Peptide and monoclonal antibody mediated targeting of nanoconjugates in cancer chemotherapy

摘要

Cancer is one of the most common causes of the death. Currently used anticancer drugs have shown to be effective against various cancers. However, these anticancer drugs can not differentiate between tumor cells and normal cells. These agents kill both types of cells resulting in severe side effects. Poor physico-chemical properties of anticancer drugs and development of chemo-resistance in cancer cells aggravate the problems. Over the past decade, nanotechnology-based formulations have been explored to overcome the limitations of anticancer drugs. These nanomedicines have shown promises to deliver drugs effectively to the cancer cells. In this research work, efforts have been made to improve the specificity of the drug loaded nanocarriers towards tumor cells. Cancer cells over express some receptors than normal cells. Therefore, nanocarriers attached with a ligand, having high affinity to particular receptor, could be targeted to cancer cells. In this context, two peptides (bombesin and cyclic RGDfK) and a monoclonal antibody, trastuzumab, were used as targeting ligand. Polymeric nanoparticles were used as drug carriers. Polymers such as poly(lactic-co-glycolic acid) (PLGA), D-α-tocopheryl polyethylene glycol succinate (TPGS), dendrimers and poly(glutamic acid) (PGA) were used for the preparation of nanoparticles. The selection of the polymers depended on the physicochemical properties of drug, desired particle size range, target tissue and the functional group available on the surface for conjugation with targeting ligand. Bombesin conjugated PLGA nanoparticles showed the potential to improve the delivery of a hydrophobic anticancer drug, docetaxel, in gastrin releasing peptide receptors over expressing breast and prostate cancer cells. Trastuzumab conjugated dendrimers demonstrated high specificity towards human epidermal growth factor 2 receptors over expressing breast cancer cells. cRGDfK conjugated TPGS nanomicelles showed significant cytotoxicity and anti-angiogenic activity of encapsulated docetaxel to integrin receptors over expressing prostate cancer cells. As integrin receptors have also been over expressed in other cancers such as ovarian, brain, lung and breast cancers, cRGDfK conjugated nanoparticles were investigated for the targeting of drugs to ovarian and brain cancers. cRGDfK conjugated PLGA nanoparticles were investigated for the delivery of hydrophilic gemcitabine hydrochloride to ovarian cancer. In a separate study, cRGDfK was conjugated to PGA nanoparticles for selective targeting of hydrophobic camptothecin to integrin over expressing brain tumor cells. In summary, this thesis presents a research done with regards to preparation of anticancer drugs loaded different nanoparticles, bioconjugation of targeting ligand on the surface of nanoparticles and evaluation of anticancer activities of these ligand mediated targeted drug delivery systems in cancer cells. The study revealed that the nanoparticle-based targeted formulations better control over the growth of cancer than plain drugs.