Advanced micro/nano-encapsulation: Controlled release of therapeutic agents and cell-based therapy

Lew, Benjamin

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https://hdl.handle.net/2142/115660 Copy

Description

Title

Advanced micro/nano-encapsulation: Controlled release of therapeutic agents and cell-based therapy

Author(s)

Lew, Benjamin

Issue Date

2022-03-09

Director of Research (if dissertation) or Advisor (if thesis)

Kim, Kyekyoon

Doctoral Committee Chair(s)

Kim, Kyekyoon

Committee Member(s)

• Choi, Hyungsoo
• Gruev, Viktor
• Popescu, Gabriel

Department of Study

Electrical & Computer Eng

Discipline

Electrical & Computer Engr

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• microencapsulation
• nanomedicine
• targeted delivery
• biomaterials

Abstract

A controlled drug delivery system is designed to release the encapsulated drug in a pre-determined period in vivo by using specific biodegradable polymers having unique physicochemical properties and appropriate size. This dissertation study demonstrated the development of advanced micro/nano-carriers using various FDA-approved polymers to facilitate controlled drug release and cell-based therapy suitable for various biomedical applications. Monodisperse microspheres, core/sell microcapsules, and nanoparticles with carefully tailored size, surface integrity, and pharmacokinetics were fabricated to enable zero-order release, long-term stability, and site-specific delivery of therapeutic agents aimed for sustained hormonal therapy, cell-based type-1 diabetes treatment, and intraoperative tumor imaging, respectively. A frequent administration of oral or injectable formulations of progesterone (P4) is the common contraception methodology for dogs and cats. It is recently discovered that exposing newborn pups to the therapeutic level of P4 induces permanent sterilization without the need for invasive surgery. However, the intake of a high dose of steroid hormone could be lethal to newborn pups lacking an immune system, especially on a daily basis. In this study, the precision particle fabrication (PPF) method was employed to produce monodisperse poly (caprolactone) microspheres (PCL MSs) as sustained-release vehicles of P4. By ensuring uniform size distribution and encapsulation of P4 without surface protrusion, PCL MSs enabled near first-order release kinetics over a given amount of period without the initial burst release phase. The subsequent preliminary in vivo study using newborn mouse pups reported encouraging results demonstrating the efficiency of a single dose of sustained-release microspheres to maintain a therapeutic amount of P4 over time without any signs of adverse effect. Alginate microcapsules (AL MCs) of size 500-800 μm have been extensively investigated as encapsulation vehicle of insulin-producing islets for the treatment of type-1 diabetes. Regardless of promising outcomes, however, many clinical studies have addressed the instability of alginate-based microcapsules compromising the islet graft survival and function in long-term therapy. Additionally, the large size and poor encapsulation efficiency of AL MCs has limited the route of administration and number of islets transplanted. This study involves procurement and encapsulation of healthy porcine islets within the core/shell microcapsules composed of alginate and PCL as core and shell material, respectively. The PCL shell has excellent stability to resist degradation for a prolonged period, whereas the alginate core provides a hospitable microenvironment for encapsulated islets to survive and function accordingly to the given glycemic conditions. The mean diameter of monodisperse alginate-core PCL shell microcapsules (AL-PCL MSs) was 200 μm which was expanded up to 300 μm depending on the size and number of encapsulated islets. The smaller capsule diameter of AL-PCL MSs allows reduced islet mass and flexible injection sites to improve the islet graft survival and function. The shell thickness was set to 5 μm to minimize the distance between the capsule core and the external environment. The in vitro study revealed comparable levels of viability and insulin-producing function between islets encapsulated in AL-PCL MSs and naked islets. These findings demonstrated the feasibility of employing islet-AL-PCL MSs as a clinically translational methodology for improved islet transplantation. Indocyanine green (ICG) is an FDA-approved near-infrared (NIR) fluorescence dye that has proven to be effective in highlighting primary tumors to improve the clinical outcome of cancer surgery. Gelatin nanoparticles (GNPs) were fabricated as delivery vehicles further exploiting the potential of ICG-mediated imaging by resolving its innate limitations including short half-life and non-specificity. GNPs were capable of selectively delivering ICG to primary tumors in response to protease-triggered degradation. As a result, ICG-loaded GNPs (ICG-GNPs) exhibited significantly higher fluorescence intensity than free ICG at the same dose when administered to primary breast tumor-bearing mice. In particular, the fluorescence intensity was more enhanced by the ICG-GNPs of a size of 80 nm in diameter (ICG-GNP-80) than that of 160 nm (ICG-GNP-160), manifesting its dependency on the particle size. Furthermore, ICG-GNP-80 equivalent to 1.0 mg/kg of ICG achieved the highest tumor-to-background ratio (TBR) at 24 hours post-administration. A novel bio-inspired image sensor capable of projecting both color and NIR images simultaneously was employed to fluorescently highlight the tumor with negligible background fluorescence applicable for image-guided surgery. The ex vivo imaging of resected tumors displayed a strong contrast between the tumor and adjacent healthy tissue to further demonstrate the efficient intratumoral ICG delivery via GNPs. All these results suggest that the application of ICG-GNPs in intraoperative imaging of cancer can be clinically viable.

Graduation Semester

2022-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2022 Benjamin Lew

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