Targeted micelles with chemotherapeutics and gene drugs to inhibit the G1/S and G2/M mitotic cycle of prostate cancer

Abstract

Background Chemotherapy and gene therapy are used in clinical practice for the treatment of castration-resistant prostate cancer. However, the poor efficiency of drug delivery and serious systemic side effects remain an obstacle to wider application of these drugs. Herein, we report newly designed PEO-PCL micelles that were self-assembled and modified by spermine ligand, DCL ligand and TAT peptide to carry docetaxel and anti-nucleostemin siRNA. Results The particle size of the micelles was 42 nm, the zeta potential increased from − 12.8 to 15 mV after grafting with spermine, and the optimal N/P ratio was 25:1. Cellular MTT experiments suggested that introduction of the DCL ligand resulted in high toxicity toward PSMA-positive cells and that the TAT peptide enhanced the effect. The expression of nucleostemin was significantly suppressed in vitro and in vivo, and the tumour-inhibition experiment showed that the dual-drug delivery system suppressed CRPC tumour proliferation. Conclusions This targeted drug delivery system inhibited the G1/S and G2/M mitotic cycle via synergistic interaction of chemotherapeutics and gene drugs.

GNL3 is an evolutionarily conserved stem cell gene influencing cell proliferation, animal growth and regeneration in the hydrozoan Hydractinia

“…Thus, further experimentation would be needed to specify the reason(s) for the slow growth phenotype observed in Hydractinia GNL3 knockout colonies. A link could be made between GNL3 / NS involvement in organismal growth ([33,36,37]; this study) and tumour growth [46,47], highlighting the potential that GNL3 / NS downregulation could have in developing cancer therapies to reduce tumour growth. Nanoparticle drug delivery systems targeting NS have already been tested with successful results, obtaining smaller-sized prostate cancer tumours [47].…”

Forward Precision Medicine: Micelles for Active Targeting Driven by Peptides

“…In vivo cRGD20/TAT10 CMs, probably via receptor-mediated endocytosis and deep tumor penetration, induced the highest tumor DTX level (8.6% ID/g) and minor side effects and inhibited tumor growth. Very recently, Zhang et al described a self-assembled PEO-b-P(CL-g-SP) ligand, decorated with a dual bioactive sequence to deliver SiRNA and DTX to prostate cancer (PCa) cells [ 108 ]. Particles were grafted with N -[ N -[( S )-1,3-dicarboxypropyl] carbamoyl]-( S )-lysine (DCL) in order to bind, via strong hydrogen bonds, prostate-specific membrane antigen (PSMA), which is a trans membrane glycoprotein that is overexpressed by 100–1000 times in PCa cells by means of a further increased expression in metastatic and castration-resistant carcinomas [ 109 ].…”

Progress in gene therapy treatments for prostate cancer

“…Tumor‐suppressor gene therapy in prostate cancer is achieved when a wild‐type gene is introduced into prostate cancer cells to suppress the tumor phenotype and proliferation 29 . The genes commonly studied for tumor‐suppressor gene therapy include p21, p53, and retinoblastoma (RB) 30,31 .…”

“…Tumor-suppressor gene therapy in prostate cancer is achieved when a wild-type gene is introduced into prostate cancer cells to suppress the tumor phenotype and proliferation. 29 The genes commonly studied for tumorsuppressor gene therapy include p21, p53, and retinoblastoma (RB). 30,31 The most common type of limitation encountered in this gene therapy is when prostate cancer cells are unable to express p53, p21, and RB genes.…”