epothilone-a and arginyl-glycyl-aspartic-acid

The targeted nanoagents have shown great potential clinically for cancer therapy. Traditional targeted nanodrugs are usually prepared through surface postmodification. Herein, a nanodrug is self-assembled from the amphiphilic precursor of targeting peptide RGD conjugated with cytotoxin epothilone B (Epo B) through a linker containing the thioketal (tk) group that is sensitive to reactive oxygen species (ROS). The obtained RGD-tk-Epo B conjugate nanoparticles (RECNs) are stable and uniform, which facilitates improving tumor-targeting capacity and accumulation of the drug because of the large number of RGD on the surface of the RECN. After internalization by cancer cells, the blood-inert tk group between RGD and Epo B can be cleaved in the presence of high level of ROS to release Epo B, exhibiting a markedly tumor selectivity and excellent anticancer efficiency

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Epothilones; Humans; Mice; Nanoconjugates; Neoplasms, Experimental; Oligopeptides; Reactive Oxygen Species; Xenograft Model Antitumor Assays

Patupilone (EPO906) is a microtubule stabilizer with a potent antitumor effect. Integrin αVβ3-binding (RGD) liposomes were loaded with EPO906, and their antitumor efficacy was evaluated in two pediatric tumor models, ie, neuroblastoma and rhabdomyosarcoma.. Integrin αVβ3 gene expression, RGD-liposome cellular association, and the effect of EPO906 and liposomal formulations of EPO906 on cell viability were assessed in vitro in human umbilical vein endothelial cells (HUVEC), in the RH-30 rhabdomyosarcoma cell line, and in the Kelly neuroblastoma cell line. In vivo, mice bearing neuroblastoma or rhabdomyosarcoma tumors were treated with EPO906, EPO906-liposomes, or EPO906-RGD-liposomes. Tumor growth, cumulative survival, and toxicity were monitored.. Integrin αVβ3 was highly expressed in HUVEC and RH-30, but not in Kelly cells. Accordingly, RGD-liposomes were highly associated with HUVEC and RH-30 cells in vitro, but not with the Kelly cells. EPO906 and its liposomal formulations inhibited HUVEC, RH-30, and Kelly cell viability to the same extent. In vivo, EPO906 1.5 mg/kg and liposomal EPO906 potently inhibited tumor growth in both xenograft models without triggering major toxicity. At this dose, liposomal EPO906 did not enhance the antitumor effect of EPO906 in neuroblastoma, but tended to have an increased antitumor effect in rhabdomyosarcoma. Using a lower dose of EPO906-RGD-liposomes significantly enhanced cumulative survival in rhabdomyosarcoma compared with EPO906 alone.. EPO906 shows a strong antitumor effect in neuroblastoma and rhabdomyosarcoma, without triggering major side effects. Its liposomal encapsulation does not alter its activity, and enhances cumulative survival when EPO906-RGD-liposomes are used at low dose in rhabdomyosarcoma.

Topics: Animals; Antineoplastic Agents; Body Weight; Cell Line, Tumor; Cell Survival; Drug Carriers; Epothilones; Female; Human Umbilical Vein Endothelial Cells; Humans; Integrin alphaVbeta3; Kaplan-Meier Estimate; Liposomes; Mice; Mice, SCID; Neuroblastoma; Oligopeptides; Rhabdomyosarcoma; Xenograft Model Antitumor Assays