia-inducible factor(HIF),which are the key transcriptional factors in response to inflammation and hypoxia,respectively.PC-3/MRS-BLI,a human prostate cancer cell line that stably retains the MRS-BLI reporter genes,was applied to the caudal-artery injection model of bone metastasis to observe the status of cancer cells during bone metastasis development and ZA treatment(<1 month).Results:MRS-BLI reveals key events during the bone metastasis development:NF-κB and HIF are activated in cancer cells after migration to the bone marrow and are transiently reduced,followed by rapid activation before proliferation begins.ZA treatment suppresses the growth of metastasized cancer cells by suppressing NF-κB and HIF activities that may be indirectly induced by osteoclast activation.Conclusion:By visualizing the NF-κB and HIF activities of PC-3/MRS-BLI in bone,MRS-BLI has enabled new discoveries regarding the regulation of bone metastases.Further analysis of the progression of bone metastases using MRS-BLI may provide important information for developing new therapeutic strategies.

An antigen self-assembled and dendritic cell-targeted nanovaccine for enhanced immunity against cancer

The rise of nanotechnology has opened new horizons for cancer immunotherapy.However,most nano vaccines fabricated with nanomaterials suffer from carrier-related concerns,including low drug loading capacity,unpredictable metabolism,and potential systemic toxicity,which bring obstacles for their clinical translation.Herein,we developed an antigen self-assembled nanovaccine,which was resulted from a simple acryloyl modification of the antigen to induce self-assembly.Furthermore,a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid(Zol)were integrated or absorbed onto the nanoparticles(denoted as MEAO-Z)to intensify the immune response.The synthesized nano vaccine with a diameter of around 70 nm showed successful lymph node transportation,high dendritic cell internalization,promoted costimulatory molecule expression,and preferable antigen cross-presentation.In virtue of the above superiorities,MEAO-Z induced remarkably higher titers of serum antibody,stronger cytotoxic T lymphocyte immune responses and IFN-γsecretion than free antigen and adjuvants.In vivo,MEAO-Z significantly suppressed EG7-OVA tumor groth and prolonged the survival time of tumor-bearing mice.These results indicated the translation promise of our self-assembled nano vaccine for immune potentiation and cancer immunotherapy.

Stimulation of in vitro bone formation by canine prostate cancer

Aim:Patients with prostate cancer frequently develop osteoblastic bone metastases.Canine models are important because dogs are the only mammal to develop spontaneous prostate cancer with osteoblastic bone metastases similar to men.The mechanism by which prostate cancer induces bone formation is unclear;however,it depends on the complex interaction between prostate cancer cells and bone microenvironment.This study investigated the effects of three canine prostate cancer cell lines(Ace-1,LuMa,and Probasco)on bone formation and resorption in vitro.Methods:Mouse calvaria were treated with conditioned medium(CM)from cell lines.Calvaria were evaluated by histology,fluorescent calcein uptake at sites of bone mineralization,medium calcium assay,and alkaline phosphatase activity.The expression of bone-related genes was measured using quantitative reverse transcription PCR.Results:A novel calcein uptake assay was developed to measure bone formation and mineralization in vitro.Ace-1 CM induced predominantly bone resorption in calvaria,while Probasco CM induced marked bone formation,mineralization,and healing of calvaria defects.The expression of osteoblast-related genes in calvaria showed that Probasco CM stimulated the maturation and differentiation of osteoblasts and inhibited osteoclastogenesis.Both bone modeling and remodeling were involved in Probasco CM-induced bone formation and mineralization by inhibiting remodeling with zoledronic acid.Inhibition of WNT activity by DKK-1 decreased the osteoblastic activity of Probasco cells.Conclusion:Probasco cells induced bone formation and mineralization in vitro that depended on the WNT signaling pathway.Probasco cells will serve as a valuable model for studying the mechanisms of osteoblastic bone metastasis in prostate cancer.