ABSTRACT
Brain metastasis is a common and serious complication of breast cancer, which is commonly associated with poor survival and prognosis. In particular, the treatment of brain metastasis from triple-negative breast cancer (BM-TNBC) has to face the distinct therapeutic challenges from tumor heterogeneity, circulating tumor cells (CTCs), blood-brain barrier (BBB) and blood-tumor barrier (BTB), which is in unmet clinical needs. Herein, combining with the advantages of synthetic and natural targeting moieties, we develop a "Y-shaped" peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC. Inherited from the activated platelet, the hybrid liposomes still retain the native affinity toward CTCs. Further, the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo. The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions, and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug. Overall, this work provides a promising prospect for the comprehensive treatment of BM-TNBC, which could be generalized to other cell types or used in imaging platforms in the future.
ABSTRACT
Objective:To investigate the effects of cabazitaxel on lung cancer cell metastasis and proliferation and the related mechanisms.Methods:Lung cancer cells A549 were divided into two groups. The experimental group were cultured with a low concentration of 50 μg/ml cabazitaxel, and the control group were cultured with an equal volume of a solution of cabazitaxel. The proliferation ability of the two groups of cells was examined using CCK8 and plate cloning experiments. The migration ability of A459 cells was verified by transwell and cell scratch experiments. The expression levels of MMP2/9, CDK4/6, and P16 protein were detected by Western blotting.Results:Compared with the control group, the cell proliferation ability of the A549 cell was weakened in the experimental group. The plate clone formation rate of the experimental group was 17.5%±2.3%, and A549 cell clone formation rate of the control group was 74.8%±4.5%. The cloning ability was reduced in the experimental group. Western blot results showed that the expression of CDK4/6 in the experimental group was down-regulated and the expression of P16 was up-regulated. The scratch healing percentage of the cells in the experimental group was 56.2%±3.8%, and the scratch healing percentage of the cells in the control group was 86.8%±5.2%. The scratch healing ability of the cells in the experimental group decreased. The transwell results showed that the experimental group had 35±4 cells per field of view, while it was 78±9 in the control group. The cell migration ability of the experimental group was decreased. Western blot results showed that the expression of MMP2/9 in the experimental group was down-regulated.Conclusion:Cabazitaxel leads to a decrease in the metastasis ability of lung cancer cells A549 through the extracellular matrix pathway, and inhibits cell proliferation by up-regulating P16.
ABSTRACT
Liposomes have made remarkable achievements as drug delivery vehicles in the clinic. Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs, but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents, thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy. In this study, a series of weak acid drug derivatives were designed by a simplistic one step synthesis, which could be remotely loaded into liposomes by pH gradient method. Cabazitaxel (CTX) weak acid derivatives were selected to evaluate regarding its safety profiles, pharmacodynamics, and pharmacokinetics. CTX weak acid derivative liposomes were superior to Jevtana® in terms of safety profiles, including systemic toxicity, hematological toxicity, and potential central nerve toxicity. Specifically, it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons. Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.
ABSTRACT
The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen receptor signaling pathway remains active in metastatic castration-resistant prostate cancer. Docetaxel and cabazitaxel are the first- and second-line chemotherapy, respectively, for patients with metastatic castration-resistant prostate cancer. These two taxanes, in general, function by (i) inhibiting mitosis and inducing apoptosis and (ii) preventing microtubule-dependent cargo trafficking. In prostate cancer, taxanes have been reported to inhibit the nuclear translocation and activity of the androgen receptor. However, whether this is attainable or not clinically remains controversial. In this review, we will provide a comprehensive view of the effects of taxanes on androgen receptor signaling in prostate cancer.
ABSTRACT
OBJECTIVE:To establish a method for the determination of related substances in Cabazitaxel injection. METHODS:HPLC method was used. The determination was performed on Agilent Eclipse XDB-C18column with mobile phase consisted of water-acetonitrile-ethanol(gradient elution)at the flow rate of 1.0 mL/min. The column temperature was 35 ℃,and the detection wavelength was set at 230 nm. The sample size was 20 μ L. Established method was used to determine related substances in 3 batches of Cabazitaxel injection. RESULTS:The linear relationship of cabazitaxel were 0.039-11.60 μ g/mL(r=0.999 8,n=7). The detection limit was 2×10-4μg,and quantitation limit was 8×10-4μg. RSD of precision and reproducibility tests were all lower than 10.0%(n=6). The amount of single impurity in 3 batches of samples ranged 0.07%-0.08%,and total amount of impurities were 0.26%-0.29%. CONCLUSIONS:Established method is simple,accurate and reliable,can be used for the determination of related substances in Cabazitaxel injection.
ABSTRACT
OBJECTIVE: We present our data comparing retrospectively the efficacy of abiraterone and cabazitaxel in patients who progress after docetaxel treatment. PATIENTS AND METHODS: The study included 56 patients diagnosed with hormone‑refractory metastatic prostate cancer who were previously treated with abiraterone therapy at four oncology centers in Turkey. RESULTS: With abiraterone, the patients had a median progression‑free survival (PFS) of 5.9 months (95% confidence interval (CI) for hazard ratio (HR) (4.4–7.4)) and an overall survival of 13.4 months (95% CI for HR (5.5–21.3)). When we compared the disease‑free survival (DFS) of reference patients treated with cabazitaxel as a second‑line treatment with those receiving second‑line abiraterone therapy, there was no significant difference. (PFS = 5.9 months with cabazitaxel vs. 6.7 months with abiraterone, P = 0.213). CONCLUSION: This study has shown that in our experience abiraterone acetate is an effective agent in metastatic castration‑resistant prostate cancer (mCRPC) regardless of the line of treatment.
ABSTRACT
Background: There are limited data regarding cabazitaxel use beyond 10 cycles. Patients and Methods: Retrospective analysis of prospectively collected data of patients with metastatic castrate-resistant prostate cancer who received over 10 cycles of cabazitaxel after docetaxel failure. Results: Four patients received between 14 and 27 cycles. Reasons for stopping cabazitaxel were toxicity (2), progression (1) and logistics (1). Two of the three patients with measurable disease attained a partial remission (PR). Three patients continued to have a PSA response after 10 cycles; PSA nadir occurred between 17 and 23 cycles. Other than peripheral neuropathy (PN), all the cabazitaxel-related toxicities occurred after the initial cycles and did not increase cumulatively. Clinically significant neuropathy occurred after 15-17 cycles. The cabazitaxel-induced PN was partially reversible, with improvement from grade 3 to grade 2 after a 3-5-month long drug holiday. Conclusion: Cautiously continuing cabazitaxel until progression or intolerable toxicity may maximize efficacy.