Graduation Date

Spring 5-7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Ram I. Mahato

Second Advisor

Amar B. Singh

Third Advisor

Geoffrey M Thiele

Fourth Advisor

Tatiana K. Bronich

Abstract

The aim of this thesis is to develop delivery systems for the novel small molecules which inhibit tubulin polymerization. One of the small molecules was modified to lipid conjugate to increase the lipophilicity of the molecules which in turn drastically improved the drug loading in amphiphilic polymeric system. The second molecule was conjugated to the amphiphilic polymeric backbone with pH sensitive Schiff’s linker for the tumor site specific delivery in lung metastatic melanoma model.

Chapter 1 discusses the tumor microenvironment for the solid tumor especially focusing on Pancreatic Ductal Adenocarcinoma (PDAC). Further the drug delivery system currently researched for addressing desmoplasia, hypoxia and cancer stem cells in PDAC is discussed. In Chapter 2,CH-3-8, a novel microtubule polymerization inhibitor with little susceptibility to transporter-mediated chemoresistance and its binding ability to the colchicine-binding site in tubulin protein explored. CH-3-8 disrupted microtubule dynamics, inhibited the proliferation of these cells, induced G2/M cell cycle arrest, and led to apoptosis at the nanomolar concentration in pancreatic cancer cell lines. The compound is hydrophobic and had very little loading so, we conjugated it with dodecanol through diglycolate linker to increase hydrophobicity and thus loading in lipid-based delivery systems. The conjugate (LDC) was loaded 10 ± 1.0% (w/w) in mPEG-b-PCC-g-DC

polymer. In vivo study using the nanoparticles at the dose of 20 mg/kg in orthotopic pancreatic tumor-bearing NSG mice resulted in significant tumor regression.

In Chapter 3, another new compound, CH-2-102 and its pH sensitive delivery system is discussed. We confirmed that CH-2-102 bound to the colchicine binding site of the tubulin and strongly inhibits microtubule polymerization. CH-2-102 suppressed microtubule polymerization and subsequently induced G2 phase cell arrest as one of the possible mechanisms. Notably, CH-2-102 maintained its efficacy even in the paclitaxel resistance melanoma cells due to different binding sites and a non Pgp substrate. We showed that the metabolic activity of the cells is reduced using this small molecule. We developed a pH-responsive drug-polymer Schiff bases linker for high drug loading into nanoparticles. Our CH-2-102 conjugated nanoparticles induced tumor regression more effectively than Abraxane, free drug, and non-sensitive nanoparticles in the B16-F10 cell-derived lung metastasis murine model. Further, our results suggest that the formulation has a high impact on in vivo efficacy of the drug and warrants further investigation in other cancers, particularly taxane resistant.

Finally, Chapter 4 summarizes the results of this thesis and gives suggestions for future research.

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