Reversion of multidrug resistance by tumor targeted delivery of antisense oligodeoxynucleotides in hydroxypropyl-chitosan nanoparticles
Chitosan and its derivatives have shown great potential as non-viral vectors for gene delivery therapy. Folic acid receptor (FR) is an important anti-cancer therapy target that is applicable to many cancer types. In this study, we developed an efficient and targeted delivery of antisense oligodeoxynucleotides asODNs, using folic acid (FA) conjugated hydroxypropyl-chitosan (HPCS). These nanoparticles were designed to reduce production of P-gp, in order to overcome tumor drug resistance. Nanoparticles prepared were found to be 181 nm in diameter. Spectrofluorimetry was utilized to evaluate the effect of charge ratio of the nanoparticles on loading efficiency. In PBS buffer, 40% of asODNs were released from the nanoparticles at first 24 h. However, just another 15% was released between 24 and 48 h. The antitumor effect of the nanoparticles was evaluated in KB-A-1 cells implanted in Balb/c-nu/nu mice. They inhibited the growth of tumor by 35% compared to the bare asODNs. The FA–HPCS–asODNs nanoparticles demonstrated significantly inhibition of the multi drug resistance (MDR) 1 gene levels and P-gp levels in vitro and in vivo, respectively, related with bare asODNs and HPCS–asODNs ones. During in vivo studies, FA–HPCS–asODNs nanoparticles were also found to bind specifically and efficiently to FR high-expressing cancer cells. These results suggested that the use of targeted, antisense agent nanoparticles would be potential approach to overcome tumor drug resistance.
Journal: Biomaterials - Volume 31, Issue 15, May 2010, Pages 4426–4433