Norbornene Based Copolymer for Theranostic Application in Cancer Therapy

Mukherjee, Saikat (2018) Norbornene Based Copolymer for Theranostic Application in Cancer Therapy. PhD thesis, Indian Institute of Science Education and Research Kolkata.

PDF (PhD thesis of Saikat Mukherjee (11RS026)) 11RS026.pdf - Submitted Version Restricted to Repository staff only Download (13MB)

Abstract

Towards the goal of site-specific cancer therapy to reduce the side-effects, my thesis work is mainly focused to synthesize the different amphiphilic polymeric architecture for the purpose of theranostics, a combined system which carries both imaging modalities and chemotherapeutic agent into a single molecule. For that first I have developed two different imaging agents (contrast and optical) and then both of these were utilised to develop different theranostic molecules for efficient cancer therapy. So, towards that aim, my chapter 2 has described the synthesis of a site-specific dual imaging agent. Magnetic metal cobalt carbonyl has been attached to the terminal alkyne of norbornene monomer covalently by Nicholas reaction for the purpose of contrast imaging. Next, in my chapter 3, I have focused to develop different theranostic agents for site-specific cancer therapy. The small molecule chemotherapeutic agent doxorubicin and camptothecin suffers from non-specific reaching to the tumour site, and also camptothecin suffers from the poor aqueous solubility. A new class of norbornene based copolymer, Nor-Dox-Cob-Btn is proposed as potential theranostics agent for tumour diagnosis. Three different monomers nor-cobalt (contrast agent for MRI imaging), nor-doxorubicin (hydrazone linked for therapeutic purpose) and nor-peg-biotin (for aqueous solubility and site-specific therapy) has been synthesized and copolymerized (Nor-Dox-Cob-Btn) which further form capsule like nano-aggregate in aqueous solution by stabilizing hydrophobic units into its core. In an anther work, a new class of nano-theranostic agent, Pnr-Cbt-Cpt-Pg-Bn, is proposed for the effective delivery of camptothecin. In my chapter 4, I have focused to design and synthesize a nano-carrier, functionalized with chemotherapeutic agent (chlorambucil) and emissive agent pyrene with same pH responsive ester linker to the norbornene backbone. This particular design will help to solve the issues faced by chlorambucil as it suffers from aqueous solubility and as well as the non-emissive nature make it difficult to track, thus become difficult to monitor the therapeutic pathway. In my chapter 5, I have focused on the development of a dual imageable theranostic system for the site-specific delivery of platinum (Pt) analogue such as different analogues (e.g. cis-platin, carboplatin etc.) shows anti-cancer activity towards variety of cancers, suffers from site-specificity and also non-emissive nature of it make difficult to track the therapeutic pathway. To synthesize different pro-drug for theranostic application, so far I have used different pH responsive linkers which get cleave in acidic stimuli generally present in cancerous environment. But in physiological condition there is always pH variation in different cellular compartment (e.g. early endosomal pH 6.3 and late endosomal pH 5.5, whereas lysosomal pH is 4.7). Theses pH gradient actually destabilize the nano-carrier bearing different pH responsive linker, causing for drug leakage. Which further causes for poor therapeutic efficacy with unwanted side-effects. To deal with that, in my chapter 6 I have focused on to develop a specific peptide linked drug which will be cleaved only in presence of lysosomal protease Cathepsin B, overexpressed only in cancer cells. A specific cathepsin B cleavable norbornene based valine-citrulline linker was developed, which was further linked with a spacer containing doxorubicin. The drug release study showed quick release of doxorubicin in presence of Cathepsin B. The in vitro studies confirm the efficient uptake of nano-carrier at the cellular level and showed pronounced cytotoxicity.

Actions (login required)

View Item