자료유형  

 학위논문

Control Number  

0016935760

International Standard Book Number  

9798380595254

Dewey Decimal Classification Number  

616.99

Main Entry-Personal Name  

Du, Shi.

Publication, Distribution, etc. (Imprint  

[S.l.] : The Ohio State University., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(123 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 85-04, Section: B.

General Note  

Advisor: Dong, Yizhou.

Dissertation Note  

Thesis (Ph.D.)--The Ohio State University, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Restrictions on Access Note  

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

Summary, Etc.  

요약Messenger RNA (mRNA) has gradually become an important class of therapeutic agents in recent years. mRNA therapy involves the use of synthetic mRNA molecules to instruct cells to produce therapeutic proteins, which can then be used to treat a variety of diseases. However, delivery of mRNA to desired tissues and cell populations remains a challenge for clinical translation. To address the delivery issues, researchers have investigated many types of nanomaterials such as lipid nanoparticles (LNPs) to encapsulate mRNA and overcome physiological barriers. Currently, LNP-mRNA has shown promise in treating a range of diseases, including cancer, genetic diseases, and infectious diseases. The objective of this dissertation is to develop novel LNP-mRNA formulations for cancer immunotherapy and genetic disease treatment.Chapter 1 briefly reviews the structure of in vitro transcription (IVT) mRNA, the representative lipids for mRNA delivery, and the therapeutic applications of LNP-mRNA. Chapter 2 describes an immunotherapy regimen that enables co-stimulation of TLR7/8- and CD40-mediated pathways. TLR7/8 agonist resiquimod (R848) derived amino lipids, RAL1 and RAL2, were synthesized and formulated into RAL-derived lipid nanoparticles (RAL-LNPs). The RAL2-LNPs showed efficient CD40 mRNA delivery to dendritic cells (DCs) both in vitro and in vivo. When combined with agonistic anti-CD40 antibody, this approach can produce effective antitumor activities in mouse melanoma tumor models, thereby suppressing tumor growth, prolonging mouse survival, and establishing antitumor memory immunity. Chapter 3 demonstrates the concept of LNPs for the delivery of mRNA to spermatocytes, which provides a unique method to probe male infertility caused by the genetic mutation. A series of cholesterol-amino-phosphate (CAP) lipids was developed by integrating three bioactive moieties into a geometric structure, which is favorable for mRNA delivery. The results showed that CAP LNPs can deliver RNA including traditional mRNA and self-amplifying RNA (saRNA) encoding DNA Meiotic Recombinase 1 (Dmc1) protein in spermatocytes and produce Dmc1 protein for an extended period, which restores the spermatogenesis in the Dmc1 gene knockout mouse model. Chapter 4 provides the conclusions and future perspectives of LNP-mRNA based treatment.

Subject Added Entry-Topical Term  

Pharmaceutical sciences.

Subject Added Entry-Topical Term  

Oncology.

Subject Added Entry-Topical Term  

Nanotechnology.

Subject Added Entry-Topical Term  

Immunology.

Index Term-Uncontrolled  

Lipid nanoparticles

Index Term-Uncontrolled  

RNA

Index Term-Uncontrolled  

Cancer

Index Term-Uncontrolled  

Immunotherapy

Index Term-Uncontrolled  

Genetic diseases

Added Entry-Corporate Name  

The Ohio State University Pharmaceutical Sciences

Host Item Entry  

Dissertations Abstracts International. 85-04B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:643741