Synthesis and Characterization of Norbornene Derived Functional Materials for Drug Delivery

Mane, Shivshankar Raosaheb (2014) Synthesis and Characterization of Norbornene Derived Functional Materials for Drug Delivery. PhD thesis, Indian Institute of Science Education and Research Kolkata.

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Abstract

The aim of my thesis work is to develop potential polymeric drug delivery vehicles for the treatment of cancer and tuberculosis diseases. Both the diseases are the most common diseases which causes death. Although polymeric nano-assemblies are attractive vehicles for the delivery of anticancer as well as anti-tuberculosis drugs. Recently, many nanoparticle formulations exhibit low drug loading and encapsulation efficiency and undesirable drug “burst” release kinetics. To overcome this problem, our design is described, in Part A- Chapter 2 to 4, which is expected to overcome the above limitations and permit the clinical translation of nanoparticles for polymeric targeted cancer therapy. We have synthesized norbornene derived thiobarbiturate homopolymer, NDTH. The molecular orientation of NDTH is systematically modified based on the hydrophobicity and hydrophilicity of the solvent. The thiobarbiturate functionality of each monomer unit in NDTH can act as a hydrophilic headgroup, whereas the norbornene backbone can behave as a hydrophobic moiety. Encapsulation studies of hydrophilic doxorubicin and hydrophobic Nile red suggest the reversible nature of the NDTH vesicles. Next, the most commonly used nano-carriers for the TB therapy are made of PLG polymers due to their biodegradable and biocompatible nature. Polymers such as poly(lactic acid) (PLA), and poly(glycolic acid) have been currently used for the delivery vehicle. However, due to their long biological half-life, they may not be suited for pulmonary delivery with dosing occurring very frequently. Also, the existing polymeric carriers are unable to take full advantage of potential benefits such as long blood circulation times. In most of the case the drug loading is less than 10%, high quantities of polymeric nanocarrier needs to be administrated which leads to unwanted side effects. Moreover, an ideal system should preserve the efficacy of the drugs with the physicochemical properties of water solubility, pH range, biocompatibility and bioavailability. So the need for finding new polymeric delivery system is mandatory. In Part B- Chapter 5 to 6, we have discussed the process of creating a norbornene based nanocarrier that abides by those properties besides taking on the aspect of patient non-compliance. This work is very specific about the drugs especially isoniazid (INH) and rifampicin (RIF) that are mostly prescribed for the treatment of tuberculosis. In this section we have demonstrate a useful method to conjugate the most important frontline TB drugs (RIF and INZ) who are very well known for decomposition when they have been taken together in a non-covalent approach. The main speciality here is that our norborene based nanocarrier has a multi-drug compartment consisting of isoniazid (INH) and rifampicin (RIF) along with a strong hydrophobic core. In order to achieve the controlled as well as sustained drug release, the drugs are linked to polymer backbone through hydrazone linker.

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