Application of Mesoporous Silica nanoparticles as a nano-carrier for the treatment of HCV and HIV infections

Abstract

Carrier-mediated drug delivery systems have emerged as a powerful tool for the treatment of various diseases, especially, in the field of viral infection. The therapeutic index of traditional and novel anti-virals are heightened through the enhancement in their target specificity. Anti-virals can be delivered at the targeted site without any degradation with the support of a nano-carrier. Viral disease treatment needs an upgraded drug delivery system to reduce the dosage and systemic toxic effects along with improved pharmacokinetic properties of anti-viral therapeutics. In this thesis, mesoporous silica nanoparticle (MSN) based delivery system was synthesized to deliver therapeutic agents to increase their efficiency and bioavailability. Functionalization was carried as per the requirement. The synthesized delivery vector was characterized using different techniques. The ability of MSN to interact with therapeutic agents was also evaluated. Toxicity studies using cell cultures and animal models assured the non-toxic properties of this delivery vector. The as prepared nanocarrier was able to mediate efficient transfection in mammalian cells. Preferential delivery of drugs was proven using both in vitro as well as in vivo models confirming the target-specific nature of this MSN based delivery system. Targeted delivery of small hairpin DNA (shDNA) to liver using MSN based nano-carrier to combat hepatitis C virus (HCV) infection was investigated. MSN was amine functionalized to achieve electrostatic interaction between the nanoparticle and DNA. Galactose functionalization ensured the preferential delivery to the liver through the ligand asialoglycoprotein receptor interaction abundantly present on liver cell surface which was visualized in the in vivo model. Significant reduction (about 94 %) of viral RNA level was achieved which confirmed the successful delivery and action of the shDNA. Target specific property of as-synthesized nanoparticle was further expanded in delivering the two herbal compounds Phyllanthin and Corilagin in HCV infection. These herbal compounds were derived from natural source Phyllanthus amarus and shown to have hepatoprotective property. The delivery of herbal compound-nanoparticle complex to the HCV JFH-1 infectious virus systems resulted in ~93% decrease in viral RNA level which was 3-fold higher than free Phyllanthin or Corilagin. Further this MSN based nano-carrier was used to enhance the bioavailability of retro-viral drugs. Here in this work MSN was coated with chitosan to inhibit the premature release of drugs and increase the cellular uptake. The amount of drug loaded in MSN was found to be 76.91 %. On applying the drug loaded nanocarrier in Balb/c mice model a 2.4-fold increase in bioavailability was noted. The work described in the present thesis presents a new MSN based delivery system which can act as an efficient nano-carrier both in gene delivery and drug delivery for virus infected diseases.