Design, Synthesis and Development of Novel Polymeric Prodrugs

Ganivada, Mutyalanaidu (2016) Design, Synthesis and Development of Novel Polymeric Prodrugs. PhD thesis, Indian Institute of Science Education and Research Kolkata.

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Abstract

The aim of my work is to develop novel polymeric prodrugs for cancer therapy. Targeted drug delivery is a vehicle that will carry the drug to the targeted site in the body. It reduces the amount of drug in the rest of the body which can cause undesired side effects. The efficacy of drugs can be increased through targeted, stimuli responsive delivery which increases the drug concentration at the diseased site. In chapter 2, we have developed a novel tumour targeted polymeric nanocarrier using polylactide and polycarbonate as polymeric backbone. Biotin and doxorubicin are attached covalently to the poylmeric backbone. Doxorubicin release from the copolymer backbone is pH dependent owing to the unique oxime linker. Cell culture studies of biotin and doxorubicin conjugated nanocarrier [Bt-(PEPA- PC)-DRoxm] shows higher intracellular doxorubicin accumulation at cancer cell. In chapter 3, we have conjugated the doxorubicin (DOXI) to PEG-polycarbonate copolymer backbone through different pH sensitive linkers (oxime, hydrozone, ester and amide) to understand the stimuli responsiveness of different linkers in same backbone. The final molecular weights of the copolymers are almost same. The in vitro drug release profile shows the importance of having the hydrazone linker which demonstrates a maximum release of the (DOXI) at the mild acidic conditions. In chapter 4, biocompatible nanocarriers conjugated with magnetic nanoparticle, doxorubicin and polyethylene oxide (PEG) motif have been designed (PVLPEG-PVLDOXI-PCLPHOS) to create a magnetic vector under magnetic field. Acylhydrazine linker is used to release the drug exactly at the mild acidic conditions resembling the pH of the cancerous cells. All the monomers and polymers are characterized carefully by the routine analytical techniques. Thermo gravimetric analysis (TGA), FT-IR spectroscopy and scanning electron microscope (SEM) techniques are employed to confirm the anchoring of iron particle (Fe3O4) to the PVLPEG-PVLDOXI-PCL-PHOS. Reservoir capabilities of the newly designed biodegradable nanocarrier are tested by both dynamic light scattering (DLS) and transmission electron microscopy (TEM). Drug release profile from nanocarrier is monitored by fluorimeter. The release profile shows the importance of having the acylhydrazine linker. Confocal laser scanning microscopy (CLSM) measurements on 4T cells indicate the internalization efficacy of nanocarrier from PVLPEG-PVLDOXI-PCL-PHOS polymer. It is very interesting to note that the nanocarrier have exhibited both biological and magnetical targeting abilities towards 4T cells in vitro. In chapter 5, the first example of nanocarrier, self-assembled from new class of copolymer, heve been explored. The synthesis and characterisation of polyethylene glycol and doxorubicin attachement to 1,6-heptadiyne derivative (Macromonomer) are clearly described. The Macromonomer is polymerised via olefin metathesis living cyclopolymerisation method using Hoveyda-Grubbs catalyst to produce water soluble copolymer (Dox-Peg-Rcp-Fmoc) for cancer therapy. The drug release profile shows the importance of having the ester linker. Confocal laser scanning microscopy (CLSM) images of Dox-Peg-Rcp copoymer shows the internalization of nanocarrier by living cell. MTT assays of Dox-Peg-Rcp copolymer micelles shows that these micelles have a high anticancer efficacy.

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