Author ORCID Identifier

https://orcid.org/0000-0001-8793-3708

Date Available

8-5-2027

Year of Publication

2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Arts and Sciences

Department/School/Program

Chemistry

Faculty

Dr. Christopher I. Richards

Faculty

Dr. Kenneth R. Graham

Abstract

Cerebrovasculature refers to the network of blood vessels in the brain, and its coupling with neurons plays a critical role in regulating ion exchange, molecule transport, nutrient and oxygen delivery, and waste removal in the brain. Abnormalities in cerebrovasculature and disruptions of the blood supply are associated with a variety of cerebrovascular and neurodegenerative disorders. Nanocarriers, a nano-sized drug delivery system synthesized from various materials, have been designed to encapsulate therapeutic agents and overcome delivery challenges in crossing the blood-brain barrier (BBB) to achieve targeted and enhanced therapy for these diseases. Unraveling the transport of drugs and nanocarriers in the cerebrovasculature is important for pharmacokinetic and hemodynamic studies but is challenging due to difficulties in detecting these particles within the circulatory system of a live animal. In this dissertation, we developed a technique to achieve real-time in vivo tracking of nanocarriers in the cerebrovasculature using fluorescence correlation spectroscopy (FCS), which has great potential for determining the pharmacokinetics of drugs and nanocarriers, as well as for studying disease-related connections between the cerebrovascular and neurodegenerative diseases.

We utilized novel fluorescent probes composed of DNA-stabilized silver nanocluster (DNA-Ag16NC), that emit in the first near-infrared window (NIR-I) upon two-photon excitation in the second NIR window (NIR-II), encapsulated in liposomes, which were then used to measure cerebral blood flow rates in live mice with high spatiotemporal resolution by two-photon in vivo FCS. Liposome encapsulation concentrated and protected DNA-Ag16NCs from in vivo degradation, enabling the quantification of cerebral blood flow velocity within individual capillaries of a living mouse. We also loaded another DNA-stabilized silver nanocluster, which exhibited higher quantum yield and anti-Stokes fluorescence upon upconversion absorption, into cationic mesoporous silica nanoparticles (CMSNs) and successfully coated them with liposomes. The cerebrovasculature was chronically labeled using an adeno-associated viral (AAV) vector and analyzed with FCS under upconversion excitation, enabling real-time in vivo tracking of the flow velocity and particle number of these nanocarriers in the cerebrovasculature.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2025.344

Funding Information

This study was supported by:

  1. Novo Nordisk Foundation (NNF20OC0064207) in 2020.
  2. Novo Nordisk Foundation (NNF22OC0073734) in 2022.
  3. National Institute of General Medical Sciences (GM138882) in 2022.
  4. National Institute of General Medical Sciences (GM138837) in 2023.

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Available for download on Thursday, August 05, 2027

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