Synthesis and In vitro/In vivo Characterization of Raloxifene Grafted Poly(Styrene Maleic Acid)-Poly(Amide-Ether-Ester-Imide) Micelles for Targeted Delivery of Docetaxel in G Protein-Coupled Estrogen Receptor Breast Cancer

摘要

Background: To reduce the nonspecifically distribution of chemotherapeutic agents throughout the wholebody, which causes severe toxicity in normal tissues, targeting them towards a receptor overexpressed on tumortissue, is a promising method for cancer therapy.Objective: The aim of the present study was development of novel copolymeric micelles of raloxifene targetedStyrene Maleic Acid-Poly Amide Ether Ester Imide-Poly Ethylene Glycol (SMA-PAEEI-PEG-RA) and loading themwith Docetaxel (DTX).Methods: Successful synthesis of the targeted copolymer was confirmed by FTIR and C-NMR spectroscopy. Themicelles physicochemical properties like morphology, particle size, poly dispersity index, zeta potential, drugloading, release, stability, in vitro cytotoxicity and cellular uptake were analyzed. The in vivo antitumor activity ofDTX-loaded micelles were assessed and compared with free DTX and non-targeted micelles in breast cancer bearingBalb-c mice.Results: Particle sizes, zeta potentials and the encapsulation efficiency of the drug in targeted micelles were 115.9-142.8 nm, -4.9 to -12.9 mV, and 54.1-67.8%, respectively. Cell toxicity tests showed that IC50 of DTX-loaded SMAPAEEI-PEG-RA micelles increased five-fold as compared with free DTX. Survival rate of the mice improved moreeffectively than free DTX so that, the percentage of increase in lifespan (ILS%) and the tumor inhibition ratio (TIR)changed from 41.66% and 51.19% in free drug to 83.33% and 78.57% in the targeted micelles, respectively.Conclusion: Therefore, the raloxifene conjugated PEG-derived micelles may provide a novel and effective deliverysystem for DTX in breast cancer.