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Lipid Nanoparticles Based Nanomedicine and Liquid Biopsy in Lung Cancer Therapy and Diagnosis.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Lipid Nanoparticles Based Nanomedicine and Liquid Biopsy in Lung Cancer Therapy and Diagnosis./
Author:	Liu, Chang.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	168 p.
Notes:	Source: Dissertations Abstracts International, Volume: 79-10, Section: B.
Contained By:	Dissertations Abstracts International79-10B.
Subject:	Biomedical engineering. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10744242
ISBN:	9780355679663

Lipid Nanoparticles Based Nanomedicine and Liquid Biopsy in Lung Cancer Therapy and Diagnosis.
Liu, Chang.

Lipid Nanoparticles Based Nanomedicine and Liquid Biopsy in Lung Cancer Therapy and Diagnosis. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 168 p.

Source: Dissertations Abstracts International, Volume: 79-10, Section: B.

Thesis (Ph.D.)--State University of New York at Buffalo, 2018.

This item must not be added to any third party search indexes.

Lung cancer is one of the most lethal diseases worldwide with a disappointing survival rate. Current clinical treatments of lung cancer, including surgeries, chemotherapies and radiotherapies are still facing the obstacles of low therapeutic efficacy and serious side effects. Due to low sensitivity or invasive process, conventional detection methods such as imaging and tissue biopsies may not be able to diagnose lung cancer at the early stage, which is a critical time for successful treatment. In this thesis, we aim to develop lipid nanoparticles based nanomedicine and liquid biopsy technologies to overcome these challenges and provide effective therapies and sensitive diagnostic tests for lung cancer. Lipid nanoparticles, such as liposomes, have shown excellent properties as drug delivery systems for cancer treatment. The controllable physiochemical properties and simple manufacturing process make liposomes attractive nanocarriers for tumor-targeted drug delivery. We have developed an EGFR-targeted, liposome based drug co-delivery system loading 1,25-dihydroxyvitamin D3 (1,25D3) and its catabolizing enzyme inhibitor CTA091 (EGFR-LP-CTA091-VD) as a novel therapeutic reagent for the treatment of lung cancer patients who build resistance to EGFR tyrosine kinase inhibitors (TKI). We have shown that such nanoparticles improve cellular uptake of 1,25D3 and CTA091, drive the pro-epithelial signaling by upregulating CYP24A1 and CDH1, resensitize lung cancer cells to erlotinib, and inhibit lung cancer cell growth. Our results demonstrate that the delivery of vitamin D based drug payloads via tumor-targeted liposomes may be an effective therapy for EFGR TKI resistant lung cancer. We have also developed a lipid nanoparticle based liquid biopsy test to detect exosomal RNAs as a highly sensitive, non-invasive and cost-effective diagnostic assay for lung cancer. Exosomes are nanoparticles secreted by cells and stably present in almost all body fluids. Exosomes are actively involved in cancer development, metastasis and drug resistance, therefore, they are fine biomarkers for cancer screening, early detection and surveillance. We have developed a tethered cationic lipoplex nanoparticle (tCLN) biochip to first capture exosomes via electrostatic interactions between tCLN and exosomes, and then characterize exosomal RNAs via molecular beacons without additional sample processing. We have measured the expression of exosomal miR-21, miR-25, miR-155, miR-210, miR-486 and TTF-1 mRNA in serum samples from lung cancer patients and healthy controls. With tCLN biochip, exosomal miR-21 and miR-25 showed AUC of 1.000 in distinguishing no cancer controls from stage I/II patients, miR-21 and TTF-1 showed AUC of 0.972 in distinguishing no cancer controls from stage III/IV patients, and miR-21, miR-25 and miR-486 showed AUC of 0.944 in distinguishing stage I/II patients from stage III/IV patients. The tCLN biochip showed much higher detection sensitivity and specificity than qRT-PCR assay (AUCs were 0.710, 0.861 and 0.642 respectively), demonstrating its great potential in lung cancer diagnosis. In addition to exosomal RNAs, we have also developed a compact surface plasmon resonance (SPR) biosensor to detect exosomal proteins. The capture of exosomes by antibodies bound on the biochip surface changes local refractive index, affects the optical properties of the SP modes, and thus allows optical detection of exosomal proteins. The compact SPR biosensor successfully detected exosomal EGFR and PD-L1 from cell culture medium and lung cancer patient serum samples. Compared with ELISA, the compact SPR biosensor showed higher detection sensitivity and comparable sensing accuracy. In the future, we will continue the development and validation of lipid nanoparticles based nanomedicine and liquid biopsy tests. For lung cancer therapy, we will evaluate the therapeutic efficacy, biodistribution, and potential toxicity of EGFR-LP-CTA091-VD in vivo. For lung cancer diagnosis, we will advance the design of liquid biopsy assay by integrating the tCLN biochip with compact SPR biosensor to achieve simultaneous sensing of exosomal proteins and RNAs on a single platform. We will optimize the integrated assay to achieve highly sensitive, multiplexed, fast and cost-effective detection of exosomal biomarkers. We will validate the assay with large cohort of lung cancer patients to demonstrate its clinical utility. We hope our contributions may provide lung cancer with more effective therapies and better diagnosis to help reduce the mortality of this serious disease.

ISBN: 9780355679663Subjects--Topical Terms:

535387
Biomedical engineering.

Lipid Nanoparticles Based Nanomedicine and Liquid Biopsy in Lung Cancer Therapy and Diagnosis.
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520 $a Lung cancer is one of the most lethal diseases worldwide with a disappointing survival rate. Current clinical treatments of lung cancer, including surgeries, chemotherapies and radiotherapies are still facing the obstacles of low therapeutic efficacy and serious side effects. Due to low sensitivity or invasive process, conventional detection methods such as imaging and tissue biopsies may not be able to diagnose lung cancer at the early stage, which is a critical time for successful treatment. In this thesis, we aim to develop lipid nanoparticles based nanomedicine and liquid biopsy technologies to overcome these challenges and provide effective therapies and sensitive diagnostic tests for lung cancer. Lipid nanoparticles, such as liposomes, have shown excellent properties as drug delivery systems for cancer treatment. The controllable physiochemical properties and simple manufacturing process make liposomes attractive nanocarriers for tumor-targeted drug delivery. We have developed an EGFR-targeted, liposome based drug co-delivery system loading 1,25-dihydroxyvitamin D3 (1,25D3) and its catabolizing enzyme inhibitor CTA091 (EGFR-LP-CTA091-VD) as a novel therapeutic reagent for the treatment of lung cancer patients who build resistance to EGFR tyrosine kinase inhibitors (TKI). We have shown that such nanoparticles improve cellular uptake of 1,25D3 and CTA091, drive the pro-epithelial signaling by upregulating CYP24A1 and CDH1, resensitize lung cancer cells to erlotinib, and inhibit lung cancer cell growth. Our results demonstrate that the delivery of vitamin D based drug payloads via tumor-targeted liposomes may be an effective therapy for EFGR TKI resistant lung cancer. We have also developed a lipid nanoparticle based liquid biopsy test to detect exosomal RNAs as a highly sensitive, non-invasive and cost-effective diagnostic assay for lung cancer. Exosomes are nanoparticles secreted by cells and stably present in almost all body fluids. Exosomes are actively involved in cancer development, metastasis and drug resistance, therefore, they are fine biomarkers for cancer screening, early detection and surveillance. We have developed a tethered cationic lipoplex nanoparticle (tCLN) biochip to first capture exosomes via electrostatic interactions between tCLN and exosomes, and then characterize exosomal RNAs via molecular beacons without additional sample processing. We have measured the expression of exosomal miR-21, miR-25, miR-155, miR-210, miR-486 and TTF-1 mRNA in serum samples from lung cancer patients and healthy controls. With tCLN biochip, exosomal miR-21 and miR-25 showed AUC of 1.000 in distinguishing no cancer controls from stage I/II patients, miR-21 and TTF-1 showed AUC of 0.972 in distinguishing no cancer controls from stage III/IV patients, and miR-21, miR-25 and miR-486 showed AUC of 0.944 in distinguishing stage I/II patients from stage III/IV patients. The tCLN biochip showed much higher detection sensitivity and specificity than qRT-PCR assay (AUCs were 0.710, 0.861 and 0.642 respectively), demonstrating its great potential in lung cancer diagnosis. In addition to exosomal RNAs, we have also developed a compact surface plasmon resonance (SPR) biosensor to detect exosomal proteins. The capture of exosomes by antibodies bound on the biochip surface changes local refractive index, affects the optical properties of the SP modes, and thus allows optical detection of exosomal proteins. The compact SPR biosensor successfully detected exosomal EGFR and PD-L1 from cell culture medium and lung cancer patient serum samples. Compared with ELISA, the compact SPR biosensor showed higher detection sensitivity and comparable sensing accuracy. In the future, we will continue the development and validation of lipid nanoparticles based nanomedicine and liquid biopsy tests. For lung cancer therapy, we will evaluate the therapeutic efficacy, biodistribution, and potential toxicity of EGFR-LP-CTA091-VD in vivo. For lung cancer diagnosis, we will advance the design of liquid biopsy assay by integrating the tCLN biochip with compact SPR biosensor to achieve simultaneous sensing of exosomal proteins and RNAs on a single platform. We will optimize the integrated assay to achieve highly sensitive, multiplexed, fast and cost-effective detection of exosomal biomarkers. We will validate the assay with large cohort of lung cancer patients to demonstrate its clinical utility. We hope our contributions may provide lung cancer with more effective therapies and better diagnosis to help reduce the mortality of this serious disease.
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