Date of Award

2020

Document Type

Thesis

Degree Name

Master of Science (M.S.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Xin Guo

First Committee Member

Miki Susanto Park

Second Committee Member

Myo Kyoung Kim

Abstract

Lung cancer is the second most common cancer in both men and women around the world, and 85% of it is non-small cell lung cancer (NSCLC). It is estimated that in 2020, there will be 228,820 cases of lung cancer and 135,720 deaths from lung (American Cancer Society, 2020). The prognosis of lung cancer is poor (

Traditionally, the most commonly used in vitro method for screening therapeutic drugs is monolayer cell cultures, which are reproducible, convenient and of low cost. However, monolayer cell culture models are unable to reproduce many properties of in vivo solid tumors such as the morphological features and the microenvironment including cellular heterogeneity, cell-cell interactions, and gradients of oxygen, pH, and nutrients. Consequently, excessive ineffective drug candidates would proceed to animal studies, which would prolong the time for drug development and increase the overall cost of drug discovery.

In consideration of the foregoing, in vitro models of cancer based on three-dimensional multicellular spheroids (MCS) have been developed in our group to characterize drug candidates and drug delivery systems. Compared to monolayer cells, the multicellular spheroids can better simulate drug penetration and drug resistance in solid tumors. Therefore, the multicellular spheroids represent a more clinically relevant in vitro model to evaluate the efficacy of anticancer drugs.

This project aims to characterize MCS of lung cancer cells as an improved platform to evaluate drug candidates against lung cancer. Cell viability assays on cisplatin, carboplatin, gemcitabine, and doxorubicin have been conducted to compare the anticancer activities between conventional monolayer cells and the corresponding MCS of human lung cancer cell lines, A549 and A549-iRFP (fluorescently labeled A549 cells). Higher concentrations of the tested anticancer drugs is consistently needed to inhibit 50% the cell viability in MCS than the corresponding monolayer cells of A549 and A549-iRFP.

Cycled dosing schedules based on guidelines for NSCLC from National Comprehensive Cancer Network have been designed and used to treat A549-iRFP MCS. The A549-iRFP MCS have been exposed to anticancer drugs either continuously, or in pulsed concentrations according to the drugs’ pharmacokinetics (PK). The continuous drug exposure has been found to inhibit more cell growth in MCS than the corresponding PK-mimetic drug exposure. Such phenomenon would bring significant positive bias to the activity of many anticancer drug candidates during their early discovery and development.

Taken together, MCS of A549 and A549 iRFP cells better represent the efficacy of anticancer drugs in clinic than the monolayer. MCS can also be used to evaluate anticancer drug candidates by pulsed drug exposure based on their pharmacokinetics, and by commonly used cycled dosing regiments to better predict their efficacy in clinical settings.

Pages

69

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